Breast tumors from CHEK2 1100delC-mutation carriers: genomic landscape and clinical implications.

PubMed

Muranen, Taru A; Greco, Dario; Fagerholm, Rainer; Kilpivaara, Outi; Kämpjärvi, Kati; Aittomäki, Kristiina; Blomqvist, Carl; Heikkilä, Päivi; Borg, Ake; Nevanlinna, Heli

2011-09-20

Checkpoint kinase 2 (CHEK2) is a moderate penetrance breast cancer risk gene, whose truncating mutation 1100delC increases the risk about twofold. We investigated gene copy-number aberrations and gene-expression profiles that are typical for breast tumors of CHEK2 1100delC-mutation carriers. In total, 126 breast tumor tissue specimens including 32 samples from patients carrying CHEK2 1100delC were studied in array-comparative genomic hybridization (aCGH) and gene-expression (GEX) experiments. After dimensionality reduction with CGHregions R package, CHEK2 1100delC-associated regions in the aCGH data were detected by the Wilcoxon rank-sum test. The linear model was fitted to GEX data with R package limma. Genes whose expression levels were associated with CHEK2 1100delC mutation were detected by the bayesian method. We discovered four lost and three gained CHEK2 1100delC-related loci. These include losses of 1p13.3-31.3, 8p21.1-2, 8p23.1-2, and 17p12-13.1 as well as gains of 12q13.11-3, 16p13.3, and 19p13.3. Twenty-eight genes located on these regions showed differential expression between CHEK2 1100delC and other tumors, nominating them as candidates for CHEK2 1100delC-associated tumor-progression drivers. These included CLCA1 on 1p22 as well as CALCOCO1, SBEM, and LRP1 on 12q13. Altogether, 188 genes were differentially expressed between CHEK2 1100delC and other tumors. Of these, 144 had elevated and 44, reduced expression levels.Our results suggest the WNT pathway as a driver of tumorigenesis in breast tumors of CHEK2 1100delC-mutation carriers and a role for the olfactory receptor protein family in cancer progression. Differences in the expression of the 188 CHEK2 1100delC-associated genes divided breast tumor samples from three independent datasets into two groups that differed in their relapse-free survival time. We have shown that copy-number aberrations of certain genomic regions are associated with CHEK2 mutation 1100delC. On these regions, we identified potential drivers of CHEK2 1100delC-associated tumorigenesis, whose role in cancer progression is worth investigating. Furthermore, poorer survival related to the CHEK2 1100delC gene-expression signature highlights pathways that are likely to have a role in the development of metastatic disease in carriers of the CHEK2 1100delC mutation.

Breast tumors from CHEK2 1100delC-mutation carriers: genomic landscape and clinical implications

PubMed Central

2011-01-01

Introduction Checkpoint kinase 2 (CHEK2) is a moderate penetrance breast cancer risk gene, whose truncating mutation 1100delC increases the risk about twofold. We investigated gene copy-number aberrations and gene-expression profiles that are typical for breast tumors of CHEK2 1100delC-mutation carriers. Methods In total, 126 breast tumor tissue specimens including 32 samples from patients carrying CHEK2 1100delC were studied in array-comparative genomic hybridization (aCGH) and gene-expression (GEX) experiments. After dimensionality reduction with CGHregions R package, CHEK2 1100delC-associated regions in the aCGH data were detected by the Wilcoxon rank-sum test. The linear model was fitted to GEX data with R package limma. Genes whose expression levels were associated with CHEK2 1100delC mutation were detected by the bayesian method. Results We discovered four lost and three gained CHEK2 1100delC-related loci. These include losses of 1p13.3-31.3, 8p21.1-2, 8p23.1-2, and 17p12-13.1 as well as gains of 12q13.11-3, 16p13.3, and 19p13.3. Twenty-eight genes located on these regions showed differential expression between CHEK2 1100delC and other tumors, nominating them as candidates for CHEK2 1100delC-associated tumor-progression drivers. These included CLCA1 on 1p22 as well as CALCOCO1, SBEM, and LRP1 on 12q13. Altogether, 188 genes were differentially expressed between CHEK2 1100delC and other tumors. Of these, 144 had elevated and 44, reduced expression levels. Our results suggest the WNT pathway as a driver of tumorigenesis in breast tumors of CHEK2 1100delC-mutation carriers and a role for the olfactory receptor protein family in cancer progression. Differences in the expression of the 188 CHEK2 1100delC-associated genes divided breast tumor samples from three independent datasets into two groups that differed in their relapse-free survival time. Conclusions We have shown that copy-number aberrations of certain genomic regions are associated with CHEK2 mutation 1100delC. On these regions, we identified potential drivers of CHEK2 1100delC-associated tumorigenesis, whose role in cancer progression is worth investigating. Furthermore, poorer survival related to the CHEK2 1100delC gene-expression signature highlights pathways that are likely to have a role in the development of metastatic disease in carriers of the CHEK2 1100delC mutation. PMID:21542898

Expression of exon-8-skipped kindlin-1 does not compensate for defects of Kindler syndrome.

PubMed

Natsuga, Ken; Nishie, Wataru; Shinkuma, Satoru; Nakamura, Hideki; Matsushima, Yoichiro; Tatsuta, Aya; Komine, Mayumi; Shimizu, Hiroshi

2011-01-01

Kindler syndrome (KS) is a rare, inherited skin disease characterized by blister formation and generalized poikiloderma. Mutations in KIND1, which encodes kindlin-1, are responsible for KS. c.1089del/1089+1del is a recurrent splice-site deletion mutation in KS patients. To elucidate the effects of c.1089del/1089+1del at the mRNA and protein level. Two KS patients with c.1089del/1089+1del were included in this study. Immunofluorescence analysis of KS skin samples using antibodies against the dermo-epidermal junction proteins was performed. Exon-trapping experiments were performed to isolate the mRNA sequences transcribed from genomic DNA harbouring c.1089del/1089+1del. β1 integrin activation in HeLa cells transfected with truncated KIND1 cDNA was analyzed. Immunofluorescence study showed positive expression of kindlin-1 in KS skin with c.1089del/1089+1del mutation. We identified the exon-8-skipped in-frame transcript as the main product among multiple splicing variants derived from that mutation. HeLa cells transfected with KIND1 cDNA without exon 8 showed impaired β1 integrin activation. Exon-8-coding amino acids are located in the FERM F2 domain, which is conserved among species, and the unstructured region between F2 and the pleckstrin homology domain. This study suggests that exon-8-skipped truncated kindlin-1 is functionally defective and does not compensate for the defects of KS, even though kindlin-1 expression in skin is positive. Copyright © 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

CHEK2*1100delC Variant and BRCA1/2-Negative Familial Breast Cancer - A Family-Based Genetic Association Study

DTIC Science & Technology

2007-10-01

AD_________________ Award Number: DAMD17-03-1-0774 TITLE: CHEK2 *1100delC Variant and BRCA1/2...NUMBER CHEK2 *1100delC Variant and BRCA1/2-Negative Familial Breast Cancer - A Family- Based Genetic Association Study 5b. GRANT NUMBER DAMD17...association between the CHEK2 *1100delC gene variant and breast cancer among BRCA1/2-negative families. Vital to DNA replication and normal growth of breast

Dinámica global en galaxias elípticas

NASA Astrophysics Data System (ADS)

Pérez, M. J.; Cincotta, P. M.; Giordano, C. M.

Con el propósito de determinar propiedades dinámicas globales en sistemas triaxiales no integrables, utilizamos una nueva herramienta conocida como ``Mean Exponential Growth factor of Nearby Orbits'' (MEGNO), introducida por Cincotta y Simó (2000). Esta técnica no sólo resulta eficiente para investigar ambas componentes del espacio fase, regular y caótica, sino que también, provee una medida de la hiperbolicidad en el dominio caótico que coincide con la dada por el Lyapunov Characteristic Number (LCN). Previamente este método ha sido aplicado al estudio de modelos simples, y últimamente en el campo de la Mecánica Celeste, al estudio de sistemas planetarios extrasolares. En esta presentación, ilustraremos algunas de las propiedades más importantes del MEGNO, aplic& acute;andolo al potencial tridimensional de Stäckel perturbado.

Genesis of two most prevalent PROP1 gene variants causing combined pituitary hormone deficiency in 21 populations.

PubMed

Dusatkova, Petra; Pfäffle, Roland; Brown, Milton R; Akulevich, Natallia; Arnhold, Ivo J P; Kalina, Maria A; Kot, Karolina; Krzisnik, Ciril; Lemos, Manuel C; Malikova, Jana; Navardauskaite, Ruta; Obermannova, Barbora; Pribilincova, Zuzana; Sallai, Agnes; Stipancic, Gordana; Verkauskiene, Rasa; Cinek, Ondrej; Blum, Werner F; Parks, John S; Austerlitz, Frederic; Lebl, Jan

2016-03-01

Two variants (c.[301_302delAG];[301_302delAG] and c.[150delA];[150delA]) in the PROP1 gene are the most common genetic causes of recessively inherited combined pituitary hormones deficiency (CPHD). Our objective was to analyze in detail the origin of the two most prevalent variants. In the multicentric study were included 237 patients with CPHD and their 15 relatives carrying c.[301_302delAG];[301_302delAG] or c.[150delA];[150delA] or c.[301_302delAG];[ 150delA]. They originated from 21 different countries worldwide. We genotyped 21 single-nucleotide variant markers flanking the 9.6-Mb region around the PROP1 gene that are not in mutual linkage disequilibrium in the general populations--a finding of a common haplotype would be indicative of ancestral origin of the variant. Haplotypes were reconstructed by Phase and Haploview software, and the variant age was estimated using an allelic association method. We demonstrated the ancestral origin of both variants--c.[301_302delAG] was carried on 0.2 Mb-long haplotype in a majority of European patients arising ~101 generations ago (confidence interval 90.1-116.4). Patients from the Iberian Peninsula displayed a different haplotype, which was estimated to have emerged 23.3 (20.1-29.1) generations ago. Subsequently, the data indicated that both the haplotypes were transmitted to Latin American patients ~13.8 (12.2-17.0) and 16.4 (14.4-20.1) generations ago, respectively. The c.[150delA] variant that was carried on a haplotype spanning about 0.3 Mb was estimated to appear 43.7 (38.4-52.7) generations ago. We present strong evidence that the most frequent variants in the PROP1 gene are not a consequence of variant hot spots as previously assumed, but are founder variants.

Genesis of two most prevalent PROP1 gene variants causing combined pituitary hormone deficiency in 21 populations

PubMed Central

Dusatkova, Petra; Pfäffle, Roland; Brown, Milton R; Akulevich, Natallia; Arnhold, Ivo JP; Kalina, Maria A; Kot, Karolina; Krzisnik, Ciril; Lemos, Manuel C; Malikova, Jana; Navardauskaite, Ruta; Obermannova, Barbora; Pribilincova, Zuzana; Sallai, Agnes; Stipancic, Gordana; Verkauskiene, Rasa; Cinek, Ondrej; Blum, Werner F; Parks, John S; Austerlitz, Frederic; Lebl, Jan

2016-01-01

Two variants (c.[301_302delAG][301_302delAG] and c.[150delA][150delA]) in the PROP1 gene are the most common genetic causes of recessively inherited combined pituitary hormones deficiency (CPHD). Our objective was to analyze in detail the origin of the two most prevalent variants. In the multicentric study were included 237 patients with CPHD and their 15 relatives carrying c.[301_302delAG][301_302delAG] or c.[150delA][150delA] or c.[301_302delAG][ 150delA]. They originated from 21 different countries worldwide. We genotyped 21 single-nucleotide variant markers flanking the 9.6-Mb region around the PROP1 gene that are not in mutual linkage disequilibrium in the general populations – a finding of a common haplotype would be indicative of ancestral origin of the variant. Haplotypes were reconstructed by Phase and Haploview software, and the variant age was estimated using an allelic association method. We demonstrated the ancestral origin of both variants – c.[301_302delAG] was carried on 0.2 Mb-long haplotype in a majority of European patients arising ~101 generations ago (confidence interval 90.1–116.4). Patients from the Iberian Peninsula displayed a different haplotype, which was estimated to have emerged 23.3 (20.1–29.1) generations ago. Subsequently, the data indicated that both the haplotypes were transmitted to Latin American patients ~13.8 (12.2–17.0) and 16.4 (14.4–20.1) generations ago, respectively. The c.[150delA] variant that was carried on a haplotype spanning about 0.3 Mb was estimated to appear 43.7 (38.4–52.7) generations ago. We present strong evidence that the most frequent variants in the PROP1 gene are not a consequence of variant hot spots as previously assumed, but are founder variants. PMID:26059845

Changes in frailty conditions and phenotype components in elderly after hospitalization.

PubMed

Marchiori, Gianna Fiori; Tavares, Darlene Mara Dos Santos

2017-07-10

describing the changes in frailty conditions over the period of a year after hospital discharge, verifying predictive variables for changes in frailty conditions and frailty phenotype components according to worsening, improving and stable groups. a longitudinal survey carried out with 129 elderly. A structured form for socioeconomic and health data, scales (Geriatric Depression Scale - short form, Katz scale, Lawton and Brody scale) and frailty phenotype according to Fried were used. Descriptive analysis and multinomial logistic regression model (p<0.05) were performed. we found that 56.7% of older adults changed their condition from non-frail to pre-frail, with no changes from non-frail to frail. Deaths were found between frail and pre-frail elderly. In the worsening group, the increase in the number of morbidities was a predictor for exhaustion and/or fatigue, while in the improving group, increased dependence on instrumental activities of daily living was a predictor for weight loss, and reduced scores indicative of depression due to low level of physical activity. a greater percentage of changes from non-frail condition to pre-frail older adults were observed, and health variables were only predictive for frailty phenotype components. descrever as mudanças nas condições de fragilidade ao longo de um ano após a alta hospitalar, e verificar as variáveis preditoras da mudança das condições de fragilidade e dos componentes do fenótipo de fragilidade, segundo grupos de piora, melhora e estabilidade. inquérito longitudinal, realizado com 129 idosos. Utilizou-se formulário estruturado para dados socioeconômicos e saúde, escalas (Depressão Geriátrica Abreviada, Katz, Lawton e Brody) e fenótipo de fragilidade, segundo Fried. Procederam-se às análises descritiva e modelo de regressão logística multinomial (p<0,05). constatou-se que 56,7% dos idosos mudaram sua condição de não frágeis para pré-frágeis, não ocorrendo mudança dos não frágeis para frágeis. Observou-se o óbito entre idosos frágeis e pré-frágeis. No grupo de piora, o aumento do número de morbidades foi preditor para exaustão e/ou fadiga, enquanto que, no grupo de melhora, o aumento na dependência das atividades instrumentais de vida diária foi preditor para a perda de peso, e a diminuição dos escores do indicativo de depressão para o baixo nível de atividade física. houve maior percentual de mudança na condição de idosos não frágeis para pré-frágeis e as variáveis de saúde foram preditoras apenas para os componentes do fenótipo de fragilidade. describir los cambios en las condiciones de fragilidad a lo largo de un año después del alta hospitalaria, y verificar las variables predictoras del cambio de las condiciones de fragilidad y de los componentes del fenotipo de fragilidad, según grupos de empeoramiento, mejoría y estabilidad. encuesta longitudinal, realizada con 129 ancianos. Se utilizó formulario estructurado para recoger datos socioeconómicos y salud; se utilizaron las escalas Depresión Geriátrica Abreviada (GDS-15), Actividades Básicas de Vida Diaria de Katz, Actividades Instrumentales de Vida Diaria de Lawton y Brody, y Fenotipo de Fragilidad, según Fried. Se procedió al análisis descriptivo y modelo de regresión logística multinomial (p<0,05). se constató que 56,7% de los ancianos cambiaron su condición de no-frágiles para prefrágiles, no habiendo ocurriendo cambio de los no-frágiles para frágiles. Se observó muerte entre ancianos frágiles y prefrágiles. En el grupo de empeoramiento, el aumento del número de morbilidades fue predictor para agotamiento y/o fatiga, en cuanto en el grupo de mejoría, el aumento en la dependencia de las actividades instrumentales de vida diaria fue predictor para la pérdida de peso y la disminución de los puntajes del indicativo de depresión para el bajo nivel de actividad física. hubo mayor porcentaje de cambio en la condición de ancianos no-frágiles para prefrágiles y las variables de salud fueron predictoras apenas para los componentes del fenotipo de fragilidad.

Spatial characteristics of groundwater temperature in the Ishikari Lowland, Hokkaido, northern Japan: analytical and numerical applications

NASA Astrophysics Data System (ADS)

Dim, J. R.; Sakura, Y.; Fukami, H.; Miyakoshi, A.

2002-03-01

In porous sediments of the Ishikari Lowland, there is a gradual increase in the background geothermal gradient from the Ishikari River (3-4 °C 100 m-1) to the southwest highland area (10 °C 100 m-1). However, the geothermal gradient at shallow depths differs in detail from the background distribution. In spite of convective heat-flow loss generally associated with groundwater flow, heat flow remains high (100 mW m-2) in the recharge area in the southwestern part of the Ishikari basin, which is part of an active geothermal field. In the northeastern part of the lowland, heat flow locally reaches 140 mW m-2, probably due to upward water flow from the deep geothermal field. Between the two areas the heat flow is much lower. To examine the role of hydraulic flow in the distortion of the isotherms in this area, thermal gradient vs. temperature analyses were made, and they helped to define the major components of the groundwater-flow system of the region. Two-dimensional simulation modeling aided in understanding not only the cause of horizontal heat-flow variations in this field but also the contrast between thermal properties of shallow and deep groundwater reservoirs. Résumé. Dans les sédiments poreux des basses terres d'Ishikari, on observe une augmentation graduelle du gradient géothermal général depuis la rivière Ishikari (3-4 °C 100 m-1) vers la zone élevée située au sud-ouest (10 °C 100 m-1). Toutefois, le gradient géothermal aux faibles profondeurs diffère dans le détail de la distribution générale. Malgré la perte de flux de chaleur par convection, généralement associée aux écoulements souterrains, le flux de chaleur reste élevé (100 mW m-2) dans la zone de recharge de la partie sud-ouest du bassin de l'Ishikari, qui appartient à un champ géothermal actif. Dans la partie nord-est des basses terres, le flux de chaleur atteint localement 140 mW m-2, probablement à cause d'un écoulement souterrain ascendant depuis le champ géothermal profond. Entre les deux zones, le flux de chaleur est beaucoup plus faible. Afin de déterminer le rôle du flux d'eau souterraine dans la distorsion des isothermes dans cette zone, des analyses du gradient thermal en fonction de la température ont été réalisées elles ont permis de définir les composantes majeures du système aquifère régional. Une modélisation deux-dimensionnelle pour la simulation a ensuite contribué à la compréhension non seulement de la cause des variations horizontales du flux de chaleur dans cette région, mais également du contraste entre les propriétés des réservoirs superficiel et profond. Resumen. En los sedimentos porosos de las tierras bajas de Ishikari, hay un incremento gradual en el gradiente geotérmico desde el río Ishikari (3-4 °C 100 m-1) hacia la zona elevada del sudoeste (10 °C 100 m-1). Sin embargo, el gradiente geotérmico a profundidades someras difiere de la distribución de fondo. A pesar de las pérdidas por el flujo convectivo de calor asociadas generalmente al flujo de aguas subterráneas, el flujo de calor permanece elevado (100 mW m-2) en el área de recarga, hacia el sudoeste de la cuenca del Ishikari, la cual pertenece a un campo geotérmico activo. Al nordeste de las tierras bajas, el flujo de calor alcanza 140 mW m-2, probablemente por el flujo ascendente de agua procedente del campo geotérmico profundo. Entre ambas áreas, el flujo de calor es mucho menor. Para examinar el papel del flujo hidráulico en la distorsión de las isotermas de esta región, se ha comparado el gradiente térmico con la temperatura, con lo cual se ha podido definir los componentes mayoritarios del sistema de flujo de las aguas subterráneas. El uso de modelos bidimensionales ha servido para comprender no sólo del origen de las variaciones horizontales del flujo de calor en este campo, sino también el contraste entre las propiedades térmicas de los reservorios someros y profundos de aguas subterráneas.

CHEK2*1100delC homozygosity in the Netherlands—prevalence and risk of breast and lung cancer

PubMed Central

Huijts, Petra EA; Hollestelle, Antoinette; Balliu, Brunilda; Houwing-Duistermaat, Jeanine J; Meijers, Caro M; Blom, Jannet C; Ozturk, Bahar; Krol-Warmerdam, Elly MM; Wijnen, Juul; Berns, Els MJJ; Martens, John WM; Seynaeve, Caroline; Kiemeney, Lambertus A; van der Heijden, Henricus F; Tollenaar, Rob AEM; Devilee, Peter; van Asperen, Christi J

2014-01-01

The 1100delC mutation in the CHEK2 gene has a carrier frequency of up to 1.5% in individuals from North-West Europe. Women heterozygous for 1100delC have an increased breast cancer risk (odds ratio 2.7). To explore the prevalence and clinical consequences of 1100delC homozygosity in the Netherlands, we genotyped a sporadic breast cancer hospital-based cohort, a group of non-BRCA1/2 breast cancer families, and breast tumors from a tumor tissue bank. Three 1100delC homozygous patients were found in the cohort of 1434 sporadic breast cancer patients, suggesting an increased breast cancer risk for 1100delC homozygotes (odds ratio 3.4, 95% confidence interval 0.4–32.6, P=0.3). Another 1100delC homozygote was found in 592 individuals from 108 non-BRCA1/2 breast cancer families, and two more were found after testing 1706 breast tumors and confirming homozygosity on their wild-type DNA. Follow-up data was available for five homozygous patients, and remarkably, three of them had developed contralateral breast cancer. A possible relationship between 1100delC and lung cancer risk was investigated in 457 unrelated lung cancer patients but could not be confirmed. Due to the small number of 1100delC homozygotes identified, the breast cancer risk estimate associated with this genotype had limited accuracy but is probably higher than the risk in heterozygous females. Screening for CHEK2 1100delC could be beneficial in countries with a relatively high allele frequency. PMID:23652375

Genetic modifiers of CHEK2*1100delC associated breast cancer risk

PubMed Central

Muranen, Taru A.; Greco, Dario; Blomqvist, Carl; Aittomäki, Kristiina; Khan, Sofia; Hogervorst, Frans; Verhoef, Senno; Pharoah, Paul D.P.; Dunning, Alison M.; Shah, Mitul; Luben, Robert; Bojesen, Stig E.; Nordestgaard, Børge G.; Schoemaker, Minouk; Swerdlow, Anthony; García-Closas, Montserrat; Figueroa, Jonine; Dörk, Thilo; Bogdanova, Natalia V.; Hall, Per; Li, Jingmei; Khusnutdinova, Elza; Bermisheva, Marina; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Peto, Julian; dos Santos Silva, Isabel; Couch, Fergus J.; Olson, Janet E.; Hillemans, Peter; Park-Simon, Tjoung-Won; Brauch, Hiltrud; Hamann, Ute; Burwinkel, Barbara; Marme, Frederik; Meindl, Alfons; Schmutzler, Rita K.; Cox, Angela; Cross, Simon S.; Sawyer, Elinor J.; Tomlinson, Ian; Lambrechts, Diether; Moisse, Matthieu; Lindblom, Annika; Margolin, Sara; Hollestelle, Antoinette; Martens, John W.M.; Fasching, Peter A.; Beckmann, Matthias W.; Andrulis, Irene L.; Knight, Julia A.; Anton-Culver, Hoda; Ziogas, Argyrios; Giles, Graham G.; Milne, Roger L.; Brenner, Hermann; Arndt, Volker; Mannermaa, Arto; Kosma, Veli-Matti; Chang-Claude, Jenny; Rudolph, Anja; Devilee, Peter; Seynaeve, Caroline; Hopper, John L.; Southey, Melissa C.; John, Esther M.; Whittemore, Alice S.; Bolla, Manjeet K.; Wang, Qin; Michailidou, Kyriaki; Dennis, Joe; Easton, Douglas F.; Schmidt, Marjanka K.; Nevanlinna, Heli

2016-01-01

Purpose CHEK2*1100delC is a founder variant in European populations conferring a 2–3 fold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC). Methods With genotype data of 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction. Results The PRS conferred an odds ratio (OR) of 1.59 [95% CI 1.21–2.09] per standard deviation for BC for CHEK2*1100delC carriers and 1.58 [1.55–1.62] for non-carriers. No evidence for deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 [0.86–4.78] for CHEK2*1100delC carriers placing them to the high risk category according to UK NICE guidelines. OR for the lowest quintile was 0.52 [0.16–1.74], indicating life-time risk close to population average. Conclusion Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify the carriers at a high life-time risk for clinical actions. PMID:27711073

Genetic modifiers of CHEK2*1100delC-associated breast cancer risk.

PubMed

Muranen, Taru A; Greco, Dario; Blomqvist, Carl; Aittomäki, Kristiina; Khan, Sofia; Hogervorst, Frans; Verhoef, Senno; Pharoah, Paul D P; Dunning, Alison M; Shah, Mitul; Luben, Robert; Bojesen, Stig E; Nordestgaard, Børge G; Schoemaker, Minouk; Swerdlow, Anthony; García-Closas, Montserrat; Figueroa, Jonine; Dörk, Thilo; Bogdanova, Natalia V; Hall, Per; Li, Jingmei; Khusnutdinova, Elza; Bermisheva, Marina; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Investigators, Nbcs; Peto, Julian; Dos Santos Silva, Isabel; Couch, Fergus J; Olson, Janet E; Hillemans, Peter; Park-Simon, Tjoung-Won; Brauch, Hiltrud; Hamann, Ute; Burwinkel, Barbara; Marme, Frederik; Meindl, Alfons; Schmutzler, Rita K; Cox, Angela; Cross, Simon S; Sawyer, Elinor J; Tomlinson, Ian; Lambrechts, Diether; Moisse, Matthieu; Lindblom, Annika; Margolin, Sara; Hollestelle, Antoinette; Martens, John W M; Fasching, Peter A; Beckmann, Matthias W; Andrulis, Irene L; Knight, Julia A; Investigators, kConFab/Aocs; Anton-Culver, Hoda; Ziogas, Argyrios; Giles, Graham G; Milne, Roger L; Brenner, Hermann; Arndt, Volker; Mannermaa, Arto; Kosma, Veli-Matti; Chang-Claude, Jenny; Rudolph, Anja; Devilee, Peter; Seynaeve, Caroline; Hopper, John L; Southey, Melissa C; John, Esther M; Whittemore, Alice S; Bolla, Manjeet K; Wang, Qin; Michailidou, Kyriaki; Dennis, Joe; Easton, Douglas F; Schmidt, Marjanka K; Nevanlinna, Heli

2017-05-01

CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC). Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction. The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average. Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016.

Estudio del CH interestelar

NASA Astrophysics Data System (ADS)

Olano, C.; Lemarchand, G.; Sanz, A. J.; Bava, J. A.

El objetivo principal de este proyecto consiste en el estudio de la distribución y abundancia del CH en nubes interestelares a través de la observación de las líneas hiperfinas del CH en 3,3 GHz. El CH es una molécula de amplia distribución en el espacio interestelar y una de las pocas especies que han sido observadas tanto con técnicas de radio como ópticas. Desde el punto de vista tecnológico se ha desarrollado un cabezal de receptor que permitirá la realización de observaciones polarimétricas en la frecuencia de 3,3 GHz, con una temperatura del sistema de 60 K y un ancho de banda de 140 MHz, y que será instalado en el foco primario de la antena parabólica del IAR. El cabezal del receptor es capaz de detectar señales polarizadas, separando las componentes de polarización circular derecha e izquierda. Para tal fin el cabezal consta de dos ramas receptoras que amplificarán la señal y la trasladarán a una frecuencia más baja (frecuencia intermedia), permitiendo de esa forma un mejor transporte de la señal a la sala de control para su posterior procesamiento. El receptor además de tener características polarimétricas, podrá ser usado en el continuo y en la línea, utilizando las ventajas observacionales y de procesamiento de señal que actualmente posee el IAR.

Association of methylenetetrahydrofolate reductase (MTHFR 677C>T) and thymidylate synthase (TSER and TS 1494del6) polymorphisms with premature ovarian failure in Korean women.

PubMed

Rah, HyungChul; Jeon, Young Joo; Choi, Youngsok; Shim, Sung Han; Yoon, Tae Ki; Choi, Dong Hee; Cha, Sun Hee; Kim, Nam Keun

2012-11-01

The aim of our study was to investigate whether methylenetetrahydrofolate reductase (MTHFR) gene variant (MTHFR 677C>T) and thymidylate synthase (TS) gene variants (TS enhancer region [TSER] and TS 1494del6) confer a risk for premature ovarian failure (POF). We genotyped 136 POF patients and 236 controls among Korean women for the three single nucleotide polymorphism sites using polymerase chain reaction restriction fragment length polymorphism analysis. Differences in the MTHFR 677C>T, TSER, and TS 1494del6 genotype frequencies between POF patients and controls were compared, and odds ratios (ORs) and 95% CIs were determined as a measure of the strength of the association between genotypes and POF. The MTHFR 677CT and CT + TT variant genotypes were more frequent in POF patients than in controls (OR, 2.249; 95% CI, 1.317-3.843; and OR, 2.132; 95% CI, 1.268-3.585, respectively). The combined genotype frequencies of MTHFR 677CT + TT/TSER 3R3R and 677CT + TT/TS 1494del6 del6/del6 were higher in patients than in controls (OR, 2.300; 95% CI, 1.219-4.337; and OR, 3.314; 95% CI, 1.623-6.767, respectively). The T-3R-del6 and T-2R-del6 (MTHFR 677C>T/TSER/TS 1494del6) haplotypes were more frequent in patients (OR, 1.450; 95% CI, 1.050-2.002; and OR, 2.911; 95% CI, 1.191-7.117, respectively), whereas the C-2R-del6 haplotype was less frequent in patients (OR, 0.372; 95% CI, 0.152-0.912). The T-del6 (MTHFR 677/TS 1494del6) haplotype frequency was higher among patients (OR, 1.653; 95% CI, 1.206-2.266), whereas the C-del6 haplotype frequency was lower among patients (OR, 0.700; 95% CI, 0.516-0.950). We did not find an association between TSER or TS 1494del6 polymorphisms and POF. Our data suggest that the MTHFR 677T allele may increase the risk for POF, which could lead to the development of novel genetic markers for predicting the risk of POF in patients.

Tratamiento Quirúrgico de los Meningiomas del Foramen Óptico, Técnicay Resultados de una Serie de 18 Pacientes

PubMed Central

Goldschmidt, Ezequiel; Ajler, Pablo; Campero, Álvaro; Landriel, Federico; Sposito, Maximiliano; Carrizo, Antonio

2014-01-01

Introducción: los meningiomas del foramen óptico producen un rápido deterioro de la función visual aún cuando su tamaño es pequeño, por eso su diagnóstico y manejo difiere del resto de los meningiomas clinoideos. El propósito de este estudio es presentar la técnica y los resultados de nuestro manejo quirúrgico de meningiomas foraminales (MF). Pacientes y Métodos: se llevó a cabo una revisión de las historias clínicas de 47 pacientes con meningiomas primarios intraorbitarios. Se realizaron 52 cirugías en los pacientes con MF. Se empleó una craneotomía fronto-orbitaria, seguida de una descompresión extradural del canal óptico, resección del componente intraorbitario y exploración intradural del nervio óptico. Resultados: de los 12 pacientes con MF que presentaban la visión conservada, la agudeza visual fue preservada en 7 casos, mejoró en 2, y empeoró en 3. En 18 pacientes, el principal síntoma fue exoftalmos y en 35 pacientes ceguera unilateral. Ocurrieron 6 recurrencias, 2 a 10 años después de la resección quirúrgica. Cinco de ellos fueron reoperados. Se indicó radioterapia después de la recurrencia en 3 pacientes. Conclusión: el manejo de los MF continúa siendo controvertido y frecuentemente se propone un tratamiento conservador. Basados en nuestros hallazgos de frecuente extensión intracraneal, proponemos realizar una resección total o subtotal del tumor, preservando el nervio óptico en pacientes con visión prequirúrgica conservada. PMID:25165616

Teorí­as de primer y segundo orden sobre el potencial de ciertas figuras de equilibrio de cuerpos celestes

NASA Astrophysics Data System (ADS)

Gumbau, Manuel Forner

2010-11-01

Uno de los problemas que aborda la Mecánica Celeste es la determinación de las figuras de equilibrio de los cuerpos celestes. Para investigar su solución mediante métodos directos, se precisa evaluar el potencial generado por su autogravitación, el generado por su fuerza centrí­fuga y el generado por la fuerza de atracción entre los cuerpos. Los métodos clásicos de Finlay y Kopal que afrontan estos problemas, para determinar el potencial autogravitatorio en las configuraciones de equilibrio, emplean desarrollos en serie de los potenciales interior y exterior del potencial autogravitatorio. Estos métodos incurren en el error de suponer la convergencia en capas donde resulta cuestionable dicha convergencia para estos desarrollos en serie. En este trabajo se han elaborado unos algoritmos que contemplan toda la casuí&stica y que permiten una manipulación efic iente del producto de polinomios de Legendre, del producto de funciones asociada s de Legendre y del producto de armónicos esféricos como combinacióon lineal de ellos mismos, respectivamente. Se han obtenido, para primer y segundo orden en las amplitudes, los desarrollos correctos para los potencial es interior y exterior del potencial autogravitatorio para configuraciones de equilibrio aisladas, y , en primer orden de amplitudes, los mismos potenciales para los sistemas binarios próximos. Se ha elaborado un método analítico, en primer orden respecto de las amplitudes, para la determinación del potencial de marea en sistemas binarios próximos en el cual se manifiesta la forma de la componente secundaria del sistema

Análisis de los determinantes socioeconómicos del gasto de bolsillo en medicamentos en seis zonas geográficas de Panamá.

PubMed

Herrera-Ballesteros, Victor H; Castro, Franz; Gómez, Beatriz

2018-04-27

Caracterizar el gasto de bolsillo privado en medicamentos en función de los determinantes sociodemográficos y socioeconómicos. MATERIALES Y MéTODOS: La fuente de datos es la Encuesta de Gasto de Bolsillo en Medicamentos de 2014. Se caracterizó el gasto de bolsillo privado mediante variables explicativas sociodemográficas (SOD) y socioeconómicas (SES). Se hizo análisis factorial por componentes principales, regresión logística y lineal simple. Los Odds Ratio demuestran que la educación y la zona geográfica son determinantes fundamentales que inciden en el gasto de bolsillo. Los medicamentos son productos necesarios, en adición a que el gasto de bolsillo aumenta a un promedio del 2% por cada año de vida cronológica adicional. Existe mayor vulnerabilidad en las zonas más pauperizadas respecto del acceso a medicamentos, en especial en las indígenas e implica un mayor riesgo de gasto catastrófico a menor ingreso ante la mayor prevalencia de enfermedades crónicas. Copyright © 2018. Published by Elsevier Inc.

Control System of a Three DOF Spacecraft Simulator by Vectorable Thrusters and Control Moment Gyros

DTIC Science & Technology

2006-12-01

1 s 1 s -K- -K- -K- -K- -K- -K- -K- -K- -K- 2 STATE 1 REF Tc urel Fx Fy Figure 42. Controller SIMULINK Model As an initial step in the...f1c a1c a1True a2c a2True f1act Thruster 1 Firing Logic [DelTrue] [a1True] [a2True] [DelTrue] Fx Fy T theta del F1c a1c F2c a2c Tcmg fcn Tc deltrue...cmgdd command CMG Steering Logic 3 theta 2 act_fb 1 uCOMMANDED Fx Fy Tc 52 to slew and fire independently, MSGCMG position is used to generate a

60. C.J.T., photographer December 23, 1955 KLAMATH RIVER BRIDGE, DEL ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

60. C.J.T., photographer December 23, 1955 KLAMATH RIVER BRIDGE, DEL NORTE COUNTY, SECTION A, HIGHWAY 1. DN-1-A #538, KLAMATH RIVER BR. FROM SO. END, 12/23/55, C.J.T. - Redwood National & State Parks Roads, California coast from Crescent City to Trinidad, Crescent City, Del Norte County, CA

CHEK2*1100delC and risk of malignant melanoma: Danish and German studies and meta-analysis.

PubMed

Weischer, Maren; Heerfordt, Ida M; Bojesen, Stig E; Eigentler, Thomas; Garbe, Claus; Röcken, Martin; Hölmich, Lisbet Rosenkrantz; Schmidt, Henrik; Klyver, Helle; Bastholt, Lars; Nordestgaard, Børge G

2012-02-01

It is possible that reduced function of DNA repair and cell-cycle control genes increases the individual susceptibility to malignant melanoma. As CHEK2 is a cell-cycle master controller, we tested the hypothesis that heterozygosity for the frameshift alteration CHEK2*1100delC is associated with increased risk of malignant melanoma. First, we performed case-control studies of 1,152 Danish and 752 German individuals with malignant melanoma compared with 9,142 Danish and 3,718 German controls. Second, we performed a meta-analysis of CHEK2*1100delC and malignant melanoma, involving 2,619 cases and 17,481 controls. Third, we examined the risk of malignant melanoma associated with CHEK2*1100delC heterozygosity in an analysis stratified for sun exposure, as well as for subtype and location on the body. The odds ratios for malignant melanoma for CHEK2(*)1100del heterozygotes compared with those for noncarriers were 2.01 (95% confidence interval (CI), 1.03-3.91) in Danes, 1.42 (95% CI, 0.46-4.31) in Germans, and 1.79 (95% CI, 1.02-3.17) in Danes and Germans combined. In a meta-analysis, the odds ratio of malignant melanoma for CHEK2*1100delC heterozygotes compared with that for noncarriers was 1.81 (95% CI, 1.07-3.05). Stratifications did not alter these results. CHEK2*1100delC heterozygotes have a twofold risk of malignant melanoma compared with noncarriers.

Prevalence of the BRCA1 founder mutation c.5266dupin Brazilian individuals at-risk for the hereditary breast and ovarian cancer syndrome

PubMed Central

2011-01-01

About 5-10% of breast and ovarian carcinomas are hereditary and most of these result from germline mutations in the BRCA1 and BRCA2 genes. In women of Ashkenazi Jewish ascendance, up to 30% of breast and ovarian carcinomas may be attributable to mutations in these genes, where 3 founder mutations, c.68_69del (185delAG) and c.5266dup (5382insC) in BRCA1 and c.5946del (6174delT) in BRCA2, are commonly encountered. It has been suggested by some authors that screening for founder mutations should be undertaken in all Brazilian women with breast cancer. Thus, the goal of this study was to determine the prevalence of three founder mutations, commonly identified in Ashkenazi individuals in a sample of non-Ashkenazi cancer-affected Brazilian women with clearly defined risk factors for hereditary breast and ovarian cancer (HBOC) syndrome. Among 137 unrelated Brazilian women from HBOC families, the BRCA1c.5266dup mutation was identified in seven individuals (5%). This prevalence is similar to that encountered in non-Ashkenazi HBOC families in other populations. However, among patients with bilateral breast cancer, the frequency of c.5266dup was significantly higher when compared to patients with unilateral breast tumors (12.1% vs 1.2%, p = 0.023). The BRCA1 c.68_69del and BRCA2 c.5946del mutations did not occur in this sample. We conclude that screening non-Ashkenazi breast cancer-affected women from the ethnically heterogeneous Brazilian populations for the BRCA1 c.68_69del and BRCA2 c.5946del is not justified, and that screening for BRCA1c.5266dup should be considered in high risk patients, given its prevalence as a single mutation. In high-risk patients, a negative screening result should always be followed by comprehensive BRCA gene testing. The finding of a significantly higher frequency of BRCA1 c.5266dup in women with bilateral breast cancer, as well as existence of other as yet unidentified founder mutations in this population, should be further assessed in a larger well characterized high-risk cohort. PMID:22185575

Abordaje a la Cisterna Ambiens

PubMed Central

Ajler, Pablo; Bravo, Michael Cruz; Garategui, Lucas; Goldschmidt, Ezequiel; Isolan, Gustavo; Campero, Álvaro

2016-01-01

Resumen Objetivo: Describir paso a paso el abordaje a la cisterna ambiens por la vía suboccipital retrosigmoidea supracerebelosa infratentorial (SRSI). Descripción: El abordaje SRSI se realiza de la misma manera que el abordaje suboccipital retrosigmoideo (SR), utilizado habitualmente para acceder a la patología del ángulo pontocerebeloso, con las siguientes modificaciones: (1) utilizamos siempre la posición semisentado, (2) la craneotomia-craniectomia debe exponer el seno transverso y extenderse 5 cm medialmente hacia el inion, (3) al realizar la apertura dural es necesario rebatir la duramadre junto con el seno transverso hacia cefálico con puntos de tracción, (4) bajo magnificación con microscopio quirúrgico se debe realizar la apertura de la cisterna cerebelobulbar para drenar líquido cefalorraquídeo, (5) en el plano supracerebeloso es fundamental cortar las bridas aracnoidales y de ser necesario debemos coagular y cortar las venas puente, todas estas maniobras sumadas al efecto de la gravedad brindan mayor apertura del corredor supracerebeloso. Conclusión: El abordaje a la cisterna ambiens por la vía SRSI es una opción segura para el acceso de patologías tumorales que se alojan en esta zona con un componente predominantemente infratentorial. PMID:27999709

Vínculos sobre um modelo de quartessência de Chaplygin usando observações do satélite chandra da fração de massa de gás em aglomerados de galáxias

NASA Astrophysics Data System (ADS)

de Souza, R. S.

2003-08-01

Observações de Supernovas do tipo Ia mostram que a expansão do Universo está acelerando. Segundo as equações de Einstein uma componente com pressão negativa (energia escura) é necessária para explicar a aceleração cósmica. Além da energia escura é usualmente admitido que no Universo há também uma matéria exótica com pressão zero, que é chamada de matéria escura. Essa componente possui um papel fundamental na formação de estruturas no Universo. Recentemente tem se explorado a possibilidade de que matéria e energia escura poderiam ser unificadas através de uma única componente, que tem sido denominada de quartessência. Um exemplo de fluido com essas características é o Gás de Chaplygin Generalizado, que possui uma equação de estado da forma p = -A/ra. Inicialmente consideramos o caso especial a = 1 (gás de Chaplygin) e vinculamos parâmetros do modelo utilizando observações em raios-X do satélite Chandra da fração de massa de gás em aglomerados de galáxias. Uma comparação dos vínculos obtidos com esse teste com outros testes, tais como supernovas e idade do Universo, mostra que esse teste é bastante restritivo. Exibiremos ainda resultados para o caso em que a curvatura é nula e o parâmetro a está compreendido no intervalo -1 < a 1.

Increased Risk for Other Cancers in Addition to Breast Cancer for CHEK2*1100delC Heterozygotes Estimated From the Copenhagen General Population Study.

PubMed

Näslund-Koch, Charlotte; Nordestgaard, Børge G; Bojesen, Stig E

2016-04-10

CHEK2 is a cell cycle checkpoint regulator, and the CHEK2*1100delC germline mutation leads to loss of function and increased breast cancer risk. It seems plausible that this mutation could also predispose to other cancers. Therefore, we tested the hypothesis that CHEK2*1100delC heterozygosity is associated with increased risk for other cancers in addition to breast cancer in the general population. We examined 86,975 individuals from the Copenhagen General Population Study, recruited from 2003 through 2010. The participants completed a questionnaire on health and lifestyle, were examined physically, had blood drawn for DNA extraction, were tested for presence of CHEK2*1100delC using Taqman assays and sequencing, and were linked over 1943 through 2011 to the Danish Cancer Registry. Incidences and risks of individual cancer types, including breast cancer, were calculated using Kaplan-Meier estimates, Fine and Gray competing-risks regressions, and stratified analyses with interaction tests. Among 86,975 individuals, 670 (0.8%) were CHEK2*1100delC heterozygous, 2,442 developed breast cancer, and 6,635 developed other cancers. The age- and sex-adjusted hazard ratio for CHEK2*1100delC heterozygotes compared with noncarriers was 2.08 (95% CI, 1.51 to 2.85) for breast cancer and 1.45 (95% CI, 1.15 to 1.82) for other cancers. When stratifying for sex, the age-adjusted hazard ratios for other cancers were 1.54 (95% CI, 1.08 to 2.18) for women and 1.37 (95% CI, 1.01 to 1.85) for men (sex difference: P = .63). For CHEK2*1100delC heterozygotes compared with noncarriers, the age- and sex-adjusted hazard ratios were 5.76 (95% CI, 2.12 to 15.6) for stomach cancer, 3.61 (95% CI, 1.33 to 9.79) for kidney cancer, 3.45 (95% CI, 1.09 to 10.9) for sarcoma, and 1.60 (95% CI, 1.00 to 2.56) for prostate cancer. CHEK2*1100delC heterozygosity is associated with 15% to 82% increased risk for at least some cancers in addition to breast cancer. This information may be useful in clinical counseling of patients with this loss-of-function mutation. © 2016 by American Society of Clinical Oncology.

BRCA1 And BRCA2 analysis of Argentinean breast/ovarian cancer patients selected for age and family history highlights a role for novel mutations of putative south-American origin.

PubMed

Solano, Angela Rosaria; Aceto, Gitana Maria; Delettieres, Dreanina; Veschi, Serena; Neuman, Maria Isabel; Alonso, Eduardo; Chialina, Sergio; Chacón, Reinaldo Daniel; Renato, Mariani-Costantini; Podestá, Ernesto Jorge

2012-01-01

The spectrum of BRCA1/2 genetic variation in breast-ovarian cancer patients has been scarcely investigated outside Europe and North America, with few reports for South America, where Amerindian founder effects and recent multiracial immigration are predicted to result in high genetic diversity. We describe here the results of BRCA1/BRCA2 germline analysis in an Argentinean series of breast/ovarian cancer patients selected for young age at diagnosis or breast/ovarian cancer family history. The study series (134 patients) included 37 cases diagnosed within 40 years of age and no family history (any ethnicity, fully-sequenced), and 97 cases with at least 2 affected relatives (any age), of which 57 were non-Ashkenazi (fully-sequenced) and 40 Ashkenazi (tested only for the founder mutations c.66_67delAG and c.5263insC in BRCA1 and c.5946delT in BRCA2). We found 24 deleterious mutations (BRCA1:16; BRCA2: 8) in 38/134 (28.3%) patients, of which 6/37 (16.2%) within the young age group, 15/57 (26.3%) within the non-Ahkenazi positive for family history; and 17/40 (42.5%) within the Ashkenazi. Seven pathogenetic mutations were novel, five in BRCA1: c.1502_1505delAATT, c.2626_2627delAA c.2686delA, c.2728 C > T, c.3758_3759delCT, two in BRCA2: c.7105insA, c.793 + 1delG. We also detected 72 variants of which 54 previously reported and 17 novel, 33 detected in an individual patient. Four missense variants of unknown clinical significance, identified in 5 patients, are predicted to affect protein function. While global and European variants contributed near 45% of the detected BRCA1/2 variation, the significant fraction of new variants (25/96, 26%) suggests the presence of a South American genetic component. This study, the first conducted in Argentinean patients, highlights a significant impact of novel BRCA1/2 mutations and genetic variants, which may be regarded as putatively South American, and confirms the important role of founder BRCA1 and BRCA2 mutations in Argentinean Ashkenazi Jews.

[Genotyping of BRCA1, BRCA2 and CHEK2 germline mutations in Russian breast cancer patients using diagnostic biochips].

PubMed

Nasedkina, T V; Gromyko, O E; Emel'ianova, M A; Ignatova, E O; Kazubskaia, T P; Portnoĭ, S M; Zasedatelev, A S; Liubchenko, L N

2014-01-01

Germline mutations of BRCA1/2 genes cause the predisposition of their carriers to breast or/and ovary cancers (BC or/and OC) during the lifetime. Identification of these mutations is a basis of molecular diagnosis for BC susceptibility. Rapid genotyping technique using microarrays for identification of BRCA1 185delAG, 300T>G, 4153delA, 5382insC mutations and 4158 A>G sequence variant; BRCA2 695insT and 6174delT mutations; 1100delC mutation in CHEK2 gene was applied for 412 randomly collected breast cancer samples from the central region of European area of Russia. In 25 (6.0%) patients (6.0%) BC was associated with other tumours: OC, cervical cancer, colorectal cancer etc. BRCA1/2 and CHEK2 mutations were found in 33 (8.0%) BC patients. The most frequent mutation was BRCA1 5382insC, occurred in 16 (3.9%) BC patients, and CHEK2 1100delC, revealed in 7 (1.7%) BC patients. An application of diagnostic BC-microarray for genetic testing of BRCA1/2 and CHEK2 founder mutations has been discussed.

CHEK2 (∗) 1100delC Mutation and Risk of Prostate Cancer.

PubMed

Hale, Victoria; Weischer, Maren; Park, Jong Y

2014-01-01

Although the causes of prostate cancer are largely unknown, previous studies support the role of genetic factors in the development of prostate cancer. CHEK2 plays a critical role in DNA replication by responding to double-stranded breaks. In this review, we provide an overview of the current knowledge of the role of a genetic variant, 1100delC, of CHEK2 on prostate cancer risk and discuss the implication for potential translation of this knowledge into clinical practice. Currently, twelve articles that discussed CHEK2 (∗)1100delC and its association with prostate cancer were identified. Of the twelve prostate cancer studies, five studies had independent data to draw conclusive evidence from. The pooled results of OR and 95% CI were 1.98 (1.23-3.18) for unselected cases and 3.39 (1.78-6.47) for familial cases, indicating that CHEK2 (∗)1100delC mutation is associated with increased risk of prostate cancer. Screening for CHEK2(∗)1100delC should be considered in men with a familial history of prostate cancer.

CHEK2 ∗1100delC Mutation and Risk of Prostate Cancer

PubMed Central

Park, Jong Y.

2014-01-01

Although the causes of prostate cancer are largely unknown, previous studies support the role of genetic factors in the development of prostate cancer. CHEK2 plays a critical role in DNA replication by responding to double-stranded breaks. In this review, we provide an overview of the current knowledge of the role of a genetic variant, 1100delC, of CHEK2 on prostate cancer risk and discuss the implication for potential translation of this knowledge into clinical practice. Currently, twelve articles that discussed CHEK2 ∗1100delC and its association with prostate cancer were identified. Of the twelve prostate cancer studies, five studies had independent data to draw conclusive evidence from. The pooled results of OR and 95% CI were 1.98 (1.23–3.18) for unselected cases and 3.39 (1.78–6.47) for familial cases, indicating that CHEK2 ∗1100delC mutation is associated with increased risk of prostate cancer. Screening for CHEK2∗1100delC should be considered in men with a familial history of prostate cancer. PMID:25431674

Genomic profiling of CHEK2*1100delC-mutated breast carcinomas.

PubMed

Massink, Maarten P G; Kooi, Irsan E; Martens, John W M; Waisfisz, Quinten; Meijers-Heijboer, Hanne

2015-11-09

CHEK2*1100delC is a moderate-risk breast cancer susceptibility allele with a high prevalence in the Netherlands. We performed copy number and gene expression profiling to investigate whether CHEK2*1100delC breast cancers harbor characteristic genomic aberrations, as seen for BRCA1 mutated breast cancers. We performed high-resolution SNP array and gene expression profiling of 120 familial breast carcinomas selected from a larger cohort of 155 familial breast tumors, including BRCA1, BRCA2, and CHEK2 mutant tumors. Gene expression analyses based on a mRNA immune signature was used to identify samples with relative low amounts of tumor infiltrating lymphocytes (TILs), which were previously found to disturb tumor copy number and LOH (loss of heterozygosity) profiling. We specifically compared the genomic and gene expression profiles of CHEK2*1100delC breast cancers (n = 14) with BRCAX (familial non-BRCA1/BRCA2/CHEK2*1100delC mutated) breast cancers (n = 34) of the luminal intrinsic subtypes for which both SNP-array and gene expression data is available. High amounts of TILs were found in a relatively small number of luminal breast cancers as compared to breast cancers of the basal-like subtype. As expected, these samples mostly have very few copy number aberrations and no detectable regions of LOH. By unsupervised hierarchical clustering of copy number data we observed a great degree of heterogeneity amongst the CHEK2*1100delC breast cancers, comparable to the BRCAX breast cancers. Furthermore, copy number aberrations were mostly seen at low frequencies in both the CHEK2*1100delC and BRCAX group of breast cancers. However, supervised class comparison identified copy number loss of chromosomal arm 1p to be associated with CHEK2*1100delC status. In conclusion, in contrast to basal-like BRCA1 mutated breast cancers, no apparent specific somatic copy number aberration (CNA) profile for CHEK2*1100delC breast cancers was found. With the possible exception of copy number loss of chromosomal arm 1p in a subset of tumors, which might be involved in CHEK2 tumorigenesis. This difference in CNAs profiles might be explained by the need for BRCA1-deficient tumor cells to acquire survival factors, by for example specific copy number aberrations, to expand. Such factors may not be needed for breast tumors with a defect in a non-essential gene such as CHEK2.

Mating opportunities in Sangalopsis veliterna females: Costs and benefits

PubMed Central

Hernández Duran, Linda C.; Fajardo Medina, Gonzalo E.; Fuentes Quinter, Luz S.; Martin, Oliver

2014-01-01

Abstract In nature, females of several animal taxa exhibit considerable variation in their mating system, and this variation involves different balances of costs (e.g., energetic, reproductive) and benefits (e.g., increased net reproductive rate of the female, increased longevity). Many studies have focused on discovering the potential advantages and disadvantages that females could have when increasing their mating rate and the possible evolutionary consequences that may result. Butterflies and moths are an ideal study system because it is easy to determine and to manipulate experimentally their mating frequency. In this study, the effect of continuous availability of different numbers of males (1, 2, 4, 8) on female mating rate and fitness components was estimated by comparing the number of spermatophores in the corpus bursa (an estimate of the number of copulations, but not of the number males involved in these copulations), female longevity, lifetime number of laid eggs (fecundity), and proportion of hatching eggs (fertility) in the moth Sangalopsis veliterna Druce (Lepidoptera: Geometridae). The results showed that there were no significant differences in either fertility or fecundity when treatments were compared, but longevity and in some cases fecundity increased when females had several matings. Resumen En la naturaleza, hembras de varios taxa animal muestran una variación considerable en su sistema de apareamiento, esta variación involucra diferentes costos (energéticos, reproductivos, etc) y beneficios (aumento de la tasa reproductiva neta de la hembra, mayor longevidad, entre otros). En años recientes, muchos estudios se han enfocado en descubrir las potenciales ventajas y desventajas que las hembras podrían tener al aumentar su número de cópulas y las posibles consecuencias evolutivas que podrían resultar. Las mariposas y polillas son un sistema de estudio ideal, dada la facilidad para determinar y manipular experimentalmente su frecuencia de apareamiento. En este estudio, el efecto de la disponibilidad continua de diferente número de machos (1, 2, 4, 8) sobre la frecuencia de apareamiento de las hembras y los componentes del potencial reproductivo (fitness) fueron estimados al comparar el número de espermatóforos hallados en la bursa copulatrix (un estimado del número de copulas, pero no del número de machos involucrados en estas copulas), la longevidad de las hembras, número de huevos colocados (fecundidad) y proporción de huevos fecundados (fertilidad) en la polilla Sangalopsis veliterna Druce (Lepidóptera: Geometridae). Los resultados indican que no existen diferencias en la fertilidad ni en la fecundidad; sin embargo la longevidad aumentó a medida que se las hembras presentaron más de una cópula y de igual manera en algunos casos la fecundidad aumentó con varios apareamientos. PMID:25205137

Transcriptomic profiling and quantitative high-throughput (qHTS) drug screening of CDH1 deficient hereditary diffuse gastric cancer (HDGC) cells identify treatment leads for familial gastric cancer.

PubMed

Chen, Ina; Mathews-Greiner, Lesley; Li, Dandan; Abisoye-Ogunniyan, Abisola; Ray, Satyajit; Bian, Yansong; Shukla, Vivek; Zhang, Xiaohu; Guha, Raj; Thomas, Craig; Gryder, Berkley; Zacharia, Athina; Beane, Joal D; Ravichandran, Sarangan; Ferrer, Marc; Rudloff, Udo

2017-05-01

Patients with hereditary diffuse gastric cancer (HDGC), a cancer predisposition syndrome associated with germline mutations of the CDH1 (E-cadherin) gene, have few effective treatment options. Despite marked differences in natural history, histopathology, and genetic profile to patients afflicted by sporadic gastric cancer, patients with HDGC receive, in large, identical systemic regimens. The lack of a robust preclinical in vitro system suitable for effective drug screening has been one of the obstacles to date which has hampered therapeutic advances in this rare disease. In order to identify therapeutic leads selective for the HDGC subtype of gastric cancer, we compared gene expression profiles and drug phenotype derived from an oncology library of 1912 compounds between gastric cancer cells established from a patient with metastatic HDGC harboring a c.1380delA CDH1 germline variant and sporadic gastric cancer cells. Unsupervised hierarchical cluster analysis shows select gene expression alterations in c.1380delA CDH1 SB.mhdgc-1 cells compared to a panel of sporadic gastric cancer cell lines with enrichment of ERK1-ERK2 (extracellular signal regulated kinase) and IP3 (inositol trisphosphate)/DAG (diacylglycerol) signaling as the top networks in c.1380delA SB.mhdgc-1 cells. Intracellular phosphatidylinositol intermediaries were increased upon direct measure in c.1380delA CDH1 SB.mhdgc-1 cells. Differential high-throughput drug screening of c.1380delA CDH1 SB.mhdgc-1 versus sporadic gastric cancer cells identified several compound classes with enriched activity in c.1380 CDH1 SB.mhdgc-1 cells including mTOR (Mammalian Target Of Rapamycin), MEK (Mitogen-Activated Protein Kinase), c-Src kinase, FAK (Focal Adhesion Kinase), PKC (Protein Kinase C), or TOPO2 (Topoisomerase II) inhibitors. Upon additional drug response testing, dual PI3K (Phosphatidylinositol 3-Kinase)/mTOR and topoisomerase 2A inhibitors displayed up to >100-fold increased activity in hereditary c.1380delA CDH1 gastric cancer cells inducing apoptosis most effectively in cells with deficient CDH1 function. Integrated pharmacological and transcriptomic profiling of hereditary diffuse gastric cancer cells with a loss-of-function c.1380delA CDH1 mutation implies various pharmacological vulnerabilities selective to CDH1-deficient familial gastric cancer cells and suggests novel treatment leads for future preclinical and clinical treatment studies of familial gastric cancer.

Founder haplotype analysis of Fanconi anemia in the Korean population finds common ancestral haplotypes for a FANCG variant.

PubMed

Park, Joonhong; Kim, Myungshin; Jang, Woori; Chae, Hyojin; Kim, Yonggoo; Chung, Nack-Gyun; Lee, Jae-Wook; Cho, Bin; Jeong, Dae-Chul; Park, In Yang; Park, Mi Sun

2015-05-01

A common ancestral haplotype is strongly suggested in the Korean and Japanese patients with Fanconi anemia (FA), because common mutations have been frequently found: c.2546delC and c.3720_3724delAAACA of FANCA; c.307+1G>C, c.1066C>T, and c.1589_1591delATA of FANCG. Our aim in this study was to investigate the origin of these common mutations of FANCA and FANCG. We genotyped 13 FA patients consisting of five FA-A patients and eight FA-G patients from the Korean FA population. Microsatellite markers used for haplotype analysis included four CA repeat markers which are closely linked with FANCA and eight CA repeat markers which are contiguous with FANCG. As a result, Korean FA-A patients carrying c.2546delC or c.3720_3724delAAACA did not share the same haplotypes. However, three unique haplotypes carrying c.307+1G>C, c.1066C > T, or c.1589_1591delATA, that consisted of eight polymorphic loci covering a flanking region were strongly associated with Korean FA-G, consistent with founder haplotypes reported previously in the Japanese FA-G population. Our finding confirmed the common ancestral haplotypes on the origins of the East Asian FA-G patients, which will improve our understanding of the molecular population genetics of FA-G. To the best of our knowledge, this is the first report on the association between disease-linked mutations and common ancestral haplotypes in the Korean FA population. © 2015 John Wiley & Sons Ltd/University College London.

Age- and Tumor Subtype–Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers

PubMed Central

Hogervorst, Frans; van Hien, Richard; Cornelissen, Sten; Broeks, Annegien; Adank, Muriel A.; Meijers, Hanne; Waisfisz, Quinten; Hollestelle, Antoinette; Schutte, Mieke; van den Ouweland, Ans; Hooning, Maartje; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia N.; Antoniou, Antonis C.; Arndt, Volker; Bermisheva, Marina; Bogdanova, Natalia V.; Bolla, Manjeet K.; Brauch, Hiltrud; Brenner, Hermann; Brüning, Thomas; Burwinkel, Barbara; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Dunning, Alison M.; Fasching, Peter A.; Figueroa, Jonine; Fletcher, Olivia; Flyger, Henrik; Galle, Eva; García-Closas, Montserrat; Giles, Graham G.; Haeberle, Lothar; Hall, Per; Hillemanns, Peter; Hopper, John L.; Jakubowska, Anna; John, Esther M.; Jones, Michael; Khusnutdinova, Elza; Knight, Julia A.; Kosma, Veli-Matti; Kristensen, Vessela; Lee, Andrew; Lindblom, Annika; Lubinski, Jan; Mannermaa, Arto; Margolin, Sara; Meindl, Alfons; Milne, Roger L.; Muranen, Taru A.; Newcomb, Polly A.; Offit, Kenneth; Park-Simon, Tjoung-Won; Peto, Julian; Pharoah, Paul D.P.; Robson, Mark; Rudolph, Anja; Sawyer, Elinor J.; Schmutzler, Rita K.; Seynaeve, Caroline; Soens, Julie; Southey, Melissa C.; Spurdle, Amanda B.; Surowy, Harald; Swerdlow, Anthony; Tollenaar, Rob A.E.M.; Tomlinson, Ian; Trentham-Dietz, Amy; Vachon, Celine; Wang, Qin; Whittemore, Alice S.; Ziogas, Argyrios; van der Kolk, Lizet; Nevanlinna, Heli; Dörk, Thilo; Bojesen, Stig; Easton, Douglas F.

2016-01-01

Purpose CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC. Patients and Methods CHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies. Results Proportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center–based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10−20). The OR was higher for estrogen receptor (ER)–positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10−21]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10−4). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom. Conclusion These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up. PMID:27269948

Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers.

PubMed

Schmidt, Marjanka K; Hogervorst, Frans; van Hien, Richard; Cornelissen, Sten; Broeks, Annegien; Adank, Muriel A; Meijers, Hanne; Waisfisz, Quinten; Hollestelle, Antoinette; Schutte, Mieke; van den Ouweland, Ans; Hooning, Maartje; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia N; Antoniou, Antonis C; Arndt, Volker; Bermisheva, Marina; Bogdanova, Natalia V; Bolla, Manjeet K; Brauch, Hiltrud; Brenner, Hermann; Brüning, Thomas; Burwinkel, Barbara; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Couch, Fergus J; Cox, Angela; Cross, Simon S; Czene, Kamila; Dunning, Alison M; Fasching, Peter A; Figueroa, Jonine; Fletcher, Olivia; Flyger, Henrik; Galle, Eva; García-Closas, Montserrat; Giles, Graham G; Haeberle, Lothar; Hall, Per; Hillemanns, Peter; Hopper, John L; Jakubowska, Anna; John, Esther M; Jones, Michael; Khusnutdinova, Elza; Knight, Julia A; Kosma, Veli-Matti; Kristensen, Vessela; Lee, Andrew; Lindblom, Annika; Lubinski, Jan; Mannermaa, Arto; Margolin, Sara; Meindl, Alfons; Milne, Roger L; Muranen, Taru A; Newcomb, Polly A; Offit, Kenneth; Park-Simon, Tjoung-Won; Peto, Julian; Pharoah, Paul D P; Robson, Mark; Rudolph, Anja; Sawyer, Elinor J; Schmutzler, Rita K; Seynaeve, Caroline; Soens, Julie; Southey, Melissa C; Spurdle, Amanda B; Surowy, Harald; Swerdlow, Anthony; Tollenaar, Rob A E M; Tomlinson, Ian; Trentham-Dietz, Amy; Vachon, Celine; Wang, Qin; Whittemore, Alice S; Ziogas, Argyrios; van der Kolk, Lizet; Nevanlinna, Heli; Dörk, Thilo; Bojesen, Stig; Easton, Douglas F

2016-08-10

CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC. CHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies. Proportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center-based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10(-20)). The OR was higher for estrogen receptor (ER)-positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10(-21)]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10(-4)). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom. These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up. © 2016 by American Society of Clinical Oncology.

Absence of CHEK2*1100delC mutation in families with hereditary breast cancer in North America.

PubMed

Iniesta, Maria D; Gorin, Michael A; Chien, Ling-Chen; Thomas, Samantha M; Milliron, Kara J; Douglas, Julie A; Merajver, Sofia D

2010-10-15

The CHEK2*1100delC mutation has been reported to confer a twofold increased risk of breast cancer among carriers. The frequency of the mutation varies among populations. The highest frequency has been described in Northern and Eastern European countries; the frequency may be much lower in North America. In this study, our aim was to determine the frequency of CHEK2*1100delC in members of breast cancer families who tested negative for a deleterious mutation in BRCA1/2 at the University of Michigan Comprehensive Cancer Center. We genotyped 102 members from 90 families for CHEK2*1100delC. Most of these families had several cases of breast cancer or ovarian cancer (or both), as well as multiple members with other cancer types in a single lineage. No CHEK2*1100delC mutations were detected in any of the 102 individuals, including 51 women diagnosed with breast cancer at an early age (<45 years), 8 women with bilateral breast cancer, 3 men with breast cancer, and 8 women with ovarian cancer. Our data are consistent with the reported very low frequency of CHEK2*1100delC mutations in North American populations (compared with Northern Europe), rendering CHEK2*1100delC such an unlikely culprit in BRCA1/2 negative families that routine testing of these families appears unwarranted. Copyright © 2010 Elsevier Inc. All rights reserved.

Development of quality control procedures for mass produced and released Bactrocera Philippinensis (Diptera: Tephritidae) for sterile insect technique programs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Resilva, S.; Obra, G.; Zamora, N.

Quality control procedures for Bactrocera philippinensis Drew and Hancock 1994 (Diptera: Tephritidae) used in sterile insect technique (SIT) programs were established in the mass rearing facility at the Philippine Nuclear Research Institute. Basic studies on pupal irradiation, holding/packaging systems, shipping procedures, longevity, sterility studies, and pupal eye color determination in relation to physiological development at different temperature regimes were investigated. These studies will provide baseline data for the development of quality control protocols for an expansion of B. philippinensis field programs with an SIT component in the future. (author) [Spanish] Los procedimientos de control de calidad para Bactrocera philippinensis Drewmore » y Hancock 1994 (Diptera: Tephritidae) usados en programas de la tecnica de insecto esteril (TIE) fueron establecidos en la facilidad de cria en masa del Instituto Filipino de Investigacion Nuclear. Estudios basicos sobre la irradiacion de las pupas, sistemas de almacenaje/empaque, procedimientos del envio, longevidad, estudios de esterilidad y la determinacion del color de ojo de la pupa en relacion con el desarrollo fisiologico en regimenes diferentes de temperatura fueron investigados. Estos estudios proveeran una linea de informacion basica para el desarrollo de protocolos de control de calidad para una expansion de los programas de campo para B. philippinensis con un componente de TIS en el futuro. (author)« less

[Analysis of MAT1A gene mutations in a child affected with simple hypermethioninemia].

PubMed

Sun, Yun; Ma, Dingyuan; Wang, Yanyun; Yang, Bin; Jiang, Tao

2017-02-10

To detect potential mutations of MAT1A gene in a child suspected with simple hypermethioninemia by MS/MS neonatal screening. Clinical data of the child was collected. Genomic DNA was extracted by a standard method and subjected to targeted sequencing using an Ion Ampliseq TM Inherited Disease Panel. Detected mutations were verified by Sanger sequencing. The child showed no clinical features except evaluated methionine. A novel compound mutation of the MAT1A gene, i.e., c.345delA and c.529C>T, was identified in the child. His father and mother were found to be heterozygous for the c.345delA mutation and c.529C>T mutation, respectively. The compound mutation c.345delA and c.529C>T of the MAT1A gene probably underlie the disease in the child. The semi-conductor sequencing has provided an important means for the diagnosis of hereditary diseases.

Evaluation of HLA-G 14-bp ins/del and +3142G>C polymorphisms with susceptibility to recurrent spontaneous abortion.

PubMed

Hashemi, Mohammad; Mokhtari, Mojgan; Khazaeian, Safura; Bahari, Gholamreza; Rezaei, Maryam; Nakhaee, Alireza; Taheri, Mohsen

2017-06-01

HLA-G is critically important for successful implantation during pregnancy. Increasing evidence supposed that HLA-G plays a key role in tolerance of the semi-allogeneic graft in pregnancy by inhibiting the cytotoxic functions of T and NK cells. The present study aimed to evaluate the impact of HLA-G rs1063320 (+3142G>C) and 14-bp insertion (ins)/deletion (del) polymorphisms on recurrent spontaneous abortion (RSA). Genomic DNA from 93 RSA patients and 93 normal fertile women was isolated using the salting out method. Genotyping of HLA-G +3142G>C and 14-bp ins/del variants was done by polymerase chain reaction restriction fragment length polymorphism (PCR-RFP) and PCR method, respectively. The HLA-G +3142G>C polymorphism increased the risk of RSA in codominant (OR = 2.39, 95%CI = 1.27-4.49, p = 0.010, GC vs GG; OR = 3.28, 95%CI = 1.16-9.72, p = 0.040, CC vs GG) and dominant (OR = 2.52, 95%CI = 1.37-4.64, p = 0.004, GC + CC vs GG) tested inheritance models. HLA-G rs1063320 C allele was associated with increased risk of RSA (OR = 1.84, 95%CI = 1.20-2.83, p = 0.007). The del/del genotype as well as del allele of 14-bp ins/del variant increased that risk of RSA (OR = 3.02, 95%CI = 1.23-7.41, p = 0.025 and OR = 1.65, 95%CI = 1.09-2.50, p = 0.022, respectively). In summary, our results showed that HLA-G gene polymorphisms significantly increased the risk of RSA in a sample of the Iranian population. Copyright © 2017. Published by Elsevier B.V.

[CHEK2-mutation in Dutch breast cancer families: expanding genetic testing for breast cancer].

PubMed

Adank, Muriel A; Hes, Frederik J; van Zelst-Stams, Wendy A G; van den Tol, M Petrousjka; Seynaeve, Caroline; Oosterwijk, Jan C

2015-01-01

In the majority of breast cancer families, DNA testing does not show BRCA1 or BRCA2 mutations and the genetic cause of breast cancer remains unexplained. Routine testing for the CHEK2*1100delC mutation has recently been introduced in breast cancer families in the Netherlands. The 1100delC mutation in the CHEK2-gene may explain the occurrence of breast cancer in about 5% of non-BRCA1/2 families in the Netherlands. In the general population the CHEK2*1100delC mutation confers a slightly increased breast cancer risk, but in a familial breast cancer setting this risk is between 35-55% for first degree female carriers. Female breast cancer patients with the CHEK2*1100delC mutation are at increased risk of contralateral breast cancer and may have a less favourable prognosis. Female heterozygous CHEK2*1100delC mutation carriers are offered annual mammography and specialist breast surveillance between the ages of 35-60 years. Prospective research in CHEK2-positive families is essential in order to develop more specific treatment and screening strategies.

Meta-analysis of CHEK2 1100delC variant and colorectal cancer susceptibility.

PubMed

Xiang, He-ping; Geng, Xiao-ping; Ge, Wei-wei; Li, He

2011-11-01

Cell cycle checkpoint kinase 2 (CHEK2) gene has been inconsistently associated with colorectal cancer (CRC), particularly the 1100delC variant. To generate large-scale evidence on whether the CHEK2 1100delC variant is associated with CRC susceptibility we have conducted a meta-analysis. Data were collected from the following electronic databases: PubMed, Excerpta Medica Database and Chinese Biomedical Literature Database, with the last report up to November 2010. The odds ratio (OR) and its 95% confidence interval (95% CI) were used to assess the strength of association. We evaluated the contrast of carriers versus non-carriers. Meta-analysis was performed in a fixed/random effect model by using the software Review Manager 4.2. A total of six studies including 4194 cases and 10,010 controls based on the search criteria were involved in this meta-analysis. A significant association of the CHEK2 1100delC variant with unselected CRC was found (OR=2.11, 95% CI=1.41-3.16, P=0.0003). We also found an association of the CHEK2 1100delC variant with familial CRC (OR=2.80, 95% CI=1.74-4.51, P<0.0001). However, the association was not established for sporadic CRC (OR=1.45, 95% CI=0.49-4.30, P=0.50). This meta-analysis demonstrates that the CHEK2 1100delC variant may be an important CRC-predisposing gene, which increases CRC risk. Copyright © 2011. Published by Elsevier Ltd.

High Resolution Melting Analysis is Very Useful to Identify BRCA1 c.4964_4982del19 (rs80359876) Founder Calabrian Pathogenic Variant on Peripheral Blood and Buccal Swab DNA.

PubMed

Minucci, Angelo; De Bonis, Maria; De Paolis, Elisa; Gentile, Leonarda; Santonocito, Concetta; Concolino, Paola; Mignone, Flavio; Capoluongo, Ettore

2017-04-01

Detection of pathogenic variants in hereditary breast and ovarian cancer-related breast cancer type 1 and type 2 susceptibility proteins (BRCA1/2) genes is an effective strategy in cancer prevention and treatment. Some ethnic and geographical regions show different BRCA1/2 mutation spectrum and prevalence. In Italy, elucidation of founder effect in BRCA1/2 genes can have an impact on the management of hereditary cancer families on a healthcare system level, making genetic testing more affordable and cost effective in certain regions. The purpose of this paper is to develop a rapid, low-cost, high-throughput single-tube technology for genotyping the Italian founder mutation c.4964_4982del19 (rs80359876) in the BRCA1 gene, starting from peripheral blood and/or buccal swab DNA. Heterozygote samples for c.4964_4982del19 variant were easily and unambiguously identified by the altered shape of the melting curves and were clearly distinguished by a change in melting temperature that differed by approximately 5 °C. The same results were obtained both with DNA from peripheral blood than buccal swab. We provide evidence about application of high-resolution melting analysis (HRMA) in unambiguously genotyping of the founder BRCA1 c.4964_4982del19 variant (rs80359876) in individuals from the Calabria region of Italy. In fact, HRMA was confirmed to be particularly suitable for the identification of BRCA1 c.4964_4982del19 variant, making this approach useful in clinical molecular diagnostics.

Dust and Erosion Control Methods for US Army Construction Projects in Honduras

DTIC Science & Technology

1989-06-01

sano TomT&S *15 14t Ar,,&Ws A.1 141 SanS5 Ivotor 1"M aLa IA. ,.. s-. 8t YOU LA~, Coo O / A 17 I1 (a de Guana~aISLAS SAWrANILLA 30,I i3 2 5...parte del ano; prornedlo de ’H nori above 18’C, temperatura del mes nias fresco, arriba de .ainf c ilTROPICAL WET AND DRY CLIMATE-Dis. CLIMA TROPICAL...temperature del mes mas te :3 tefresco arriba do 18~’C. b1 abH mo [4 WARM TEMPERATE CLIMATE-Winter dry; CL ’MA TEMPLADO HUMEDO-Invierno seco; at least

Implementación de un modelo de capacitación multimedial para brindar orientación alimentaria a los beneficiarios de un programa de ayuda social en México.

PubMed

Amaya-Castellanos, Maritza Alejandra; Morales-Ruan, María Del Carmen; Uribe-Carvajal, Rebeca; Jiménez-Aguilar, Alejandra; Salazar-Coronel, Araceli Apolonia; Martínez-Tapia, Brenda; Shamah-Levy, Teresa

2018-03-01

Introducción: Se implementó un modelo de capacitación en orientación alimentaria para la población beneficiaria y el personal operativo del Programa de Abasto Rural (PAR) de Diconsa, el cual es una iniciativa social de ayuda alimentaria que abastece productos básicos y complementarios, además de brindar capacitación en localidades de alta marginación en México. Objetivo: Documentar la utilización de la Metodología de Capacitación Multimedial (MCM) en el desarrollo de un esquema de capacitación sobre orientación alimentaria y su implementación en la población beneficiaria del PAR, a través de la propia estructura operativa del PAR. Metodología: El modelo se fundamenta en la MCM, integrada por cuatro elementos didácticos e indivisibles que conforman el paquete pedagógico multimedial (PPM), compuesto a su vez por tres videos y rotafolios, material impreso, prácticas y las relaciones interpersonales. Los ejes temáticos fueron: alimentación correcta para una vida saludable, alimentación materno-infantil, elecciones saludables y gasto familiar. El modelo fue replicado en cascada en los tres niveles operativos del PAR (responsables de capacitación, supervisores operativos y beneficiarios del PAR), con un componente de multiplicación horizontal, e implementado como piloto en cuatro estados de México. Resultados: Se observó un cambio positivo sobre los conocimientos en alimentación correcta en todos los niveles de capacitación, principalmente en los beneficiarios del PAR. La evaluación del proceso mostró conocimientos previos de los responsables de capacitación en los temas, buen desempeño como facilitadores, y habilidades de presentación y manejo del grupo de los supervisores operativos. A partir de las evaluaciones y del acompañamiento en la prueba piloto, fueron modificados las actividades, las estrategias y los materiales educativos del PPM. Conclusiones: La capacitación multimedial y la educación nutricional promueven procesos de cambio y desarrollo comunitario, posibles a través de la toma de conciencia y la puesta en práctica de acciones que favorecen la salud.

Molecular Characterization of β-Thalassemia Intermedia in Southeast Iran.

PubMed

Miri-Moghaddam, Ebrahim; Bahrami, Sara; Naderi, Majid; Bazi, Ali; Karimipoor, Morteza

2016-06-01

Inheritance of mild mutations within the β-globin gene and coinheritance of α-thalassemia (α-thal) are known as two important genetic modifiers in β-thalassemia (β-thal) intermedia (β-TI). We aimed to evaluate the spectrum of β- and α-thal mutations in β-TI patients in Southeast Iran. Common β- and α-globin gene mutations were detected by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and multiplex gap-PCR, respectively. There were 26 male (57.8%) and 19 female (42.2%) patients. HBB: c.92 + 5T > C [IVS-I-5 (G > C)] and HBB: c.-138C + 1G > A [IVS-II-I (G > A)] represented the prevalent alleles with respective frequencies of 60.0 and 10.0%. Other β-globin mutations included HBB: c.-138C > T [-88 (C > T)], HBB: c.27_28insG [frameshift codons (FSC) 8/9 (+G)], HBB: c.46delT [codon 15 (-T)], HBB: c.93-22_95del (IVS-I, 25 del), and the 619 bp deletion (NG_000007.3: g.71609_72227del619). The predominant genotypic combinations were β(0)/β(0) (68.9%), β(0)/β(+ )(8.9%) and β(+)/β(+ )(2.2%). Coinheritance of α-thal was observed in 33.0% of the patients, with the -α(3.7) (rightward) (NG_000006.1: g.34164_37967del3804) as the most common deletion (86.0%). One patient was diagnosed with the -α(4.2) (leftward) (AF221717) and one with the - -(MED) (g.24664_41064del16401) deletions, while no patients carried the -(α)(20.5) (g.15164_37864del22701), α(-5 nt) (HBA2: c.95 + 2_95_6delTGAGG) or codon 19 (-G) (HBA2: c.56delG) mutations. The alleviating molecular mechanism was not explainable by β(+ )or concurrent α-thal in more than half of our β-TI patients. This encourages conducting more studies to identify other contributing factors, especially Hb F-inducing genetic modifiers.

CHEK2 1100delC variant and breast cancer risk in Caucasians: a meta-analysis based on 25 studies with 29,154 cases and 37,064 controls.

PubMed

Yang, Yuan; Zhang, Fan; Wang, Yang; Liu, Sheng-Chun

2012-01-01

Links between the CHEK2 1100delC heterozygote and breast cancer risk have been extensively explored. However, both positive and negative associations with this variant have been reported in individual studies. For a detailed assessment of the CHEK2 1100delC heterozygote and breast cancer risk, relevant studies published as recently as May 2012 were identified using PUBMED and EMBASE and selected using a priori defined criteria. The strength of the relationship between the CHEK2 1100delC variant and breast cancer risks was assessed by odds ratios (ORs) under the fixed effects model. A total of 29,154 cases and 37,064 controls from 25 case-control studies were identified in this meta-analysis. The CHEK2 1100delC heterozygote was more frequently detected in cases than in controls (1.34% versus 0.44%). A significant association was found between CHEK2 1100delC heterozygote and breast cancer risk (OR=2.75, 95% CI: [2.25, 3.36]). The ORs and CIs were 2.33 (95% CI: [1.79, 3.05]), 3.72 (95% CI: [2.61, 5.31]) and 2.78 (95% CI: [2.28, 3.39]) respectively in unselected, family, early-onset breast cancer subgroups. The CHEK2 1100delC variant could be a potential factor for increased breast cancer risk in Caucasians. However, more consideration is needed in order to apply it to allele screening or other clinical work.

The relationship of TP53 R72P polymorphism to disease outcome and TP53 mutation in myelodysplastic syndromes

PubMed Central

McGraw, K L; Zhang, L M; Rollison, D E; Basiorka, A A; Fulp, W; Rawal, B; Jerez, A; Billingsley, D L; Lin, H-Y; Kurtin, S E; Yoder, S; Zhang, Y; Guinta, K; Mallo, M; Solé, F; Calasanz, M J; Cervera, J; Such, E; González, T; Nevill, T J; Haferlach, T; Smith, A E; Kulasekararaj, A; Mufti, G; Karsan, A; Maciejewski, J P; Sokol, L; Epling-Burnette, P K; Wei, S; List, A F

2015-01-01

Nonsynonymous TP53 exon 4 single-nucleotide polymorphism (SNP), R72P, is linked to cancer and mutagen susceptibility. R72P associations with specific cancer risk, particularly hematological malignancies, have been conflicting. Myelodysplastic syndrome (MDS) with chromosome 5q deletion is characterized by erythroid hypoplasia arising from lineage-specific p53 accumulation resulting from ribosomal insufficiency. We hypothesized that apoptotically diminished R72P C-allele may influence predisposition to del(5q) MDS. Bone marrow and blood DNA was sequenced from 705 MDS cases (333 del(5q), 372 non-del(5q)) and 157 controls. Genotype distribution did not significantly differ between del(5q) cases (12.6% CC, 38.1% CG, 49.2% GG), non-del(5q) cases (9.7% CC, 44.6% CG, 45.7% GG) and controls (7.6% CC, 37.6% CG, 54.8% GG) (P=0.13). Allele frequency did not differ between non-del(5q) and del(5q) cases (P=0.91) but trended towards increased C-allele frequency comparing non-del(5q) (P=0.08) and del(5q) (P=0.10) cases with controls. Median lenalidomide response duration increased proportionate to C-allele dosage in del(5q) patients (2.2 (CC), 1.3 (CG) and 0.89 years (GG)). Furthermore, C-allele homozygosity in del(5q) was associated with prolonged overall and progression-free survival and non-terminal interstitial deletions that excluded 5q34, whereas G-allele homozygozity was associated with inferior outcome and terminal deletions involving 5q34 (P=0.05). These findings comprise the largest MDS R72P SNP analysis. PMID:25768405

Observación espectroscópica de NGC 2442

NASA Astrophysics Data System (ADS)

Agüero, E.; Bajaja, E.; Paolantonio, S.

La galaxia NGC 2442 (SAB(s)bc pec) fue observada con el telescopio de 2,15 m y el espectrógrafo REOSC del CASLEO utilizando el detector CCD Tektronix de 1024 × 1024 pixels de 24 μ m (0,26"). Las exposiciones fueron realizadas con la ranura de 3,3'' × 348'', en el plano focal, ubicadas en seis posiciones, cinco a 40o de áng. de pos. y una a 79o. La mayor parte de las exposiciones se efectuó con la red de 1200 líneas mm-1, a un ángulo de 25,53o cubriendo el rango de λλ 6200 a 6900 con dispersión de 32Å mm-1 y resolución de 2,5 Å. Las relaciones entre las intensidades de las líneas de emisión en el núcleo de NGC 2442 indican que es un LINER lo cual es compatible con la sugerencia de Shobrook de que se trataría de una galaxia Seyfert u otro tipo de galaxia activa. La temperatura y densidad electrónicas nucleares son Te ~14.000 K y Ne ~ 530 cm-3, respectivamente. Una región a 87'' al NE en cambio, donde las intensidades son también altas, presenta características espectrales típicas de una Región HII con Te ~6500 K y Ne ~10 cm-3. La correlación de las intensidades con el CO en 115 GHz y con el continuo en 843 MHz y de las velocidades ópticas con las del CO, a lo largo del eje mayor, son muy buenas. La mayor resolución angular de las observaciones, sin embargo, permite apreciar la existencia de dos componentes de velocidad en el núcleo que pueden corresponder a un anillo en rotación o a un fenómeno de expansión.

Association Between CHEK2*1100delC and Breast Cancer: A Systematic Review and Meta-Analysis.

PubMed

Liang, Mingming; Zhang, Yun; Sun, Chenyu; Rizeq, Feras Kamel; Min, Min; Shi, Tingting; Sun, Yehuan

2018-06-16

The association between the checkpoint kinase 2*1100delC (CHEK2*1100delC) and breast cancer has been extensively explored. In light of the recent publication of studies on these specific findings, particularly regarding male patients with breast cancer, we performed an updated meta-analysis to investigate a more reliable estimate. This meta-analysis included 26 published studies selected in a search of electronic databases up to January 2018, including 118,735 breast cancer cases and 195,807 controls. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association between 1100delC and breast cancer. Meta-analysis results suggested that 1100delC contributed to an increased breast cancer risk in overall populations (OR 2.89; 95% CI 2.63-3.16). Subgroup analysis found ORs of 3.13 (95% CI 1.94-5.07) for male breast cancer, 2.88 (95% CI 2.63-3.16) for female breast cancer, 2.87 (95% CI 1.85-4.47) for early-onset breast cancer, 2.92 (95% CI 2.65-3.22) for invasive breast cancer, and 3.21 (95% CI 2.41-4.29) for familial breast cancer. The sensitivity analysis suggested that results of this meta-analysis were generally robust. CHEK2*1100delC is associated with an increased risk of both female and male breast cancer.

CHEK2 c.1100delC allele is rarely identified in Greek breast cancer cases.

PubMed

Apostolou, Paraskevi; Fostira, Florentia; Papamentzelopoulou, Myrto; Michelli, Maria; Panopoulos, Christos; Fountzilas, George; Konstantopoulou, Irene; Voutsinas, Gerassimos E; Yannoukakos, Drakoulis

2015-04-01

The CHEK2 gene encodes a protein kinase that plays a crucial role in maintenance of genomic integrity and the DNA repair mechanism. CHEK2 germline mutations are associated with increased risk of breast cancer and other malignancies. From a clinical perspective, the most significant mutation identified is the c.1100delC mutation, which is associated with an approximately 25% lifetime breast cancer risk. The distribution of this mutation shows wide geographical variation; it is more prevalent in the Northern European countries and less common, or even absent, in Southern Europe. In order to estimate the frequency of the CHEK2 c.1100delC mutation in Greek breast cancer patients, we genotyped 2,449 patients (2,408 females and 41 males), which was the largest series ever tested for c.1100delC. The mean age of female and male breast cancer diagnosis was 49 and 59 years, respectively. All patients had previously tested negative for the Greek BRCA1 founder and recurrent mutations. The CHEK2 c.1100delC mutation was detected in 0.16% (4 of 2,408) of females, all of whom were diagnosed with breast cancer before the age of 50 years. Only one c.1100delC carrier was reported with breast cancer family history. The present study indicates that the CHEK2 c.1100delC mutation does not contribute substantially to hereditary breast cancer in patients of Greek descent. Copyright © 2015 Elsevier Inc. All rights reserved.

The c.301_302delAG PROP1 gene mutation in Romanian patients with multiple pituitary hormone deficiency.

PubMed

Lazea, Cecilia; Grigorescu-Sido, Paula; Popp, Radu; Legendre, Marie; Amselem, Serge; Al-Khzouz, Camelia; Bucerzan, Simona; Creţ, Victoria; Crişan, Mirela; Brad, Cristian

2015-09-01

To establish the frequency of the c.301_302 delAG mutation of the PROP1 gene in Romanian patients with multiple pituitary hormone deficiency (MPHD). Somatic assessment, hormonal test, bone age, magnetic resonance imaging of the pituitary gland, and molecular diagnosis were performed in 26 patients with MPHD (7 patients with familial form of MPHD and 19 patients with sporadic form of MPHD). The c.301_302delAG mutation was detected in the homozygous state in 10 patients belonging to 5 unrelated families (7 patients with familial history of MPHD and 3 patients with sporadic form of MPHD). Those 10 patients presented variable pituitary hormone deficiency and pituitary morphology. The c.301_302delAG homozygous genotype had a high frequency of 38% (10/26), reaching 100% (7/7) in group with familial cases of MPHD and 16% (3/19) in group with sporadic forms of MPHD.

Prevalence of GJB2 (connexin-26) and GJB6 (connexin-30) mutations in a cohort of 300 Brazilian hearing-impaired individuals: implications for diagnosis and genetic counseling.

PubMed

Batissoco, Ana Carla; Abreu-Silva, Ronaldo Serafim; Braga, Maria Cristina Célia; Lezirovitz, Karina; Della-Rosa, Valter; Alfredo, Tabith; Otto, Paulo Alberto; Mingroni-Netto, Regina Célia

2009-02-01

Hereditary nonsyndromic deafness is an autosomal recessive condition in about 80% of cases, and point mutations in the GJB2 gene (connexin 26) and two deletions in the GJB6 gene (connexin 30), del(GJB6-D13S1830) and del(GJB6-D13S1854), are reported to account for 50% of recessive deafness. Aiming at establishing the frequencies of GJB2 mutations and GJB6 deletions in the Brazilian population, we screened 300 unrelated individuals with hearing impairment, who were not affected by known deafness related syndromes. We firstly screened the most frequently reported mutations, c.35delG and c.167delT in the GJB2 gene, and del(GJB6-D13S1830) and del(GJB6-D13S1854) in the GJB6 gene, through specific techniques. The detected c.35delG and c.167delT mutations were validated by sequencing. Other mutations in the GJB2 gene were screened by single-strand conformation polymorphism and the coding region was sequenced when abnormal patterns were found. Pathogenic mutations in GJB2 and GJB6 genes were detected in 41 individuals (13.7%), and 80.5% (33/41) presented these mutations in homozygosis or compound heterozygosis, thus explaining their hearing defect. The c.35delG in the GJB2 gene was the most frequent mutation (37/300; 12.4%), detected in 23% familial and 6.2% the sporadic cases. The second most frequent mutation (1%; 3/300) was the del(GJB6-D13S1830), always found associated with the c.35delG mutation. Nineteen different sequence variations were found in the GJB2 gene. In addition to the c.35delG mutation, nine known pathogenic alterations were detected c.167delT, p.Trp24X, p.Val37Ile, c.176_191del16, c.235delC, p.Leu90Pro, p.Arg127His, c.509insA, and p.Arg184Pro. Five substitutions had been previously considered benign polymorphisms: c.-15C>T, p.Val27Ile, p.Met34Thr, p.Ala40Ala, and p.Gly160Ser. Two previously reported mutations of unknown pathogenicity were found (p.Lys168Arg, and c.684C>A), and two novel substitutions, p.Leu81Val (c.G241C) and p.Met195Val (c.A583G), both in heterozygosis without an accompanying mutation in the other allele. None of these latter four variants of undefined status was present in a sample of 100 hearing controls. The present study demonstrates that mutations in the GJB2 gene and del(GJB6 D13S1830) are important causes of hearing impairment in Brazil, thus justifying their screening in a routine basis. The diversity of variants in our sample reflects the ethnic heterogeneity of the Brazilian population.

A Rice PECTATE LYASE-LIKE Gene Is Required for Plant Growth and Leaf Senescence1[OPEN

PubMed Central

Leng, Yujia; Yang, Yaolong; Ren, Deyong; Dai, Liping; Wang, Yuqiong; Chen, Long; Tu, Zhengjun; Gao, Yihong; Zhu, Li; Hu, Jiang; Gao, Zhenyu; Guo, Longbiao; Lin, Yongjun

2017-01-01

To better understand the molecular mechanisms behind plant growth and leaf senescence in monocot plants, we identified a mutant exhibiting dwarfism and an early-senescence leaf phenotype, termed dwarf and early-senescence leaf1 (del1). Histological analysis showed that the abnormal growth was caused by a reduction in cell number. Further investigation revealed that the decline in cell number in del1 was affected by the cell cycle. Physiological analysis, transmission electron microscopy, and TUNEL assays showed that leaf senescence was triggered by the accumulation of reactive oxygen species. The DEL1 gene was cloned using a map-based approach. It was shown to encode a pectate lyase (PEL) precursor that contains a PelC domain. DEL1 contains all the conserved residues of PEL and has strong similarity with plant PelC. DEL1 is expressed in all tissues but predominantly in elongating tissues. Functional analysis revealed that mutation of DEL1 decreased the total PEL enzymatic activity, increased the degree of methylesterified homogalacturonan, and altered the cell wall composition and structure. In addition, transcriptome assay revealed that a set of cell wall function- and senescence-related gene expression was altered in del1 plants. Our research indicates that DEL1 is involved in both the maintenance of normal cell division and the induction of leaf senescence. These findings reveal a new molecular mechanism for plant growth and leaf senescence mediated by PECTATE LYASE-LIKE genes. PMID:28455404

Premature termination of SMARCB1 translation may be followed by reinitiation in schwannomatosis-associated schwannomas, but results in absence of SMARCB1 expression in rhabdoid tumors.

PubMed

Hulsebos, Theo J M; Kenter, Susan; Verhagen, Wim I M; Baas, Frank; Flucke, Uta; Wesseling, Pieter

2014-09-01

In schwannomatosis, germline SMARCB1 mutations predispose to the development of multiple schwannomas, but not vestibular schwannomas. Many of these are missense or splice-site mutations or in-frame deletions, which are presumed to result in the synthesis of altered SMARCB1 proteins. However, also nonsense and frameshift mutations, which are characteristic for rhabdoid tumors and are predicted to result in the absence of SMARCB1 protein via nonsense-mediated mRNA decay, have been reported in schwannomatosis patients. We investigated the consequences of four of the latter mutations, i.e. c.30delC, c.34C>T, c.38delA, and c.46A>T, all in SMARCB1-exon 1. We could demonstrate for the c.30delC and c.34C>T mutations that the respective mRNAs were still present in the schwannomas of the patients. We hypothesized that these were prevented from degradation by translation reinitiation at the AUG codon encoding methionine at position 27 of the SMARCB1 protein. To test this, we expressed the mutations in MON cells, rhabdoid cells without endogenous SMARCB1 protein, and found that all four resulted in synthesis of the N-terminally truncated protein. Mutation of the reinitiation methionine codon into a valine codon prevented synthesis of the truncated protein, thereby confirming its identity. Immunohistochemistry with a SMARCB1 antibody revealed a mosaic staining pattern in schwannomas of the patients with the c.30delC and c.34C>T mutations. Our findings support the concept that, in contrast to the complete absence of SMARCB1 expression in rhabdoid tumors, altered SMARCB1 proteins with modified activity and reduced (mosaic) expression are formed in the schwannomas of schwannomatosis patients with a germline SMARCB1 mutation.

Espectroscopia del Cometa Halley

NASA Astrophysics Data System (ADS)

Naranjo, O.; Fuenmayor, F.; Ferrin, L.; Bulka, P.; Mendoza, C.

1987-05-01

Se reportan observaciones espectroscópicas del cometa Halley. Los espectros fueron tomados usando el espectrógrafo del telescopio reflector de 1 metro del Observatorio Nacional de Venezuela. Se utilizó óptica azul, con una red de difracción de 600 lineas/min, obteniéndose una dispersión de 74.2 A/mm y una resolución de 2.5 A, en el rango espectral de 3500 a 6500 A. Seis placas fueron tomadas con emulsión IIa-O y dos con IIa-D. Los tiempos de exposición fueron entre 10 y 150 minutos. El cometa se encontraba entre 0.70 y 1.04 UA del Sol, y entre 1.28 y 0.73 UA de la Tierra. Las emisiones más prominentes en el espectro, son las del CN, C2, y C3. Otras emisiones detectadas corresponden a CH, NH2 y Na. Los espectros muestran un fuerte continuo, indicando un contenido significativo de polvo. Se detectó mayor intensidad del contínuo, en la dirección anti solar, lo cual es evidencia de la cola de polvo.

Moléculas orgánicas no-rígidas

NASA Astrophysics Data System (ADS)

Senent Díez, M. L.

Se destaca la importancia del estudio espectroscópico ab initio de una serie de moléculas no-rígidas detectadas en el medio interestelar (acetona, dimetil-eter, etanol, metanol, metilamina, ldots), así como los últimos avances del desarrollo de la metodología para el tratamiento teórico de estas especies. Se describe, a modo de ejemplo, el análisis del espectro roto-torsional de la molécula de glicoaldehido que ha sido recientemente detectada en el centro Galáctico Sagitario B2 (N) [1]. Esta especie presenta dos movimientos de gran amplitud que interaccionan, descansan en el Infrarrojo Lejano y le confiere propiedades no-rígidas. La molécula puede existir en posiciones cis y trans y presenta cinco confórmeros estables, tres de simetría Cs (I, II y IV) y un doble mínimo trans de simetría C1 (III) . La conformación favorita, I, presenta simetría Cs y se estabiliza por la formación de un puente de hidrógeno entre los grupos OH y C=O. Los mínimos secundarios II, III, y IV se han determinado a 1278.2 cm-1 (trans, Cs), 1298.8 cm-1 (trans, C1) y 1865.2 cm-1 (cis, Cs) con cálculos MP4/cc-pVQZ que incluyen sustituciones triples. Para determinar que vibraciones interaccionan con las torsiones, se ha realizado un análisis armónico en los mínimos. Las frecuencias fundamentales armónicas correspondientes al mínimo I se han calculado en 213.4 cm-1 (torsión C-C) y 425.7 cm-1 (torsión OH). Es de esperar que tan sólo dos vibraciones, la flexión del grupo C-C-O y el aleteo del hidrógeno del grupo aldehídico puedan desplazar el espectro torsional de la molécula aislada. Para determinar el espectro torsional, se ha determinado la superficie de potencial en dos dimensiones mediante el cálculo ab initio de las geometrías y energías de 74 conformaciones seleccionadas. Estas últimas se han ajustado a un doble serie de Fourier. A partir de la PES y de los parámetros cinéticos del Hamiltoniano vibracional se han obtenido frecuencias e intensidades. Las frecuencias fundamentales se han calculado en 208.0 cm-1 (torsión C-C) y 349.9 cm-1 (torsión OH). Se discute el método de cálculo que se ha empleado para la clasificación de los niveles. Los niveles rotacionales se han determinado empleando el método desarrollado para el estudio del ácido acético [2]. Se emplean la base de funciones rotacionales de [3]. A partir de los niveles se han determinado las constantes rotacionales y las constantes de distorsión centrífuga que se comparan con las experimentales de Herbst et al [3].

Desarrollo de un receptor polarimétrico en banda S para aplicación en estudios radioastronómicos

NASA Astrophysics Data System (ADS)

Barberis, C. M.; Bava, J. A.; Sanz, A. J.

Desde el punto de vista tecnológico, el objetivo principal de este proyecto es desarrollar un cabezal de receptor en la frecuencia de 3.3 GHz, con una temperatura del sistema de 60 K y un ancho de banda de 140 MHz. El mismo será instalado en el foco primario de un reflector parabólico de 30 metros de diámetro que funcionará como radiómetro en el IAR. El receptor es del tipo polarimétrico, con lo cual permite la posibilidad de obtener las componentes de polarización lineal y circular. Para tal fin el cabezal constará de dos ramas receptoras que amplificarán la señal y la trasladarán a una frecuencia menor, (frecuencia intermedia), permitiendo de esa forma un mejor transporte de la señal a la sala de control para su posterior procesamiento. El receptor, además de tener características polarimétricas, podrá ser usado en el contínuo y en la línea, utilizando las ventajas observacionales y de procesamiento de señal que actualmente posee el IAR.

Bifurcación de las soluciones de vientos impulsados por radiación en estrellas Be: formación de líneas

NASA Astrophysics Data System (ADS)

Curé, M.; Rial, D.; Cidale, L.; Venero, R.

Se ha estudiado la topología de la ecuación hidrodinámica no-lineal que describe el perfil de velocidades de vientos impulsados por radiación en estrellas tempranas. Al aplicar este modelo a estrellas Be se encuentra que existen dos tipos De soluciones: la estándar, que describe el viento polar, y una nueva, que describe un viento más denso y lento y que explicaría el disco que se encuentra alrededor de estos objetos. Existe una región de transición en donde ambas soluciones coexisten (bifurcación}). Ambas soluciones satisfacen en esta región las mismas condiciones de borde. Para estas dos soluciones se han obtenido los perfiles de líneas de hidrógeno del visible y del IR, resolviendo el transporte de radiación en el ``comoving frame". Para la solución estándar, se obtienen perfiles con componentes en emisión, mientras que para la nueva solución se obtienen perfiles en absorción. Se comparan cualitativamente los resultados con las observaciones.

Novel mutations of RPGR in Chinese retinitis pigmentosa patients and the genotype-phenotype correlation.

PubMed

Yang, Liping; Yin, Xiaobei; Feng, Lina; You, Debo; Wu, Lemeng; Chen, Ningning; Li, Aijun; Li, Genlin; Ma, Zhizhong

2014-01-01

X-linked Retinitis Pigmentosa (XLRP) accounts for 10-20% of all RP cases, and represents the most severe subtype of this disease. Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene are the most common causes of XLRP, accounting for over 70-75% of all XLRP cases. In this work, we analyzed all the exons of RPGR gene with Sanger sequencing in seven Chinese XLRP families, two of these with a provisional diagnosis of adRP but without male-to-male transmission. Three novel deletions (c.2233_34delAG; c.2236_37delGA and c.2403_04delAG) and two known nonsense mutations (c.851C→G and c.2260G→T) were identified in five families. Two novel deletions (c.2233_34delAG and c.2236_37delGA) resulted in the same frame shift (p.E746RfsX22), created similar phenotype in Family 3 and 4. The novel deletion (c.2403_04delAG; p.E802GfsX31) resulted in both XLRP and x-linked cone-rod dystrophy within the male patients of family 5, which suggested the presence of either genetic or environmental modifiers, or both, play a substantial role in disease expression. Genotype-phenotype correlation analysis suggested that (1) both patients and female carriers with mutation in Exon 8 (Family 1) manifest more severe disease than did those with ORF15 mutations (Family 2&3&4); (2) mutation close to downstream of ORF15 (Family 5) demonstrate the early preferential loss of cone function with moderate loss of rod function.

Molecular Scanning of β-Thalassemia in the Southern Region of Central Java, Indonesia; a Step Towards a Local Prevention Program.

PubMed

Rujito, Lantip; Basalamah, Muhammad; Mulatsih, Sri; Sofro, Abdul Salam M

2015-08-03

Thalassemia is the most prevalent genetic blood disorder worldwide, and particularly prevalent in Indonesia. The purpose of this study was to determine the spectrum of β-thalassemia (β-thal) mutations found in the southern region of Central Java, Indonesia. The subjects of the study included 209 β-thal Javanese patients from Banyumas Residency, a southwest region of Central Java Province. DNA analysis was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), amplification refractory mutation system (ARMS), and the direct sequencing method. The results showed that 14 alleles were found in the following order: IVS-I-5 (G > C) (HBB: c.92 + 5G > C) 43.5%, codon 26 (Hb E; HBB: c.79G > A) 28.2%, IVS-I-1 (G > A) (HBB: c.92 + 1G > A) 5.0%, codon 15 (TGG > TAG) (HBB: c.47G > A) 3.8%, IVS-I-1 (G > T) (HBB: c.92 + 1G > T) 3.1%, codon 35 (-C) (HBB: c.110delC) 2.4%. The rest, including codons 41/42 (-TTCT) (HBB: c.126_129delCTTT), codons 8/9 (+G) (HBB: c.27_28insG), codon 19 (AAC > AGC) (HBB: c.59A > G), codon 17 (AAG > TAG) (HBB: c.52A > T), IVS-I-2 (T > C) (HBB: c.92 + 2T > C), codons 123/124/125 (-ACCCCACC) (HBB: c.370_378delACCCCACCA), codon 40 (-G) (HBB: c.123delG) and Cap +1 (A > C) (HBB: c.-50A > C), accounted for up to 1.0% each. The most prevalent alleles would be recommended to be used as part of β-thal screening for the Javanese, one of the major ethnic groups in the country.

Molecular Scanning of β-Thalassemia in the Southern Region of Central Java, Indonesia; a Step Towards a Local Prevention Program.

PubMed

Rujito, Lantip; Basalamah, Muhammad; Mulatsih, Sri; Sofro, Abdul Salam M

2015-01-01

Thalassemia is the most prevalent genetic blood disorder worldwide, and particularly prevalent in Indonesia. The purpose of this study was to determine the spectrum of β-thalassemia (β-thal) mutations found in the southern region of Central Java, Indonesia. The subjects of the study included 209 β-thal Javanese patients from Banyumas Residency, a southwest region of Central Java Province. DNA analysis was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), amplification refractory mutation system (ARMS), and the direct sequencing method. The results showed that 14 alleles were found in the following order: IVS-I-5 (G > C) (HBB: c.92 + 5G > C) 43.5%, codon 26 (Hb E; HBB: c.79G > A) 28.2%, IVS-I-1 (G > A) (HBB: c.92 + 1G > A) 5.0%, codon 15 (TGG > TAG) (HBB: c.47G > A) 3.8%, IVS-I-1 (G > T) (HBB: c.92 + 1G > T) 3.1%, codon 35 (-C) (HBB: c.110delC) 2.4%. The rest, including codons 41/42 (-TTCT) (HBB: c.126_129delCTTT), codons 8/9 (+G) (HBB: c.27_28insG), codon 19 (AAC > AGC) (HBB: c.59A > G), codon 17 (AAG > TAG) (HBB: c.52A > T), IVS-I-2 (T > C) (HBB: c.92 + 2T > C), codons 123/124/125 (-ACCCCACC) (HBB: c.370_378delACCCCACCA), codon 40 (-G) (HBB: c.123delG) and Cap +1 (A > C) (HBB: c.-50A > C), accounted for up to 1.0% each. The most prevalent alleles would be recommended to be used as part of β-thal screening for the Javanese, one of the major ethnic groups in the country.

CHEK2 1100delC, IVS2+1G>A and I157T mutations are not present in colorectal cancer cases from Turkish population.

PubMed

Bayram, Süleyman; Topaktaş, Mehmet; Akkız, Hikmet; Bekar, Aynur; Akgöllü, Ersin

2012-10-01

The cell cycle checkpoint kinase 2 (CHEK2) protein participates in the DNA damage response in many cell types. Germline mutations in CHEK2 (1100delC, IVS2+1G>A and I157T) have been impaired serine/threonine kinase activity and associated with a range of cancer types. This hospital-based case-control study aimed to investigate whether CHEK2 1100delC, IVS2+1G>A and I157T mutations play an important role in the development of colorectal cancer (CRC) in Turkish population. A total of 210 CRC cases and 446 cancer-free controls were genotyped for CHEK2 mutations by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele specific-polymerase chain reaction (AS-PCR) methods. We did not find the CHEK2 1100delC, IVS2+1G>A and I157T mutations in any of the Turkish subjects. Our result demonstrate for the first time that CHEK2 1100delC, IVS2+1G>A and I157T mutations have not been agenetic susceptibility factor for CRC in the Turkish population. Overall, our data suggest that genotyping of CHEK2 mutations in clinical settings in the Turkish population should not be recommended. However, independent studies are need to validate our findings in a larger series, as well as in patients of different ethnic origins. Copyright © 2012 Elsevier Ltd. All rights reserved.

A Rice PECTATE LYASE-LIKE Gene Is Required for Plant Growth and Leaf Senescence.

PubMed

Leng, Yujia; Yang, Yaolong; Ren, Deyong; Huang, Lichao; Dai, Liping; Wang, Yuqiong; Chen, Long; Tu, Zhengjun; Gao, Yihong; Li, Xueyong; Zhu, Li; Hu, Jiang; Zhang, Guangheng; Gao, Zhenyu; Guo, Longbiao; Kong, Zhaosheng; Lin, Yongjun; Qian, Qian; Zeng, Dali

2017-06-01

To better understand the molecular mechanisms behind plant growth and leaf senescence in monocot plants, we identified a mutant exhibiting dwarfism and an early-senescence leaf phenotype, termed dwarf and early-senescence leaf1 ( del1 ). Histological analysis showed that the abnormal growth was caused by a reduction in cell number. Further investigation revealed that the decline in cell number in del1 was affected by the cell cycle. Physiological analysis, transmission electron microscopy, and TUNEL assays showed that leaf senescence was triggered by the accumulation of reactive oxygen species. The DEL1 gene was cloned using a map-based approach. It was shown to encode a pectate lyase (PEL) precursor that contains a PelC domain. DEL1 contains all the conserved residues of PEL and has strong similarity with plant PelC. DEL1 is expressed in all tissues but predominantly in elongating tissues. Functional analysis revealed that mutation of DEL1 decreased the total PEL enzymatic activity, increased the degree of methylesterified homogalacturonan, and altered the cell wall composition and structure. In addition, transcriptome assay revealed that a set of cell wall function- and senescence-related gene expression was altered in del1 plants. Our research indicates that DEL1 is involved in both the maintenance of normal cell division and the induction of leaf senescence. These findings reveal a new molecular mechanism for plant growth and leaf senescence mediated by PECTATE LYASE-LIKE genes. © 2017 American Society of Plant Biologists. All Rights Reserved.

Fragment analysis represents a suitable approach for the detection of hotspot c.7541_7542delCT NOTCH1 mutation in chronic lymphocytic leukemia.

PubMed

Vavrova, Eva; Kantorova, Barbara; Vonkova, Barbara; Kabathova, Jitka; Skuhrova-Francova, Hana; Diviskova, Eva; Letocha, Ondrej; Kotaskova, Jana; Brychtova, Yvona; Doubek, Michael; Mayer, Jiri; Pospisilova, Sarka

2017-09-01

The hotspot c.7541_7542delCT NOTCH1 mutation has been proven to have a negative clinical impact in chronic lymphocytic leukemia (CLL). However, an optimal method for its detection has not yet been specified. The aim of our study was to examine the presence of the NOTCH1 mutation in CLL using three commonly used molecular methods. Sanger sequencing, fragment analysis and allele-specific PCR were compared in the detection of the c.7541_7542delCT NOTCH1 mutation in 201 CLL patients. In 7 patients with inconclusive mutational analysis results, the presence of the NOTCH1 mutation was also confirmed using ultra-deep next generation sequencing. The NOTCH1 mutation was detected in 15% (30/201) of examined patients. Only fragment analysis was able to identify all 30 NOTCH1-mutated patients. Sanger sequencing and allele-specific PCR showed a lower detection efficiency, determining 93% (28/30) and 80% (24/30) of the present NOTCH1 mutations, respectively. Considering these three most commonly used methodologies for c.7541_7542delCT NOTCH1 mutation screening in CLL, we defined fragment analysis as the most suitable approach for detecting the hotspot NOTCH1 mutation. Copyright © 2017 Elsevier Ltd. All rights reserved.

The Frequency of c.550delA Mutation of the CANP3 Gene in the Polish LGMD2A Population.

PubMed

Dorobek, Małgorzata; Ryniewicz, Barbara; Kabzińska, Dagmara; Fidziańska, Anna; Styczyńska, Maria; Hausmanowa-Petrusewicz, Irena

2015-11-01

Limb girdle muscular dystrophy 2A (LGMD2A) is the most frequent LGMD variant in the European population, representing about 40% of LGMD. The c.550delA mutation in the CANP3 (calcium activated neutral protease 3) gene is the most commonly reported mutation in LGMD2A. Prevalence of this mutation in the Polish population has not been previously investigated. The aim of this study was to identify and estimate the frequency of the c.550delA mutation in Polish LGMD2A patients. Polymerase chain reaction-sequencing analysis, restriction fragment length polymorphism polymerase chain reaction method. We analyzed 76 families affected with LGMD and identified 62 probands with mutations in the CANP3 gene. C.550delA was the most common mutation identified, being found in 78% of the LGMD2A families. The remaining mutations observed multiple times were as follows: c.598-612del15ntd; c.2242C>T; c.418dupC; c.1356insT, listed in terms of decreasing frequency. Two novel variants in the CANP3 gene, that is, c.700G>A Gly234Arg and c.661G>A Gly221Ser were also characterized. Overall, mutations in the LGMD2A gene were estimated to be present in 81% of patients with the LGMD phenotype who were without sarcoglycans and dysferlin deficiency on immunocytochemical analysis. The frequency of the heterozygous c.550delA mutation in the healthy Polish population was estimated at 1/124. The c.550delA is the most frequent CANP3 mutation in the Polish population, thus sequencing of exon 4 of this gene could identify the majority of LGMD2A patients in Poland.

Wide allelic heterogeneity with predominance of large IDS gene complex rearrangements in a sample of Mexican patients with Hunter syndrome.

PubMed

Alcántara-Ortigoza, M A; García-de Teresa, B; González-Del Angel, A; Berumen, J; Guardado-Estrada, M; Fernández-Hernández, L; Navarrete-Martínez, J I; Maza-Morales, M; Rius-Domínguez, R

2016-05-01

Hunter syndrome or mucopolysaccharidosis type II (MPSII) is caused by pathogenic variants in the IDS gene. This is the first study that examines the mutational spectrum in 25 unrelated Mexican MPSII families. The responsible genotype was identified in 96% of the families (24/25) with 10 novel pathogenic variants: c.133G>C, c.1003C>T, c.1025A>C, c.463_464delinsCCGTATAGCTGG, c.754_767del, c.1132_1133del, c.1463del, c.508-1G>C, c.1006+1G>T and c.(-217_103del). Extensive IDS gene deletions were identified in four patients; using DNA microarray analysis two patients showed the loss of the entire AFF2 gene, and epilepsy developed in only one of them. Wide allelic heterogeneity was noted, with large gene alterations (e.g. IDS/IDSP1 gene inversions, partial to extensive IDS deletions, and one chimeric IDS-IDSP1 allele) that occurred at higher frequencies than previously reported (36% vs 18.9-29%). The frequency of carrier mothers (80%) is consistent with previous descriptions (>70%). Carrier assignment allowed molecular prenatal diagnoses. Notably, somatic and germline mosaicism was identified in one family, and two patients presented thrombocytopenic purpura and pancytopenia after idursulfase enzyme replacement treatment. Our findings suggest a wide allelic heterogeneity in Mexican MPSII patients; DNA microarray analysis contributes to further delineation of the resulting phenotype for IDS and neighboring loci deletions. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Lack of effect of the alpha2C-adrenoceptor Del322-325 polymorphism on inhibition of cyclic AMP production in HEK293 cells.

PubMed

Montgomery, M D; Bylund, D B

2010-02-01

The alpha(2C)-adrenoceptor has multiple functions, including inhibiting release of noradrenaline from presynaptic nerve terminals. A human alpha(2C) polymorphism, Del322-325, a potential risk factor for heart failure, has been reported to exhibit reduced signalling in CHO cells. To further understand the role of the Del322-325 polymorphism on receptor signalling, we attempted to replicate and further study the reduced signalling in HEK293 cells. Human alpha(2C) wild-type (WT) and Del322-325 adrenoceptors were stably transfected into HEK293 cells. Radioligand binding was performed to determine affinities for both receptors. In intact cells, inhibition of forskolin-stimulated cyclic AMP production by WT and Del322-325 clones with a range of receptor densities (200-2320 fmol.mg(-1) protein) was measured following agonist treatment. Noradrenaline, brimonidine and clonidine exhibited similar binding affinities for WT and Del322-325. Brimonidine and clonidine also had similar efficacies and potencies for both receptors for the inhibition of cyclic AMP production at all receptor densities tested. A linear regression analysis comparing efficacy and potency with receptor expression levels showed no differences in slopes between WT and Del322-325. The alpha(2C) WT and Del322-325 adrenoceptors exhibited similar binding properties. Additionally, inhibition of cyclic AMP production by Del322-325 was similar to that of WT over a range of receptor densities. Therefore, in intact HEK293 cells, the alpha(2C)-Del322-325 polymorphism does not exhibit reduced signalling to adenylyl cyclase and may not represent a clinically important phenotype.

[Value of pre-gestational deafness-related mutation screening for the prevention and intervention of congenital deafness].

PubMed

Sun, Xuejing; Xing, Xinli; He, Qingqing; Zhou, Lin; Zhang, Jing; Zhao, Qing; Hou, Huili; Xi, Zuoming

2017-10-10

To assess the value of pre-gestational deafness-related mutation screening for the prevention and intervention of congenital deafness. In this study, 2168 couples with normal hearing were screened for common mutations associated with congenital deafness using real-time fluorescence quantitative PCR. The mutations have included GJB2 c.235delC and c.299_300delAT, SLC26A4 c.2168A>G and c.IVS7-2A>G, and mtDNA 12SrRNA c.1494C>T and c.1555A>G. For couples who have both carried heterozygous mutations of the same gene, genetic counseling and prenatal diagnosis were provided. Among of the 4 336 individuals, 178 (4.06%) were found to carry a mutation. Mutation rate for c.235delC and c.299_300delAT of GJB2 gene, c.IVS7-2 A>G and c.2168 A>G of SLC26A4 gene, c.1555 A>G and c.1494 C>T of DNA 12S rRNA gene were 0.91%, 0.20%, 0.68%, 0.11%, 0.1% and 0.01%, respectively. For six couples who have both carried mutations of the same gene, all fetuses showed a normal karyotype, while DNA sequencing indicated that two fetuses have carried homozygous c.235delC mutation of the GJB2 gene, one carried a heterozygous c.235delC mutation of the GJB2 gene, one carried heterozygous mutation of GJB2 gene (c.299_300delAT), and two have carried a heterozygous mutation of c.IVS7-2A>G of the SLC26A4 gene. Pre-gestational screening for deafness gene mutation can facilitate avoidance the birth of affected children and has a great clinical value for the prevention and intervention of birth defect.

PubMed

Oliver Bonet, Maria; Mach, Núria

2016-09-20

Introducción: la infertilidad es un problema global en aumento. Se estima que aproximadamente un 15% de las parejas en edad reproductiva tiene dificultades a la hora de concebir. De estas, alrededor de la mitad presentan uno o varios factores masculinos asociados a infertilidad o subfertilidad, aislados o en combinación con problemas de origen femenino. Durante la última década se ha empezado a estudiar la infertilidad desde una perspectiva multifactorial, considerando las interacciones y conexiones entre diferentes situaciones genéticas, epigenéticas, bioquímicas y fisiológicas del paciente.Objetivo: la presente revisión pretende describir mecanismos epigenéticos que pueden ser modulados mediante aspectos nutricionales y que están relacionados con la etiología de la infertilidad masculina y con la herencia transgeneracional de este fenotipo.Material y métodos: se ha realizado una extensa búsqueda de publicaciones científicas en las principales bases de datos electrónicas especializadas: NBCI, Elsevier, Scielo, Scirus y Science Direct.Resultados y conclusión: varios trabajos que muestran la importancia del estado nutricional en la fertilidad del hombre y, más específicamente, la capacidad de los componentes de la dieta para modificar los perfiles epigenéticos que no únicamente pueden afectar a su fertilidad, sino que también pueden ser transmitidos a la descendencia mediante lo que se ha denominado herencia transgeneracional, ocasionándoles problemas de salud diversos entre los que también se hallan problemas en la fertilidad.

Influencia atmosférica en la rotación terrestre

NASA Astrophysics Data System (ADS)

Fernández, L. I.; Arias, E. F.; Brunini, C. A.

Las observaciones de los parámetros de la orientación terrestre han alcanzado en estos últimos años una exactitud sin precedentes gracias al uso de modernas técnicas de geodesia espacial. Estudios previos han establecido que las variaciones en la rotación terrestre con períodos iguales o menores que dos años obedecen a cambios en la circulación atmosférica global. Para estos períodos puede comprobarse que existe un gran acuerdo entre las fluctuaciones de la longitud del día (LOD) y los cambios del momento angular atmosférico terrestre (AAM). Sin embargo, no existe un acuerdo general acerca de las causas que provocan las variaciones de largo período de la rotación de la Tierra, también conocidas como ``variaciones decenales''. En nuestro análisis examinamos las correlaciones entre las variaciones de los valores de LOD y las fluctuaciones en la componente polar del momento angular atmosférico terrestre. Con este propósito utilizamos los siguientes juegos de datos: las series de AAM, estimado siguiendo la definición de Barnes et al.(1983) para 2825 días provientes del National Meteorological Center (NMC) y del European Centre for Medium Range Weather Forecast (ECMWF); y las series de LOD que contienen valores alisados espaciados a intervalos de un día elaborados por el International Earth Rotation Service (IERS). Mostraremos que para los cambios anuales e interanuales en la rotación de la Tierra la influencia atmosférica es asombrosa, mientras que, tanto en las escalas temporales más grandes y como en las más pequeñas, ambas series, geodésica y atmosférica, parecen diverger aún cuando poseemos observaciones obtenidas con las técnicas más modernas al presente.

Plasma Total Antioxidant Capacity and Cardiometabolic Risk in Non-Obese and Clinically Healthy Young Adults.

PubMed

Costa, Jamille Oliveira; Vásquez, Cecília M Passos; Santana, Gleiciane de Jesus; Silva, Natanael de Jesus; Braz, Juciene de Matos; Jesus, Amélia M Ribeiro de; Silva, Danielle Góes da; Cunha, Luana Celina Seraphim; Barbosa, Kiriaque Barra Ferreira

2017-07-10

The oxidative biomarkers play an important role in the genesis of cardiometabolic risk-related processes. To investigate the total antioxidant capacity of plasma and its association with cardiometabolic risk in non-obese and clinically healthy young adults. University students of the state of Sergipe, Brazil, aged between 18 and 25 years, were recruited for this study from May of 2013 and October of 2014. Anthropometric, clinical and biochemical parameters were measured and analyzed using protocols which were previously standardized and described in the literature. The measurement of plasma total antioxidant capacity was based on the ability that all the antioxidants present in the sample (plasma) have to inhibit the oxidation of the oxidizable substrate ABTS (2,2`- Azino-di-[3-ethylbenzthiazoline sulphonate]) to ABTS•+ by metmyoglobin. Approximately 25% of the sample presented more than one component of cardiometabolic risk. Low HDL-cholesterol was the most prevalent component. Compared to absence of components, the subjects with at least one component presented greater body weight and waist circumference, higher levels of diastolic blood pressure and fasting glucose, greater total cholesterol/HDL-c ratio, and lower levels of HDL-c (p < 0.05). Fasting glycemia was the only parameter which was associated with total antioxidant capacity (R2 = 0.10; β = 0.17; p = 0.001). The plasma total antioxidant capacity was not able to predict the cardiometabolic risk components due possibly to the establishment of compensatory mechanisms that become activated in physiological conditions. Os biomarcadores oxidativos exercem um importante papel na gênese dos processos relacionados ao risco cardiometabólico. Investigar a capacidade antioxidante total do plasma e sua associação com risco cardiometabólico em adultos jovens, não obesos e clinicamente saudáveis. Estudantes universitários do estado de Sergipe, Brasil, com idade entre 18 e 25 anos, foram recrutados entre maio de 2013 e outubro de 2014. Parâmetros antropométricos, clínicos e bioquímicos foram medidos e analisados usando protocolos previamente padronizados e descritos na literatura. A medida da capacidade antioxidante total do plasma baseou-se na capacidade de todos os antioxidantes presentes na amostra (plasma) em inibir a oxidação do substrato oxidável ABTS (2,2-Azino-bis-(3-etilbenzotiazolina-6-sulfonato) a ABTS•+ pela metamioglobina. Aproximadamente 25% da amostra apresentaram mais de um componente do risco cardiometabólico. Valores baixos de HDL foram o componente mais prevalente. Em comparação à ausência de componentes, os indivíduos com pelo menos um componente apresentou valores mais altos de peso corporal, circunferência da cintura, pressão sanguínea diastólica, glicemia de jejum e razão colesterol total/HDL-c, e valores mais baixos de HDL-c (p < 0,05). A glicemia de jejum foi o único parâmetro que se associou com a capacidade antioxidante total (R2 = 0,10; β = 0,17; p = 0,001). A capacidade antioxidante total não foi capaz de predizer os componentes do risco cardiometabólico possivelmente devido ao estabelecimento de mecanismos compensatórios que se tornam ativados em condições fisiológicas.

Field measurements of del13C in ecosystem respiration

NASA Astrophysics Data System (ADS)

van Asperen, Hella; Sabbatini, Simone; Nicolini, Giacomo; Warneke, Thorsten; Papale, Dario; Notholt, Justus

2014-05-01

Stable carbon isotope del13C-measurements are extensively used to study ecological and biogeochemical processes in ecosystems. Above terrestrial ecosystems, atmospheric del13C can vary largely due to photosynthetic fractionation. Photosynthetic processes prefer the uptake of the lighter isotope 12C (in CO2), thereby enriching the atmosphere in 13C and depleting the ecosystem carbon. At night, when ecosystem respiratory fluxes are dominant, 13C-depleted CO2 is respired and thereby depletes the atmospheric del13C-content. Different ecosystems and different parts of one ecosystem (type of plant, leaves, and roots) fractionate and respire with a different del13C-ratio signature. By determining the del13C-signature of ecosystem respiration in temporal and spatial scale, an analysis can be made of the composition of respiratory sources of the ecosystem. A field study at a dry cropland after harvest (province of Viterbo, Lazio, Italy) was performed in the summer of 2013. A FTIR (Fourier Transform Infrared Spectrometer) was set up to continuously measure CO2-, CH4-, N2O-, CO- and del13C-concentrations. The FTIR was connected to 2 different flux measurements systems: a Flux Gradient system (sampling every half hour at 1.3m and 4.2m) and 2 flux chambers (measured every hour), providing a continuous data set of the biosphere-atmosphere gas fluxes and of the gas concentrations at different heights. Keeling plot intercept values of respiratory CO2, measured by the Flux Gradient system at night, were determined to be between -25‰ and -20‰. Keeling plot intercept values of respiratory CO2, measured by the flux chamber system, varied between -24‰ and -29‰, and showed a clear diurnal pattern, suggesting different (dominant) respiratory processes between day and night.

Study of Aerospace Materials, Coatings, Adhesions and Processes. Aircraft Icing Processes. Volume 2.

DTIC Science & Technology

1984-09-14

la direccio’n del eje de la son - da. DATOS ELECTRICOS Rint’erna 20.26 . R(OC) =5.35 Q R(22 0 C).. 5.93 Q R(100 0 C) 7.43 . Roperacio’n... son las constantes de calibraci6n propias del sensor. 1INT A FN. de Informe I-231/S10/84.076Pg. . La temperatura de funcionamiento se deterrnin6 por l...funcionamiento del sensor, T la temperatura ambiente, la densidad y v la velocidad. A, B y n son las constantes de cal- z braci6n propias del

Is the algorithm used to process heart rate variability data clinically relevant? Analysis in male adolescents.

PubMed

Soares, Antonio Henrique Germano; Farah, Breno Quintella; Cucato, Gabriel Grizzo; Bastos-Filho, Carmelo José Albanez; Christofaro, Diego Giulliano Destro; Vanderlei, Luiz Carlos Marques; Lima, Aluísio Henrique Rodrigues de Andrade; Ritti-Dias, Raphael Mendes

2016-01-01

To analyze whether the algorithm used for the heart rate variability assessment (fast Fourier transform versus autoregressive methods) influenced its association with cardiovascular risk factors in male adolescents. This cross-sectional study included 1,152 male adolescents (aged 14 to 19 years). The low frequency, high frequency components (absolute numbers and normalized units), low frequency/high frequency ratio, and total power of heart rate variability parameters were obtained using the fast Fourier transform and autoregressive methods, while the adolescents were resting in a supine position. All heart rate variability parameters calculated from both methods were different (p<0.05). However, a low effect size (<0.1) was found for all parameters. The intra-class correlation between methods ranged from 0.96 to 0.99, whereas the variation coefficient ranged from 7.4 to 14.8%. Furthermore, waist circumference was negatively associated with high frequency, and positively associated with low frequency and sympatovagal balance (p<0.001 for both fast Fourier transform and autoregressive methods in all associations). Systolic blood pressure was negatively associated with total power and high frequency, whereas it was positively associated with low frequency and sympatovagal balance (p<0.001 for both fast Fourier transform and autoregressive methods in all associations). Body mass index was negatively associated with high frequency, while it was positively associated with low frequency and sympatovagal balance (p values ranged from <0.001 to 0.007). There are significant differences in heart rate variability parameters obtained with the fast Fourier transform and autoregressive methods in male adolescent; however, these differences are not clinically significant. Analisar se o algoritmo usado para avaliação da variabilidade da frequência cardíaca (transformada rápida de Fourier versus autoregressivo) influencia em sua associação com fatores de risco cardiovascular adolescentes do gênero masculino. Estudo transversal, que incluiu 1.152 adolescentes do gênero masculino (14 a 19 anos). Componentes de baixa e alta frequência (absolutos e unidades normalizadas), razão componente de baixa frequência/componente de alta frequência e poder total da variabilidade da frequência cardíaca foram obtidos em repouso, na posição supina, usando os métodos transformada rápida de Fourier e autorregressivo. Todos os parâmetros da variabilidade da frequência cardíaca para ambos os métodos foram diferentes (p<0,05). Entretanto, um pequeno tamanho do efeito (<0,1) foi observado para todos os parâmetros. Os coeficientes de correlação intraclasse entre os métodos variaram de 0,96 a 0,99, enquanto os coeficientes de variação foram de 7,4 a 14,8%. A circunferência abdominal foi negativamente associada com o componente de alta frequência, e positivamente associada com o componente de baixa frequência e o balanço simpatovagal (p<0,001 para a transformada rápida de Fourier e o autorregressivo em todas as associações). A pressão arterial sistólica foi negativamente associada com o poder total e o componente de alta frequência, enquanto foi positivamente associada com o componente de baixa frequência e o balanço simpatovagal (p<0,001 para a transformada rápida de Fourier e o autorregressivo em todas as associações). O índice de massa corporal foi negativamente associado com o componente de alta frequência, enquanto foi positivamente associado com o componente de baixa frequência e o balanço simpatovagal (valores de p variando de <0,001 a 0,007). Houve diferenças significantes nos parâmetros da variabilidade da frequência cardíaca obtidos com os métodos transformada rápida de Fourier e autorregressivo em adolescentes masculinos, mas essas diferenças não foram clinicamente significativas.

CHEK2*1100delC homozygosity is associated with a high breast cancer risk in women.

PubMed

Adank, Muriel A; Jonker, Marianne A; Kluijt, Irma; van Mil, Saskia E; Oldenburg, Rogier A; Mooi, Wolter J; Hogervorst, Frans B L; van den Ouweland, Ans M W; Gille, Johan J P; Schmidt, Marjanka K; van der Vaart, Aad W; Meijers-Heijboer, Hanne; Waisfisz, Quinten

2011-12-01

Mutations in the CHEK2 gene confer a moderately increased breast cancer risk. The risk for female carriers of the CHEK2*1100delC mutation is twofold increased. Breast cancer risk for carrier women is higher in a familial breast cancer setting which is due to coinheritance of additional genetic risk factors. This study investigated the occurrence of homozygosity for the CHEK2*1100delC allele among familial breast cancer cases and the associated breast cancer risk. Homozygosity for the CHEK2*1100delC allele was identified in 8/2554 Dutch independent familial non-BRCA1/2 breast cancer cases. The genotype relative risk for breast cancer of homozygous and heterozygous familial breast cancer cases was 101.34 (95% CI 4.47 to 121 000) and 4.04 (95% CI 0.88 to 21.0), respectively. Female homozygotes appeared to have a greater than twofold increased breast cancer risk compared to familial CHEK2*1100delC heterozygotes (p=0.044). These results and the occurrence of multiple primary tumours in 7/10 homozygotes indicate a high cancer risk in homozygous women from non-BRCA1/2 families. Intensive breast surveillance is therefore justified in these homozygous women. It is concluded that diagnostic testing for biallelic mutations in CHEK2 is indicated in non-BRCA1/2 breast cancer families, especially in populations with a relatively high prevalence of deleterious mutations in CHEK2.

Motivational beliefs, cognitive engagement, and achievement in language and mathematics in elementary school children.

PubMed

Metallidou, Panagiota; Vlachou, Anastasia

2007-02-01

The contextual differences in the patterns of relations among various motivational, cognitive, and metacognitive components of self-regulated learning and performance in two key curriculum subject areas, language and mathematics, were examined in a sample of 263 Greek primary school children of fifth- and sixth-grade classrooms. Age and gender differences were also investigated. Students were asked to complete the Motivated Strategies for Learning Questionnaire (Pintrich & De Groot, 1990 ), which comprised five factors: (a) Self-efficacy, (b) Intrinsic Value, (c) Test Anxiety, (d) Cognitive Strategy Use, and (e) Self-regulation Strategies. They responded to the statements of the questionnaire on a 7-point Likert scale in terms of their behaviour in mathematics and language classes, respectively. Moreover, their teachers were asked to evaluate each of their students' academic achievement in Greek language and mathematics on a 1- to 20-point comparative scale in relation to the rest of the class. The results of the study indicated very few differences in the pattern of relations among self-regulated components within and across the two subject areas and at the same time revealed a context-specific character of self-regulated components at a mean level differences. Further, the current study (a) confirmed the mediatory role of strategies in the motivation-performance relation, (b) stressed the differential role of cognitive and regulatory strategies in predicting performance in subject areas that differ in their structural characteristics of the content, and (c) pointed out the key motivational role of self-efficacy. In fact, self-efficacy proved the most significant predictor not only of performance but of cognitive and regulatory strategy use as well. Gender differences in motivation and strategy use were not reported, while motivation was found to vary mainly with age. The usefulness of these findings for promoting greater clarity among motivational and metacognitive frameworks and ideas for future research are discussed. Cette étude porte sur les différences contextuelles dans les patrons relationnels entre les diverses composantes motivationnelle, cognitive et métacognitive de l'apprentissage et de la performance auto-régulés dans deux domaines d'étude clé du programme, soit la langue et les mathématiques. Ces différences contextuelles ont été examinées dans un échantillon de 263 d'enfants d'une école primaire grecque (of) en cinquième et sixième année. Les différences sexuelles et les différences d'âge ont été aussi étudiées. Les élèves ont été priés de compléter le «Motivated Strategies for Learning Questionnaire» (Pintrich & De Groot, 1990 ) qui comprend cinq facteurs: (a) l'auto-efficacité, (b) la valeur intrinsèque, (c) un test d'anxiété, (d) l'utilisation d'une stratégie cognitive et (e) les stratégies d'auto-régulation. Ils ont répondu aux énoncés du questionnaire sur une échelle de type Likert à 7 points en termes de leur comportement en classe de langue et en classe de mathématiques séparément. De plus, les enseignants ont été priés d'évaluer chaque résultat de leurs élèves dans la langue grecque et en mathématique sur une échelle allant de 1 à 20 points en comparaison au reste de la classe. Les résultats de l'étude ont indiqué très peu de différences dans les patrons relationnels entre les composantes auto-régulées à l'intérieur et entre les domaines d'étude. En même temps, les résultats ont révélé un caractère contextuel spécifique des composantes auto-regulées. De plus, la présente étude (a) a confirmé le rôle médiateur des stratégies dans la relation motivation-performance, (b) a souligné le rôle différé des stratégies cognitive et régulatoire dans la prédiction de la performance dans les domaines d'étude qui diffèrent dans leurs caractéristiques structurelles du contenu et (c) a souligné le rôle motivationnel clé de l'auto-efficacité. En effet, l'auto-efficacité s'est avérée être le prédicteur le plus significatif non seulement de la performance mais aussi de l'utilisation d'une stratégie cognitive et régulatoire. Des différences sexuelles dans la motivation et dans l'utilisation d'une stratégie n'ont pas été rapportées alors qu'il s'est avéré que la motivation variait principalement en fonction de l'âge. L'utilité de ces résultats pour la promotion d'une grande clarté entre les cadres motivationnel et métacognitif et les idées pour les études futures sont discutées. Se examinó, en una muestra de 263 niños griegos de quinto y sexto años de la escuela primaria, las diferencias contextuales en las pautas con las que se dan las relaciones entre varios componentes motivacionales, cognitivos y meta cognitivos del aprendizaje autorregulado y el desempeño en dos áreas clave del currículo, lenguaje y matemáticas. También se investigó las diferencias de edad y género. Se pidió a los alumnos que respondieran el Cuestionario de Estrategias Motivadas para el Aprendizaje (Pintrich & De Groot, 1990 ), compuesto por cinco factores: (a) Auto eficacia, (b) Valor Intrínseco, (c) Ansiedad ante los Exámenes, (d) Empleo de Estrategias Cognitivas, y (e) Estrategias Autorreguladas. Respondieron a los enunciados del cuestionario sobre una escala Likert de 7 puntos en términos de su conducta en las clases de matemáticas y lenguaje por separado. Es más, se pidió a sus profesores que evaluaran el desempeño de cada uno de sus estudiantes en Lenguaje Griego y Matemáticas de acuerdo con una escala comparativa de 1 a 20 puntos, en relación con el resto del grupo escolar. Los resultados del estudio indicaron pocas diferencias en la pauta que describen las relaciones entre los componentes de autorregulación al interior de y entre ambas áreas de estudio y, al mismo tiempo, revelaron un carácter específico del contexto de los componentes de la autorregulación con diferencias en el nivel medio. Más aún, el presente estudio (a) confirmó el papel de mediador que desempeñan las estrategias sobre la relación motivación-desempeño, (b) acentuó el papel diferencial de las estrategias cognitiva y reguladora al predecir el desempeño en áreas de estudio que difieren en las características estructurales de su contenido, y (c) señaló el papel motivacional clave que desempeña la auto eficacia. De hecho, la auto eficacia predijo de manera más significativa no sólo el desempeño, sino también el uso de la estrategia cognitiva y reguladora. No hubo diferencias de género respecto a la motivación y al uso de la estrategia, aunque se encontró que la motivación varía principalmente con la edad. Se discute la utilidad de estos hallazgos para aclarar los referentes motivacionales y meta cognitivos y promover ideas para investigaciones futuras.

Effective Universal Coverage of Diabetes Mellitus Type 2 in Chile.

PubMed

Guerrero-Núñez, Sara; Valenzuela-Suazo, Sandra; Cid-Henríquez, Patricia

2017-04-06

determine the prevalence of Effective Universal Coverage of Diabetes Mellitus Type 2 in Chile and its relation with the variables: Health Care Coverage of Diabetes Mellitus Type 2; Average of diabetics with metabolic control in 2011-2013; Mortality Rate for Diabetes Mellitus; and Percentage of nurses participating in the Cardiovascular Health Program. cross-sectional descriptive study with ecological components that uses documentary sources of the Ministry of Health. It was established that there is correlation between the Universal Effective Coverage of Diabetes Mellitus Type 2 and the independent variables; it was applied the Pearson Coefficient, being significant at the 0.05 level. in Chile Universal Health Care Coverage of Diabetes Mellitus Type 2 (HbA1c<7% estimated population) is less than 20%; this is related with Mortality Rate for Diabetes Mellitus and Percentage of nurses participating in the Cardiovascular Health Program, being significant at the 0.01 level. effective prevalence of Universal Health Coverage of Diabetes Mellitus Type 2 is low, even though some regions stand out in this research and in the metabolic control of patients who participate in health control program; its relation with percentage of nurses participating in the Cardiovascular Health Program represents a challenge and an opportunity for the health system. determinar a prevalência de Cobertura Universal Efetiva da Diabetes Mellitus tipo 2 em Chile e sua relação com as variáveis; Cobertura da Diabetes Mellitus tipo 2, Média de diabéticos com controle metabólico em 2011-2013, Taxa de Mortalidade por Diabetes Mellitus e Percentagem de participação de enfermeiras no Programa de Saúde Cardiovascular. estudo descritivo transversal com componentes ecológicos, utilizando fontes documentais do Ministério da Saúde. Foi estabelecida correlação entre Cobertura Universal Efetiva da Diabetes Mellitus tipo 2 e as variáveis independentes, aplicando o Coeficiente de Pearson, sendo significante ao 0,05. no Chile a Cobertura Universal Efetiva da Diabetes Mellitus tipo 2 (HbA1c<7% em população estimada) é menor que 20%. Esta se relaciona com uma Taxa de Mortalidade por Diabetes Mellitus e Percentagem de participação de enfermeiras no Programa de Saúde Cardiovascular, que ademais é significativa ao 0,01. a prevalência de Cobertura Universal Efetiva da Diabetes Mellitus tipo 2 é baixa, mesmo quando algumas regiões se destacam nas pesquisas e no controle metabólico de pacientes assistentes ao controle. Sua relação com a Percentagem de participação de enfermeiras no Programa de Saúde Cardiovascular se constitui em um desafio e oportunidade em saúde. determinar la prevalencia de la Cobertura Universal Efectiva de la diabetes mellitus tipo 2 en Chile y su relación con las variables: Cobertura de Diabetes Mellitus tipo 2, Promedio de diabéticos con control metabólico en 2011-2013, Tasa de Mortalidad por Diabetes Mellitus y Porcentaje de participación de enfermeros en el Programa de Salud Cardiovascular. estudio descriptivo transversal con componentes ecológicos, utilizando fuentes documentales del Ministerio de Salud. Se estableció que existe correlación entre la Cobertura Universal Efectiva de la Diabetes Mellitus tipo 2 y las variables independientes, aplicando el Coeficiente de Pearson, siendo significativa al nivel 0,05. en Chile la Cobertura Universal Efectiva de Diabetes Mellitus tipo 2 (HbA1c<7% en población estimada) es menor que 20%; esta se relaciona con la Tasa de Mortalidad por Diabetes Mellitus y con el Porcentaje de participación de enfermeras en el Programa de Salud Cardiovascular, que es significativa al nivel 0,01. la prevalencia de Cobertura Universal Efectiva de la Diabetes Mellitus tipo 2 es baja; sin embargo algunas regiones se destacan en la cobertura y en el control metabólico de pacientes que participan del control de salud. La relación de la cobertura con el porcentaje de participación de enfermeras en el Programa de Salud Cardiovascular es un desafío y una oportunidad en salud.

Frequency of the CHEK2 1100delC mutation among women with breast cancer: an international study.

PubMed

Zhang, Shiyu; Phelan, Catherine M; Zhang, Phil; Rousseau, Francois; Ghadirian, Parviz; Robidoux, Andre; Foulkes, William; Hamel, Nancy; McCready, David; Trudeau, Maureen; Lynch, Henry; Horsman, Douglas; De Matsuda, Maria Lourdes Leon; Aziz, Zeba; Gomes, Magda; Costa, Mauricio Magalhaes; Liede, Alexander; Poll, Aletta; Sun, Ping; Narod, Steven A

2008-04-01

A founder allele in the CHEK2 gene (1100delC) has been associated with an elevated risk of breast cancer. This allele is responsible for the majority of CHEK2-associated breast cancers in women from northern European countries; however, within Europe, it seems to be rare in countries that are close to the Mediterranean. The frequency of the 1100delC allele has not been measured in non-White populations. We measured the frequency of the CHEK2 founder allele in 3,882 breast cancer patients and 8,609 controls from various countries. The allele was not seen among Asian patients (from Pakistan or the Philippines) and was present in 1 of 155 cases from Brazil. Among White women, the allele was present in 1.5% of 825 familial cases of breast cancer and in 0.7% of 1,106 patients with nonfamilial breast cancer. The allele was equally frequent in Jewish and non-Jewish patients. We estimate that the CHEK2 1100delC allele is associated with an odds ratio of 2.6 for breast cancer, which corresponds to a lifetime risk of approximately 24% in Ontario.

Mutation analysis of 12 genes in Chinese families with congenital cataracts

PubMed Central

Sun, Wenmin; Xiao, Xueshan; Li, Shiqiang; Guo, Xiangming

2011-01-01

Purpose To identify mutations in 12 genes in Chinese families with congenital cataracts. Methods Twenty five families with congenital cataracts involved in this study. The coding exons and adjacent intronic regions of 12 genes were analyzed by cycle sequencing, including the alpha A crystallin (CRYAA), alpha B crystallin (CRYAB), beta A1 crystallin (CRYBA1), beta A4 crystallin (CRYBA4), beta B1 crystallin (CRYBB1), beta B2 crystallin (CRYBB2), beta B3 crystallin (CRYBB3), gamma C crystallin (CRYGC), gamma D crystallin (CRYGD), gamma S crystallin (CRYGS), alpha 3 gap junction protein (GJA3), and alpha 8 gap junction protein (GJA8) genes. Novel variants were further evaluated in 96 normal controls. Results Nine mutations were identified in 10 of the 25 families (40%), including 5 novel (c.350_352delGCT in CRYAA, c.205C>T in CRYAB, c.106G>C in CRYGD, c.77A>G in CRYGS, c.1143_1165del23 in GJA3) and 4 known (c.292G>A in CRYAA; c.215+1G>A and c.272_274delGAG in CRYBA1, and c.176C>T in GJA3). All novel mutations were predicted to be pathogenic and were not present in 96 controls. Conclusions Mutations in the 12 genes encoding crystallins and connexins were responsible for 40% Chinese families with congenital cataracts. Our results enriched our knowledge on the molecular basis of congenital cataracts in Chinese population. PMID:21866213

The Slavic NBN Founder Mutation: A Role for Reproductive Fitness?

PubMed

Seemanova, Eva; Varon, Raymonda; Vejvalka, Jan; Jarolim, Petr; Seeman, Pavel; Chrzanowska, Krystyna H; Digweed, Martin; Resnick, Igor; Kremensky, Ivo; Saar, Kathrin; Hoffmann, Katrin; Dutrannoy, Véronique; Karbasiyan, Mohsen; Ghani, Mehdi; Barić, Ivo; Tekin, Mustafa; Kovacs, Peter; Krawczak, Michael; Reis, André; Sperling, Karl; Nothnagel, Michael

2016-01-01

The vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657del5; rs587776650) in the NBN gene on chromosome 8q21. This mutation is essentially confined to Slavic populations and may thus be considered a Slavic founder mutation. Notably, not a single parenthood of a homozygous c.657del5 carrier has been reported to date, while heterozygous carriers do reproduce but have an increased cancer risk. These observations seem to conflict with the considerable carrier frequency of c.657del5 of 0.5% to 1% as observed in different Slavic populations because deleterious mutations would be eliminated quite rapidly by purifying selection. Therefore, we propose that heterozygous c.657del5 carriers have increased reproductive success, i.e., that the mutation confers heterozygote advantage. In fact, in our cohort study of the reproductive history of 24 NBS pedigrees from the Czech Republic, we observed that female carriers gave birth to more children on average than female non-carriers, while no such reproductive differences were observed for males. We also estimate that c.657del5 likely occurred less than 300 generations ago, thus supporting the view that the original mutation predated the historic split and subsequent spread of the 'Slavic people'. We surmise that the higher fertility of female c.657del5 carriers reflects a lower miscarriage rate in these women, thereby reflecting the role of the NBN gene product, nibrin, in the repair of DNA double strand breaks and their processing in immune gene rearrangements, telomere maintenance, and meiotic recombination, akin to the previously described role of the DNA repair genes BRCA1 and BRCA2.

A novel KCNQ4 one-base deletion in a large pedigree with hearing loss: implication for the genotype-phenotype correlation.

PubMed

Kamada, Fumiaki; Kure, Shigeo; Kudo, Takayuki; Suzuki, Yoichi; Oshima, Takeshi; Ichinohe, Akiko; Kojima, Kanako; Niihori, Tetsuya; Kanno, Junko; Narumi, Yoko; Narisawa, Ayumi; Kato, Kumi; Aoki, Yoko; Ikeda, Katsuhisa; Kobayashi, Toshimitsu; Matsubara, Yoichi

2006-01-01

Autosomal-dominant, nonsyndromic hearing impairment is clinically and genetically heterogeneous. We encountered a large Japanese pedigree in which nonsyndromic hearing loss was inherited in an autosomal-dominant fashion. A genome-wide linkage study indicated linkage to the DFNA2 locus on chromosome 1p34. Mutational analysis of KCNQ4 encoding a potassium channel revealed a novel one-base deletion in exon 1, c.211delC, which generated a profoundly truncated protein without transmembrane domains (p.Q71fsX138). Previously, six missense mutations and one 13-base deletion, c.211_223del, had been reported in KCNQ4. Patients with the KCNQ4 missense mutations had younger-onset and more profound hearing loss than patients with the 211_223del mutation. In our current study, 12 individuals with the c.211delC mutation manifested late-onset and pure high-frequency hearing loss. Our results support the genotype-phenotype correlation that the KCNQ4 deletions are associated with later-onset and milder hearing impairment than the missense mutations. The phenotypic difference may be caused by the difference in pathogenic mechanisms: haploinsufficiency in deletions and dominant-negative effect in missense mutations.

FANCA and FANCG are the major Fanconi anemia genes in the Korean population.

PubMed

Park, J; Chung, N-G; Chae, H; Kim, M; Lee, S; Kim, Y; Lee, J-W; Cho, B; Jeong, D C; Park, I Y

2013-09-01

Fanconi anemia (FA) is a rare disorder characterized by physical abnormalities, bone marrow failure (BMF), increased risk of malignancies, and cellular hypersensitivity to DNA cross-linking agents. This study evaluated the genetic alterations in three major Fanconi genes (FANCA, FANCC, and FANCG) in 30 FA patients using multiplex ligation-dependent probe amplification and direct sequencing. Thirteen BMF patients were genetically classified as FA-A (n = 6, 46%) and FA-G (n = 7, 54%). Four common founder mutations were identified and included two FANCA mutations (c.2546delC and c.3720_3724delAAACA) and two FANCG mutations (c.307+1G>C and c.1066C>T), which had previously been commonly observed in a Japanese FA population. We also detected four novel deleterious mutations: c.2778+1G>C and c.3627-1G>A of FANCA, and c.1589_1591delATA and c.1761-1G>A of FANCG. This study shows that mutations in FANCA and FANCG are common in Korean FA patients and the existence of four common founder mutations in an East Asian FA population. Mutation screening workflow that includes these common mutations may be useful in the creation of an international database, and to better understand the ethnic characteristics of FA. © 2012 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

CHEK2*1100delC Heterozygosity in Women With Breast Cancer Associated With Early Death, Breast Cancer–Specific Death, and Increased Risk of a Second Breast Cancer

PubMed Central

Weischer, Maren; Nordestgaard, Børge G.; Pharoah, Paul; Bolla, Manjeet K.; Nevanlinna, Heli; van't Veer, Laura J.; Garcia-Closas, Montserrat; Hopper, John L.; Hall, Per; Andrulis, Irene L.; Devilee, Peter; Fasching, Peter A.; Anton-Culver, Hoda; Lambrechts, Diether; Hooning, Maartje; Cox, Angela; Giles, Graham G.; Burwinkel, Barbara; Lindblom, Annika; Couch, Fergus J.; Mannermaa, Arto; Grenaker Alnæs, Grethe; John, Esther M.; Dörk, Thilo; Flyger, Henrik; Dunning, Alison M.; Wang, Qin; Muranen, Taru A.; van Hien, Richard; Figueroa, Jonine; Southey, Melissa C.; Czene, Kamila; Knight, Julia A.; Tollenaar, Rob A.E.M.; Beckmann, Matthias W.; Ziogas, Argyrios; Christiaens, Marie-Rose; Collée, Johanna Margriet; Reed, Malcolm W.R.; Severi, Gianluca; Marme, Frederik; Margolin, Sara; Olson, Janet E.; Kosma, Veli-Matti; Kristensen, Vessela N.; Miron, Alexander; Bogdanova, Natalia; Shah, Mitul; Blomqvist, Carl; Broeks, Annegien; Sherman, Mark; Phillips, Kelly-Anne; Li, Jingmei; Liu, Jianjun; Glendon, Gord; Seynaeve, Caroline; Ekici, Arif B.; Leunen, Karin; Kriege, Mieke; Cross, Simon S.; Baglietto, Laura; Sohn, Christof; Wang, Xianshu; Kataja, Vesa; Børresen-Dale, Anne-Lise; Meyer, Andreas; Easton, Douglas F.; Schmidt, Marjanka K.; Bojesen, Stig E.

2012-01-01

Purpose We tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer–specific death, and risk of a second breast cancer in women with a first breast cancer. Patients and Methods From 22 studies participating in the Breast Cancer Association Consortium, 25,571 white women with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median, 6.6 years). We examined risk of early death and breast cancer–specific death by estrogen receptor status and risk of a second breast cancer after a first breast cancer in prospective studies. Results CHEK2*1100delC heterozygosity was found in 459 patients (1.8%). In women with estrogen receptor–positive breast cancer, multifactorially adjusted hazard ratios for heterozygotes versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; log-rank P = .004) for early death and 1.63 (95% CI, 1.24 to 2.15; log-rank P < .001) for breast cancer–specific death. In all women, hazard ratio for a second breast cancer was 2.77 (95% CI, 2.00 to 3.83; log-rank P < .001) increasing to 3.52 (95% CI, 2.35 to 5.27; log-rank P < .001) in women with estrogen receptor–positive first breast cancer only. Conclusion Among women with estrogen receptor–positive breast cancer, CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer–specific death, and a 3.5-fold risk of a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer. PMID:23109706

CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer.

PubMed

Weischer, Maren; Nordestgaard, Børge G; Pharoah, Paul; Bolla, Manjeet K; Nevanlinna, Heli; Van't Veer, Laura J; Garcia-Closas, Montserrat; Hopper, John L; Hall, Per; Andrulis, Irene L; Devilee, Peter; Fasching, Peter A; Anton-Culver, Hoda; Lambrechts, Diether; Hooning, Maartje; Cox, Angela; Giles, Graham G; Burwinkel, Barbara; Lindblom, Annika; Couch, Fergus J; Mannermaa, Arto; Grenaker Alnæs, Grethe; John, Esther M; Dörk, Thilo; Flyger, Henrik; Dunning, Alison M; Wang, Qin; Muranen, Taru A; van Hien, Richard; Figueroa, Jonine; Southey, Melissa C; Czene, Kamila; Knight, Julia A; Tollenaar, Rob A E M; Beckmann, Matthias W; Ziogas, Argyrios; Christiaens, Marie-Rose; Collée, Johanna Margriet; Reed, Malcolm W R; Severi, Gianluca; Marme, Frederik; Margolin, Sara; Olson, Janet E; Kosma, Veli-Matti; Kristensen, Vessela N; Miron, Alexander; Bogdanova, Natalia; Shah, Mitul; Blomqvist, Carl; Broeks, Annegien; Sherman, Mark; Phillips, Kelly-Anne; Li, Jingmei; Liu, Jianjun; Glendon, Gord; Seynaeve, Caroline; Ekici, Arif B; Leunen, Karin; Kriege, Mieke; Cross, Simon S; Baglietto, Laura; Sohn, Christof; Wang, Xianshu; Kataja, Vesa; Børresen-Dale, Anne-Lise; Meyer, Andreas; Easton, Douglas F; Schmidt, Marjanka K; Bojesen, Stig E

2012-12-10

We tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer-specific death, and risk of a second breast cancer in women with a first breast cancer. From 22 studies participating in the Breast Cancer Association Consortium, 25,571 white women with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median, 6.6 years). We examined risk of early death and breast cancer-specific death by estrogen receptor status and risk of a second breast cancer after a first breast cancer in prospective studies. CHEK2*1100delC heterozygosity was found in 459 patients (1.8%). In women with estrogen receptor-positive breast cancer, multifactorially adjusted hazard ratios for heterozygotes versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; log-rank P = .004) for early death and 1.63 (95% CI, 1.24 to 2.15; log-rank P < .001) for breast cancer-specific death. In all women, hazard ratio for a second breast cancer was 2.77 (95% CI, 2.00 to 3.83; log-rank P < .001) increasing to 3.52 (95% CI, 2.35 to 5.27; log-rank P < .001) in women with estrogen receptor-positive first breast cancer only. Among women with estrogen receptor-positive breast cancer, CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer-specific death, and a 3.5-fold risk of a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer.

Velocidades radiales en Collinder 121

NASA Astrophysics Data System (ADS)

Arnal, M.; Morrell, N.

Se han llevado a cabo observaciones espectroscópicas de unas treinta estrellas que son posibles miembros del cúmulo abierto Collinder 121. Las mismas fueron realizadas con el telescopio de 2.15m del Complejo Astronómico El Leoncito (CASLEO). El análisis de las velocidades radiales derivadas del material obtenido, confirma la realidad de Collinder 121, al menos desde el punto de vista cinemático. La velocidad radial baricentral (LSR) del cúmulo es de +17 ± 3 km.s-1. Esta velocidad coincide, dentro de los errores, con la velocidad radial (LSR) de la nebulosa anillo S308, la cual es de ~20 ± 10 km.s-1. Como S308 se encuentra físicamente asociada a la estrella Wolf-Rayet HD~50896, es muy probable que esta última sea un miembro de Collinder 121. Desde un punto de vista cinemático, la supergigante roja HD~50877 (K3Iab) también pertenecería a Collinder 121. Basándonos en la pertenencia de HD~50896 a Collinder 121, y en la interacción encontrada entre el viento de esta estrella y el medio interestelar circundante a la misma, se estima para este cúmulo una distancia del orden de 1 kpc.

El rol de Ia colaboracion y el Modelo de Aprendizaje Basado en Proyectos (ABPr) mediante el lente de la Teoria de Actividad (CHAT): un estudio de caso con estudiantes de 9no grado

NASA Astrophysics Data System (ADS)

Delgado, Isabel C.

Los modelos de eensenanza y aprendizaje constructivistas conceptualizan el aprendizaje como un proceso activo. El modelo de Aprendizaje Basado en Proyectos (ABPr) se distingue por una serie de componentes, entre los cuales se destaca el aspecto colaborativo y cooperativo como un reto al momento de su implantacion. Son pocas las investigaciones que se concentran en este aspecto del modelo. En este estudio, se analizaron las diversas interacciones que surgen durante la implantacion de una unidad curricular sobre el tema de Geologia de Puerto Rico, la cual se diseno con el modelo ABPr cuyo enfoque es orientacion a proyectos. Particularmente, se examinaron las interacciones sociales que surgen entre los pares y entre pares y docente durante el proceso de planificacion y desarrollo de los productos finales, al igual que las interacciones entre los estudiantes y el material didactico en estas etapas del modelo. La investigacion es de tipo cualitativo e incorpora como diseno el estudio de caso. Las diversas interacciones constituyen la unidad de analisis. En el estudio participaron 19 estudiantes de 9no grado, a quienes se organizaron en 5 grupos colaborativos por temas de interes (Pangea, Placas tectonicas, Volcanes, Tsunamis y Terremotos). Las tecnicas que se utilizaron para recopilar los datos fueron: observaciones participativas, grupos focales y analisis de documentos (cuadernos reflexivos y respuestas de los estudiantes a la pregunta central del proyecto). Para el analisis de los datos se aplico la teoria de actividad (CHAT) que concentra la unidad de analisis en la actividad humana en un contexto particular. Los resultados del estudio senalan que las interacciones entre pares, entre pares y docente, asi como entre estudiantes y material didactico son fundamentales en el proceso de aprendizaje. Una mayor interaccion entre pares durante las etapas de planificar y desarrollar los productos finales de la unidad, promueve una mejor comprension de los conceptos de la unidad, segun evidencia los productos finales del ABPr. La interaccion con el docente es muy importante para mediar los conflictos y desacuerdos que surgen como parte de las interacciones entre pares. Por lo tanto, el uso de diversas estrategias de andamiaje por parte del docente durante las reuniones de los grupos colaborativos es esencial para el exito del modelo ABPr.

The novel c.247_249delTTC (p.F83del) GJB2 mutation in a family with prelingual sensorineural deafness.

PubMed

Petersen, Michael B; Grigoriadou, Maria; Koutroumpe, Maria; Kokotas, Haris

2012-07-01

Non-syndromic hearing loss is one of the most common hereditary determined diseases in human, and the disease is a genetically heterogeneous disorder. Mutations in the GJB2 gene, encoding connexin 26 (Cx26), are a major cause of non-syndromic recessive hearing impairment in many countries and are largely dependent on ethnic groups. Due to the high frequency of the c.35delG GJB2 mutation in the Greek population, we have previously suggested that Greek patients with sensorineural, non-syndromic deafness should be tested for the c.35delG mutation and the coding region of the GJB2 gene should be sequenced in c.35delG heterozygotes. Here we present on the clinical and molecular genetic evaluation of a family suffering from prelingual, sensorineural, non-syndromic deafness. A novel c.247_249delTTC (p.F83del) GJB2 mutation was detected in compound heterozygosity with the c.35delG GJB2 mutation in the proband and was later confirmed in the father, while the mother was homozygous for the c.35delG GJB2 mutation. We conclude that compound heterozygosity of the novel c.247_249delTTC (p.F83del) and the c.35delG mutations in the GJB2 gene was the cause of deafness in the proband and his father. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

El espectro de KX TrA entre 1990 y 1996

NASA Astrophysics Data System (ADS)

Brandi, E.; García, L.; Ferrer, O.; Barbá, R.

La estrella simbiótica KX TrA = He2-177 fue observada espectroscópicamente con el telescopio de 2.15 m del CASLEO entre los años 1990 y 1996, utilizándose resoluciones intermedia y alta. El rango espectral estudiado se extiende desde 4400 Åa 7200 Å. La historia fotométrica de KX TrA presenta explosiones del mismo tipo que las mostradas por la nova lenta RR Tel y su espectro de alta excitación, muy rico en líneas de emisión, es también similar al de RR Tel. Por lo tanto, es importante analizar la evolución espectral de KX TrA en el tiempo, prestando especial atención a los posibles cambios en los niveles de excitación. Las emisiones presentes corresponden a transiciones permitidas y prohibidas con un amplio rango de ionización, incluyéndose las anchas e intensas líneas originadas por scattering Raman de O VI en λλ 6825 y 7082 Å. En el período cubierto por nuestras observaciones se estudia la variación de la intensidad relativa de las emisiones, el comportamiento de las velocidades radiales y los cambios de perfiles de las líneas, especialmente en Hα y Hβ. El contínuo de la región roja observada indica un tipo espectral no más tardío que M3 para la componente gigante fría del sistema.

Assessment of the nursing care product (APROCENF): a reliability and construct validity study.

PubMed

Cucolo, Danielle Fabiana; Perroca, Márcia Galan

2017-04-06

to verify the reliability and construct validity estimates of the "Assessment of nursing care product" scale (APROCENF) and its applicability. this validation study included a sample of 40 (inter-rater reliability) and 172 (construct validity) assessments performed by nurses at the end of the work shift at nine inpatient services of a teaching hospital in the Brazilian Southeast. The data were collected between February and September/2014 with interruptions. Cronbach's alpha and Spearman's correlation coefficients were calculated, as well as the intraclass correlation and the weighted kappa index (inter-rater reliability). Exploratory factor analysis was used with principal component extraction and varimax rotation (construct validity). the internal consistency revealed an alpha coefficient of 0.85, item-item correlation ranging between 0.13 and 0.61 and item-total correlation between 0.43 and 0.69. Inter-rater equivalence was obtained and all items evidenced significant factor loadings. this research evidenced the reliability and construct validity of the scale to assess the nursing care product. Its application in nursing practice permits identifying improvements needed in the production process, contributing to management and care decisions. verificar as estimativas de confiabilidade e validade de construto da escala "Avaliação do produto do cuidar em enfermagem" (APROCENF) e sua aplicabilidade. este estudo de validação incluiu em sua amostra 40 (confiabilidade interavaliadores) e 172 (validade de construto) avaliações realizadas por enfermeiros ao final do turno de trabalho em nove unidades de internação de um hospital universitário do sudeste brasileiro. A coleta de dados ocorreu entre fevereiro e setembro de 2014 de forma interrupta. Foram calculados os coeficientes alfa de Cronbach e correlação de Spearman (consistência interna), a correlação intraclasse e Kappa ponderado (confiabilidade interavaliadores) e a análise fatorial exploratória foi utilizada com extração por componentes principais e rotação varimax (validação do construto). a consistência interna revelou alfa de 0,85, correlação entre itens variando de 0,13 a 0,61 e item-total de 0,43 a 0,69. A equivalência interavaliadores foi obtida e todos os itens evidenciaram cargas fatoriais significantes. esta investigação mostrou evidências de confiabilidade e validade do construto do instrumento para avaliação do produto do cuidar em enfermagem. Sua aplicação na prática de enfermagem possibilita identificar melhorias necessárias no processo produtivo contribuindo para decisões gerenciais e assistenciais. verificar las estimativas de confiabilidad y validez de constructo de la escala "Evaluación del producto del cuidar en enfermería" (APROCENF) y su aplicabilidad. este estudio de validación incluyó en su muestra 40 (confiabilidad inter-evaluadores) y 172 (validez de constructo) evaluaciones efectuadas por enfermeros al final del turno de trabajo en nueve unidades de internación de un hospital universitaria del sudeste brasileño. Los datos fueron recolectados entre febrero y septiembre de 2014 de forma interrumpida. Fueron calculados los coeficientes alfa de Cronbach y correlación de Spearman (consistencia interna), la correlación intraclase y Kappa ponderado (confiabilidad inter-evaluadores)y el análisis factorial exploratorio fue utilizado con extracción por componentes principales y rotación varimax (validación de constructo). la consistencia interna reveló alfa de0,85,correlación entre ítems variando de 0,13 a 0,61 y ítem-total de 0,43 a 0,69. La equivalencia inter-evaluadores fue alcanzada y todos los ítems evidenciaron cargas factoriales significantes. esta investigación mostró evidencias de confiabilidad y validez del constructo del instrumento para evaluación del producto del cuidar en enfermería. Su aplicación en la práctica de enfermería posibilita identificar mejoras necesarias en el proceso productivo, contribuyendo para decisiones gerenciales y asistenciales.

The CHEK2 1100delC allelic variant is not present in familial and sporadic breast cancer cases from Moroccan population.

PubMed

Marouf, Chaymaa; Hajji, Omar; Diakité, Brehima; Tazzite, Amal; Jouhadi, Hassan; Benider, Abdellatif; Nadifi, Sellama

2015-01-01

The cell-cycle checkpoint kinase 2 (CHEK2) is an important signal transducer of cellular responses to DNA damage, whose defects has been associated with increased risk for breast cancer. The CHEK2 1100delC mutation has been reported to confer a twofold increased risk of breast cancer among carriers. The frequency of the mutation varies among populations. The highest frequency has been described in Northern and Eastern European countries. However, the 1100delC mutation has been investigated in different case-control studies and none in Moroccan population. The aim of this study was to evaluate the prevalence of this variant and determine its contribution to the development of breast cancer in sporadic cases and also in members of breast cancer families who tested negative or positive for a deleterious mutation in BRCA1/BRCA2. In this case-control study we performed the CHEK2 1100delC mutation analysis by ASO-PCR in 134 breast cancer patients and 114 unaffected control individuals. Most of these families had several cases of breast cancer or ovarian cancer (or both). No CHEK2 1100delC mutations were detected in any of 134 individuals, including 59 women diagnosed with breast cancer at an early age (<40 years), 10 women with bilateral breast cancer, and 6 women with ovarian cancer. Our preliminary genetic analysis are consistent with the reported very low frequency of CHEK2 1100delC mutation in North American populations (compared with Northern Europe), rendering CHEK2 1100delC such as an unlikely to be major breast cancer susceptibility genes.

Selected exonic sequencing of the AGXT gene provides a genetic diagnosis in 50% of patients with primary hyperoxaluria type 1.

PubMed

Williams, Emma; Rumsby, Gill

2007-07-01

Definitive diagnosis of primary hyperoxaluria type 1 (PH1) requires analysis of alanine:glyoxylate aminotransferase (AGT) activity in the liver. We have previously shown that targeted screening for the 3 most common mutations in the AGXT gene (c.33_34insC, c.508G>A, and c.731T>C) can provide a molecular diagnosis in 34.5% of PH1 patients, eliminating the need for a liver biopsy. Having reviewed the distribution of all AGXT mutations, we have evaluated a diagnostic strategy that uses selected exon sequencing for the molecular diagnosis of PH1. We sequenced exons 1, 4, and 7 for 300 biopsy-confirmed PH1 patients and expressed the identified missense mutations in vitro. Our identification of at least 1 mutation in 224 patients (75%) and 2 mutations in 149 patients increased the diagnostic sensitivity to 50%. We detected 29 kinds of sequence changes, 15 of which were novel. Four of these mutations were in exon 1 (c.2_3delinsAT, c.30_32delCC, c.122G>A, c.126delG), 7 were in exon 4 (c.447_454delGCTGCTGT, c.449T>C, c.473C>T, c.481G>A, c.481G>T, c.497T>C, c.424-2A>G), and 4 were in exon 7 (c.725insT, c.737G>A, c.757T>C, c.776 + 1G>A). The missense changes were associated with severely decreased AGT catalytic activity and negative immunoreactivity when expressed in vitro. Missense mutation c.26C>A, previously described as a pathological mutation, had activity similar to that of the wild-type enzyme. Selective exon sequencing can allow a definitive diagnosis in 50% of PH1 patients. The test offers a rapid turnaround time (15 days) with minimal risk to the patient. Demonstration of the expression of missense changes is essential to demonstrate pathogenicity.

CHEK2 mutation and risk of prostate cancer: a systematic review and meta-analysis

PubMed Central

Wang, Yue; Dai, Bo; Ye, Dingwei

2015-01-01

Background: CHEK2 encodes for a G2 checkpoint kinase which plays a critical role in DNA repair. Its mutation confers an increased risk of breast cancer. It has also been suggested to increase risks of prostate cancer, but its involvement with this type of cancer has not been confirmed. Methods: We performed a systematic review and meta-analysis to clarify the association between CHEK2 1100delC, IVS2+1G>A, I157T mutation and risk of Prostate Cancer. A comprehensive, computerized literature search of PubMed until December 27, 2014 was carried out. Eligible studies were included according to specific inclusion criteria. Pooled hazard ratio was estimated using the fixed effects model or random effects model according to heterogeneity between studies. Results: Eight eligible studies were included in the analysis, all were retrospective studies. The overall meta-analysis demonstrated that the CHEK2 1100delC mutation (OR 3.29; 95% confidence interval: 1.85-5.85; P = 0.00) and I157T missense mutation (OR 1.80; 95% confidence interval: 1.51-2.14; P = 0.00) was associated with higher risk of Prostate Cancer, and CHEK2 1100delC mutation is irrelevant to familial aggregation phenomenon of prostate cancer (OR 1.59; 95% confidence interval: 0.79-3.20; P = 0.20). The IVS2+1G>A mutation is also irrelevant to Prostate Cancer (OR = 1.59, 95% CI = 0.93-2.71, P = 0.09). None of the single studies materially altered the original results and no evidence of publication bias was found. Conclusion: CHEK2 1100delC mutation and I157T missense mutation in males indicates higher risk of Prostate Cancer, but there’s no evidence to prove the CHEK2 1100delC mutation was associated with Familial prostate cancer. PMID:26629066

CHEK2 mutation and risk of prostate cancer: a systematic review and meta-analysis.

PubMed

Wang, Yue; Dai, Bo; Ye, Dingwei

2015-01-01

CHEK2 encodes for a G2 checkpoint kinase which plays a critical role in DNA repair. Its mutation confers an increased risk of breast cancer. It has also been suggested to increase risks of prostate cancer, but its involvement with this type of cancer has not been confirmed. We performed a systematic review and meta-analysis to clarify the association between CHEK2 1100delC, IVS2+1G>A, I157T mutation and risk of Prostate Cancer. A comprehensive, computerized literature search of PubMed until December 27, 2014 was carried out. Eligible studies were included according to specific inclusion criteria. Pooled hazard ratio was estimated using the fixed effects model or random effects model according to heterogeneity between studies. Eight eligible studies were included in the analysis, all were retrospective studies. The overall meta-analysis demonstrated that the CHEK2 1100delC mutation (OR 3.29; 95% confidence interval: 1.85-5.85; P = 0.00) and I157T missense mutation (OR 1.80; 95% confidence interval: 1.51-2.14; P = 0.00) was associated with higher risk of Prostate Cancer, and CHEK2 1100delC mutation is irrelevant to familial aggregation phenomenon of prostate cancer (OR 1.59; 95% confidence interval: 0.79-3.20; P = 0.20). The IVS2+1G>A mutation is also irrelevant to Prostate Cancer (OR = 1.59, 95% CI = 0.93-2.71, P = 0.09). None of the single studies materially altered the original results and no evidence of publication bias was found. CHEK2 1100delC mutation and I157T missense mutation in males indicates higher risk of Prostate Cancer, but there's no evidence to prove the CHEK2 1100delC mutation was associated with Familial prostate cancer.

Molecular analysis of hyperoxaluria type 1 in Italian patients reveals eight new mutations in the alanine: glyoxylate aminotransferase gene.

PubMed

Pirulli, D; Puzzer, D; Ferri, L; Crovella, S; Amoroso, A; Ferrettini, C; Marangella, M; Mazzola, G; Florian, F

1999-06-01

Systematic screening using the SSCP technique followed by sequencing of bands with abnormal mobility derived from the AGXT exons of 15 unrelated Italian patients with primary hyperoxaluria type 1 (PH1) allowed us to characterize both the mutant alleles in each individual. Eight new mutations were identified: C155del, C156ins, G244T, C252T, GAG408ins, G468A, G588A and G1098del. This study demonstrates both the effectiveness of the screening strategy chosen to identify all the mutant alleles and the high degree of allelic heterogeneity in PH1.

An inherited NBN mutation is associated with poor prognosis prostate cancer

PubMed Central

Cybulski, C; Wokołorczyk, D; Kluźniak, W; Jakubowska, A; Górski, B; Gronwald, J; Huzarski, T; Kashyap, A; Byrski, T; Dębniak, T; Gołąb, A; Gliniewicz, B; Sikorski, A; Świtała, J; Borkowski, T; Borkowski, A; Antczak, A; Wojnar, Ł; Przybyła, J; Sosnowski, M; Małkiewicz, B; Zdrojowy, R; Sikorska-Radek, P; Matych, J; Wilkosz, J; Różański, W; Kiś, J; Bar, K; Bryniarski, P; Paradysz, A; Jersak, K; Niemirowicz, J; Słupski, P; Jarzemski, P; Skrzypczyk, M; Dobruch, J; Domagała, P; Narod, S A; Lubiński, J

2013-01-01

Background: To establish the contribution of eight founder alleles in three DNA damage repair genes (BRCA1, CHEK2 and NBS1) to prostate cancer in Poland, and to measure the impact of these variants on survival among patients. Methods: Three thousand seven hundred fifty men with prostate cancer and 3956 cancer-free controls were genotyped for three founder alleles in BRCA1 (5382insC, 4153delA, C61G), four alleles in CHEK2 (1100delC, IVS2+1G>A, del5395, I157T), and one allele in NBS1 (657del5). Results: The NBS1 mutation was detected in 53 of 3750 unselected cases compared with 23 of 3956 (0.6%) controls (odds ratio (OR)=2.5; P=0.0003). A CHEK2 mutation was seen in 383 (10.2%) unselected cases and in 228 (5.8%) controls (OR=1.9; P<0.0001). Mutation of BRCA1 (three mutations combined) was not associated with the risk of prostate cancer (OR=0.9; P=0.8). In a subgroup analysis, the 4153delA mutation was associated with early-onset (age ⩽60 years) prostate cancer (OR=20.3, P=0.004). The mean follow-up was 54 months. Mortality was significantly worse for carriers of a NBS1 mutation than for non-carriers (HR=1.85; P=0.008). The 5-year survival for men with an NBS1 mutation was 49%, compared with 72% for mutation-negative cases. Conclusion: A mutation in NBS1 predisposes to aggressive prostate cancer. These data are relevant to the prospect of adapting personalised medicine to prostate cancer prevention and treatment. PMID:23149842

AB067. X-linked adrenoleukodystrophy: Phenotype and genotype in Vietnamese patients

PubMed Central

Nguyen, Khanh Ngoc; Nguyen, Ha Thu; Can, Ngoc Thi Bich; Bui, Thao Phuong; Nobuyuki, Shimozawa; Vu, Huynh Anh; Do, Mai Thi Thanh; Vu, Dung Chi

2017-01-01

Background X-linked adrenoleukodystrophy (X-ALD) is caused by a defect in the gene ABCD1, which maps to Xq28 and codes for a peroxisomal membrane protein that is a member of the ATP-binding cassette transporter superfamily. This disease characterized by progressive neurologic dysfunction, occasionally associated with adrenal insufficiency. Objective is to identify phenotype and genotype in Vietnamese patients with X-ALD. Methods Genomic DNA from 20 Vietnamese patients from 18 unrelated families was extracted using standard procedures from the peripheral blood leukocytes. Mutation analysis of ABCD1 was performed using polymerase chain reaction (PCR) and DNA direct sequencing. Results We identified 17 different mutations of ABCD1 in 20 patients including missense mutations (2/17), deletion (4/17), frameshift mutation (1/17) and splice site mutation (1/17). Of which, six novel mutations including c.1202G>T (p.Arg401Trp); c.1208T>A (p.Met403Lys); IVS8+28-551bp del; c.1668G>C (p.Q556H); c.292_296delTCGGC (p.S98RfsX95); and the extent of deletion included between IVS1+505 and IVS2+1501, containing whole the exon 2 (4243bp), plus insertion of 79bp from BAP31 and 8bp from unknown origin in this deleted region were identified in six unrelated patients. Eleven reported mutations including c.796G>A (p.Gly266Arg); c.1628C>T (p.Pro543Leu); c.1553G>A (p.Arg518Gln); c.1552 C>T (p.Arg518Trp); c.854G>C (p.R285P); c.1825G>A (p.E609K); c.1415_1416delAG (p.Q472RfsX83) and c.46-53del insG, c.1553G>A (p.Arg518Gln), c.1946-1947insA (p.Asp649fsX733), c.1978C>T (p.Arg660Trp) were identified in 14 patients from 12 families. Most of patients (17/20) presented cerebral ALD type with/without adrenal insufficiency and only 3 patients presented Addison type. Conclusions Mutation analysis of ABCD1 gene helped confirmation of diagnosis of X-ALD, genetic counselling and prenatal diagnosis but could not be used to predict the specific phenotype of X-ALD.

A Case of Treacher Collins Syndrome

PubMed Central

Ulusal, S; Gürkan, H; Vatansever, Ü; Kürkçü, K; Tozkir, H; Acunaş, BA

2013-01-01

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development with an incidence of 1/50,000 live births. Mutations of the TCOF1 gene have been found to be responsible for most cases of this mandibulofacial disorder. Here we report TCS in an individual who has a heterozygous c.1021_1022delAG deletion in exon 7 of the TCOF1 gene (NG_011341.1). This is the second Turkish patient with a severe TCS phenotype resulting from a de novo c.1021_1022delAG mutation. PMID:24778568

A case of treacher collins syndrome.

PubMed

Ulusal, S; Gürkan, H; Vatansever, U; Kürkçü, K; Tozkir, H; Acunaş, Ba

2013-12-01

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development with an incidence of 1/50,000 live births. Mutations of the TCOF1 gene have been found to be responsible for most cases of this mandibulofacial disorder. Here we report TCS in an individual who has a heterozygous c.1021_1022delAG deletion in exon 7 of the TCOF1 gene (NG_011341.1). This is the second Turkish patient with a severe TCS phenotype resulting from a de novo c.1021_1022delAG mutation.

Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation.

PubMed

De Stefano, Daniela; Villella, Valeria R; Esposito, Speranza; Tosco, Antonella; Sepe, Angela; De Gregorio, Fabiola; Salvadori, Laura; Grassia, Rosa; Leone, Carlo A; De Rosa, Giuseppe; Maiuri, Maria C; Pettoello-Mantovani, Massimo; Guido, Stefano; Bossi, Anna; Zolin, Anna; Venerando, Andrea; Pinna, Lorenzo A; Mehta, Anil; Bona, Gianni; Kroemer, Guido; Maiuri, Luigi; Raia, Valeria

2014-01-01

Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in Cftr(F508del) homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the F508del-CFTR mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from F508del homozygous CF patients, and these effects persisted for 24 h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both in vivo, in mice, and in vitro, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 F508del-CFTR homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells in vivo, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of TNF/TNF-alpha (tumor necrosis factor) and CXCL8 (chemokine [C-X-C motif] ligand 8) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the F508del-CFTR mutation.

Clinical characteristics and STK11 gene mutations in Chinese children with Peutz-Jeghers syndrome.

PubMed

Huang, Zhiheng; Miao, Shijian; Wang, Lin; Zhang, Ping; Wu, Bingbing; Wu, Jie; Huang, Ying

2015-11-25

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disease characterized by gastrointestinal hamartomatous polyps and mucocutaneous melanin spots. Germline mutation of the serine/threonine kinase 11 (STK11) gene are responsible for PJS. In this study, we investigated the clinical characteristics and molecular basis of the disease in Chinese children with PJS. Thirteen children diagnosed with PJS in our hospital were enrolled in this study from 2011 to 2015, and their clinical data on polyp characteristics, intussusceptions events, family histories, etc. were described. Genomic DNA was extracted from whole-blood samples from each subject, and the entire coding sequence of the STK11 gene was amplified by polymerase chain reaction and analyzed by direct sequencing. The median age at the onset of symptoms was 2 years and 4 months. To date, these children have undergone 40 endoscopy screenings, 17 laparotomies and 9 intussusceptions. Polyps were found in the stomach, duodenum, small bowel, colon and rectum, with large polyps found in 7 children. Mutations were found in eleven children, including seven novel mutations (c.481het_dupA, c.943_944het_delCCinsG, c.397het_delG, c.862 + 1G > G/A, c.348_349het_delGT, and c.803_804het_delGGinsC and c.121_139de l19insTT) and four previously reported mutations (c.658C > C/T, c.890G > G/A, c.1062 C > C/G, and c.290 + 1G > G/A). One PJS patient did not have any STK11 mutations. The polyps caused significant clinical consequences in children with PJS, and mutations of the STK11 gene are generally the cause of PJS in Chinese children. This study expands the spectrum of known STK11 gene mutations.

El proyecto AUGER

NASA Astrophysics Data System (ADS)

Etchegoyen, A.

Hace ya más de 30 años en Volcano Ranch, EE.UU., un extenso chubasco cósmico (ECC) fue detectado con energía en exceso de 1020 eV. Desde entonces, observatorios ubicados en Haverah Park del Reino Unido, Yakutsk de Rusia, AGASA de Japón y Dugway de EE.UU. también han observado ECC con energías mayores que 1020 eV. Poco se sabe de dichos rayos, y en particular cuál es la naturaleza del primario, de dónde provienen, y cómo son acelerados, pero su naturaleza ultrarelativista excluye la mayoría de las respuestas dejando sólo algunas plausibles de ser investigadas experimentalmente. Grupos de científicos de 20 países están trabajando con el fin de construir dos arreglos de detectores gigantes, uno en cada hemisferio a lo largo de 3000 km2 c/u. Dichas dimensiones son necesarias debido al flujo estimado de 1 rayo cósmico/centuria/km2/sr. La sede del Observatorio del Sur es la Argentina. El proyecto fue nombrado Pierre Auger en conmemoración del célebre físico francés que detectó por primera vez chubascos cósmicos en 1938. El proyecto focaliza su interés en rayos cósmicos con energías mayores que 1020 eV.

[JAK2 V617F and exon 12 genetic variations in Korean patients with BCR/ABL1-negative myeloproliferative neoplasms].

PubMed

Kim, Jeong Tae; Cho, Yong Gon; Choi, Sam Im; Lee, Young Jin; Kim, Hye Ran; Jang, Sook Jin; Moon, Dae Soo; Park, Young Jin; Park, Geon

2010-12-01

JAK2 genetic variations have been described in a high proportion of patients with BCR/ABL1-negative myeloproliferative neoplasms (MPN). This study was designed to analyze the frequencies of JAK2 V617F and exon 12 variations, and their correlations with clinical characteristics of Korean patients with BCR/ABL1-negative MPN. We examined a total of 154 patients with BCR/ABL1-negative MPN that included 24, 26, 89, and 15 patients with polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), and unclassified myeloproliferative neoplasms (MPNU), respectively. We performed allele-specific PCR to detect V617F in all BCR/ABL1-negative patients, and performed direct sequencing to detect exon 12 variations in 47 V617F-negative MPN patients. JAK2 c.1641+179_183del5 variation was detected by restriction fragment length polymorphism assay in 176 healthy subjects. JAK2 V617F was detected in 91 patients (59.1%): PV (91.6%), PMF (46.2%), ET (52.8%), and MPNU (66.7%). In V617F-negative MPN patients, no mutations were found in exon 12. The c.1641+179_183del5 was detected in 68.1% of V617F-negative MPN patients and 45.4% of healthy subjects (P=0.008). JAK2 V617F was closely correlated with age and leukocytosis in BCR/ABL1-negative MPN patients (P<0.05). However, c.1641+179_183del5 was not related to age, sex, or complete blood cell count parameters in V617F-negative MPN patients and healthy subjects. The c.1641+179_183del5 was associated with an increased odds ratio for MPN (odds ratio, 2.6; 95% confidences interval, 1.3-5.1; P=0.007). Frequencies of V617F are similar to reported results. JAK2 exon 12 mutations may be rare and c.1641+179_183del5 may influence the occurrence of MPN in Korean patients with V6 17F-negative MPN.

Mirror Coronograph for Argentina (MICA). Primera Luz

NASA Astrophysics Data System (ADS)

Stenborg, G.; Epple, A.; Schwenn, R.; Francile, C.; Rovira, M.

En Julio de 1997 se terminó con la primera parte de la instalación del ``Coronógrafo de Espejo para la Argentina'' en la estación de altura Carlos U. Cesco (El Leoncito), gracias al esfuerzo de la gente del Max Planck Institut für Aeronomie (Alemania), del OAFA y del IAFE. Dicho coronógrafo forma parte de un programa de ciencia bilateral entre Alemania y Argentina. El propósito del mismo, en conjunción con otros telescopios solares y terrestres, es contribuir a un mejor entendimiento de cuestiones fundamentales de la física solar. Para ello, ya está observando la corona de emisión en el verde (Fe XIV), rojo (Fe X) y Hα entre 1.05 y 2 radios solares aproximadamente. El diseño del instrumento, el cual fuera ya presentado en esta misma reunión en La Plata en 1996, es esencialmente similar al del telescopio LASCO-C1 a bordo del Solar Heliospheric Observatory (SOHO). La adquisición de datos se realiza con un CCD de 1280x1024 pixels, codificando en 12 bits, pudiendo ser el mismo operado en forma remota. En esta reunión presentaremos algunas de las observaciones realizadas durante la puesta a punto del instrumento en el período julio-setiembre de 1997. Asimismo expondremos cómo y por qué sus resultados complementarán a los de su par en el espacio.

Conceptuaciones de los estudiantes de las facultades de educacion y ciencias naturales de la Universidad de Puerto Rico, recinto de Rio Piedras, acerca de la ciencia y la pseudociencia

NASA Astrophysics Data System (ADS)

Reyes Medina, Hector A.

Esta investigacion describe las conceptuaciones de los estudiantes de tercer ano o mas a nivel de bachillerato de los programas de Educacion en Ciencia y Ciencias Naturales de la Universidad de Puerto Rico, Recinto de Rio Piedras, acerca de lo establecido en la literatura para distinguir el conocimiento cientifico de las creencias pseudocientificas. Este estudio se guio por un diseno tipo encuesta transversal que permitio conocer de manera consistente las conceptuaciones de los estudiantes encuestados acerca de la Ciencia y la Pseudociencia. Ademas, permitio desarrollar inferencias estadisticas relacionadas a la poblacion de estudio, sus conceptuaciones y su inclinacion teorica en torno al Realismo y al Racionalismo cientifico moderados. El instrumento utilizado fue el Cuestionario acerca de las concepciones de la ciencia y la pseudocienca en estudiantes universitarios, Reyes (2015). Este cuestionario fue validado mediante la recopilacion de diversas fuentes de evidencias, entre estas se encuentran las evidencias basadas en el contenido, el proceso de respuesta, la estructura interna y de constructo. Tambien, se calculo el Alfa de Crombach para la escala total y para cada componente y se realizo un analisis de factores que demostro la presencia de seis componentes claramente definidos de acuerdo a lo esperado sobre las caracteristicas originales del instrumento. Las estadisticas utilizadas fueron descriptivas. Participaron 302 alumnos, de las facultades de educacion y ciencias naturales. Se encontro que las conceptuaciones de los estudiantes de ambas facultades se inclinan en un 66.2% a favor con lo establecido en el modelo teorico en torno al Realismo y al Racionalismo cientifico moderados. Sin embargo, aun hay un 33.8% de los estudiantes de ambas facultades que poseen conceptuaciones distintas al modelo teorico propuesto.

Influence of the genetic polymorphism in the 5'-noncoding region of the CYP1A2 gene on CYP1A2 phenotype and urinary mutagenicity in smokers.

PubMed

Pavanello, Sofia; Pulliero, Alessandra; Lupi, Silvia; Gregorio, Pasquale; Clonfero, Erminio

2005-11-10

The functional significance of genetic polymorphisms on tobacco smoke-induced CYP1A2 activity was examined. The influence of three polymorphisms of the cytochrome P450 1A2 gene (CYP1A2) (-3860 G-->A (allele *1C), -2467 T-->delT (allele *1D), -163C-->A (allele *1F)), located in the 5'-noncoding promoter region of the gene, on CYP1A2 activity (measured as caffeine metabolic ratio, CMR), was studied in Caucasian current smokers (n=95). Tobacco smoke intake was calculated from the number of cigarettes/day. Also, studied was the influence of these CYP1A2 genotypes on smoking-associated urinary mutagenicity, detected in Salmonella typhimurium strain YG1024 with S9 mix, considering the urinary excretion of nicotine plus its metabolites as an internal indicator of tobacco smoke exposure. Smokers with at least one of the variant alleles CYP1A2 -3860A and -2467 delT showed a significantly increased CYP1A2 CMR (-3860 G/A versus G/G, p<0.05; -2467 delT/delT versus T/delT and T/T, p<0.01). Multiple regression analysis showed that the increase in CYP1A2 CMR (ln values) was again significantly related to the presence of CYP1A2 variants -2467delT and also to variant -163A (p<0.05), but moderately to -3860A (p=0.084). No influence of the number of cigarettes smoked per day by each subject was found. Heavy smokers (n=48, with urinary nicotine plus its metabolites>or=0.69 mg/mmol creatinine) with variant allele -2467delT or -163A had significantly increased urinary mutagenicity (p<0.01 and <0.05). CYP1A2 genetic polymorphisms are shown to influence the CYP1A2 phenotype in smokers, -2467 T-->delT having the main effect. This information is of interest for future studies assessing the possible role of tobacco smoke-inducible CYP1A2 genotypes as individual susceptibility factors in exposure to carcinogens.

[Identification of a HPGD mutation in three families affected with primary hypertrophic osteoarthropathy].

PubMed

Zhang, Wanying; Wang, Tao; Huang, Shuaiwu; Zhao, Xiuli

2018-04-10

To detect mutation of HPGD gene among three pedigrees affected with primary hypertrophic osteoarthropathy (PHO) by DNA sequencing and high-resolution melting (HRM) analysis. Genomic DNA was extracted from peripheral blood samples collected from the pedigrees. PCR and direct sequencing were carried out to identify potential mutations of the HPGD gene. Amplicons containing the mutation spot were generated by nested PCR. The products were then subjected to HRM analysis using the HR-1 instrument. Direct sequencing was carried out in family members and healthy individuals to confirm the result of HRM analysis. A homozygous mutation c.310_311delCT was detected in 2 affected probands, while a heterozygous mutation c.310_311delCT was detected in the third proband. HRM analysis of the fragments encompassing HPGD exon 3 showed 3 curve patterns representing three different genotypes, i.e., the wild type, the c.310_311delCT homozygote, and the c.310_311delCT heterozygote. Result of DNA sequencing was consistent with that of the HRM analysis and phenotype of the subjects. The c.310_311delCT mutation may be the most prevalent mutation among Chinese population. HRM analysis has provided an optimized method for genetic testing of HPGD mutation for its simplicity, rapid turnover and high sensitivity.

CHEK2 c.1100delC mutation is associated with an increased risk for male breast cancer in Finnish patient population.

PubMed

Hallamies, Sanna; Pelttari, Liisa M; Poikonen-Saksela, Paula; Jekunen, Antti; Jukkola-Vuorinen, Arja; Auvinen, Päivi; Blomqvist, Carl; Aittomäki, Kristiina; Mattson, Johanna; Nevanlinna, Heli

2017-09-05

Several susceptibility genes have been established for female breast cancer, of which mutations in BRCA1 and especially in BRCA2 are also known risk factors for male breast cancer (MBC). The role of other breast cancer genes in MBC is less well understood. In this study, we have genotyped 68 MBC patients for the known breast or ovarian cancer associated mutations in the Finnish population in CHEK2, PALB2, RAD51C, RAD51D, and FANCM genes. CHEK2 c.1100delC mutation was found in 4 patients (5.9%), which is significantly more frequent than in the control population (OR: 4.47, 95% CI 1.51-13.18, p = 0.019). Four CHEK2 I157T variants were also detected, but the frequency did not significantly differ from population controls (p = 0.781). No RAD51C, RAD51D, PALB2, or FANCM mutations were found. These data suggest that the CHEK2 c.1100delC mutation is associated with an increased risk for MBC in the Finnish population.

Gene expression profiling assigns CHEK2 1100delC breast cancers to the luminal intrinsic subtypes.

PubMed

Nagel, Jord H A; Peeters, Justine K; Smid, Marcel; Sieuwerts, Anieta M; Wasielewski, Marijke; de Weerd, Vanja; Trapman-Jansen, Anita M A C; van den Ouweland, Ans; Brüggenwirth, Hennie; van I Jcken, Wilfred F J; Klijn, Jan G M; van der Spek, Peter J; Foekens, John A; Martens, John W M; Schutte, Mieke; Meijers-Heijboer, Hanne

2012-04-01

CHEK2 1100delC is a moderate-risk cancer susceptibility allele that confers a high breast cancer risk in a polygenic setting. Gene expression profiling of CHEK2 1100delC breast cancers may reveal clues to the nature of the polygenic CHEK2 model and its genes involved. Here, we report global gene expression profiles of a cohort of 155 familial breast cancers, including 26 CHEK2 1100delC mutant tumors. In line with previous work, all CHEK2 1100delC mutant tumors clustered among the hormone receptor-positive breast cancers. In the hormone receptor-positive subset, a 40-gene CHEK2 signature was subsequently defined that significantly associated with CHEK2 1100delC breast cancers. The identification of a CHEK2 gene signature implies an unexpected biological homogeneity among the CHEK2 1100delC breast cancers. In addition, all 26 CHEK2 1100delC tumors classified as luminal intrinsic subtype breast cancers, with 8 luminal A and 18 luminal B tumors. This biological make-up of CHEK2 1100delC breast cancers suggests that a relatively limited number of additional susceptibility alleles are involved in the polygenic CHEK2 model. Identification of these as-yet-unknown susceptibility alleles should be aided by clues from the 40-gene CHEK2 signature.

[Frequency of CHEK2 gene mutations in patients with breast cancer from the Republic of Bashkortostan].

PubMed

2014-01-01

Several studies have shown, that mutation in CHEK2 gene can increase the risk of different cancers, including breast cancer (BC). Clearly, that character of mutations distribution in the defined regions is depended on genetic structure of the population. We conducted the screening of mutations c.1100delC, c.444 + 1G>A, de15395, p.I157T andIp.R145Win CHEK2 gene in patients with breast cancer (n = 977) and in control group (n = 1069) originating from the Republic of Bashkortostan. The mutation de15395 in CHEK2 gene was detected with frequency of 1,23% (12/977)in woman with BC and 0.09% (1/1069) in controls (OR:13.28, CI 95%: 1.72-102.33, p = 0.003). Mutations c.1100delC and c.444 + 1G>A were found in BC patients and controls with frequencies of 0.4%, 0.4% (4/977) and 0.09% (1/1069), 0.2% (2/1069), respectively. The missense mutation p.I157T in CHEK2 was found as the most common variant in two studied cohorts (approximately 5%), but differences did not achieved statistical significance. We found the ethnic specificity in distribution of truncating mutations, which occurs mainly among the women of Slavic origin. All three mutations were identified in women of Russian and Ukrainian ethnic origin. Mutations c.1100delC and c.444 + 1G>A in CHEK2 gene were not detected in Bashkirs and Tatars, but CHEK2 de15395 mutation was observed in Tatars.

A risk of breast cancer in women - carriers of constitutional CHEK2 gene mutations, originating from the North - Central Poland

PubMed Central

2014-01-01

Background Germline mutations of the CHEK2 gene have been reported to be associated with breast cancer. In this study, we analyzed the association of CHEK2 mutations with the risk of development of breast cancer in women of North-Central Poland. Methods 420 women with breast cancer and 435 controls were tested for three protein truncating (IVS2 + 1G > A, 1100delC, del5395) and one missense (I157T) CHEK2 mutation. IVS2 + 1G > A and I157T mutations were identified by RFLP-PCR, 1100delC variant was analyzed using an ASO-PCR and del5395 mutation by multiplex-PCR. The statistical tests: the odds ratio (OR) and Fisher’s exact test were used. Results In 33 out of 420 (7.9%) women consecutively diagnosed with breast cancer, we detected one of four analyzed CHEK2 mutations: I157T, 1100delC, IVS2 + 1G > A or del5395. Together they were not associated with the increased risk of breast cancer (North-Central control group: OR = 1.6, p = 0.124; the general Polish population: OR = 1.4, p = 0.109). This association was only seen for IVS2 + 1G > A mutation (OR = 3.0; p = 0.039). One of the three truncating CHEK2 mutations (IVS2 + 1G > A, 1100delC, del5395) was present in 9 of 420 women diagnosed with breast cancer (2.1%) and in 4 of 121 women (3.3%) with a history of breast cancer in a first- and/or second- degree relatives. Together they were associated with the increased risk of disease in these groups, compared to the general Polish population (OR = 2.1, p = 0.053 and OR = 3.2; p = 0.044, respectively). I157T mutation was detected in 25 of 420 women diagnosed with breast cancer (6.0%) and in 8 of 121 women (6.6%) with a history of breast cancer in first- and/or second- degree relatives. The prevalance of I157T mutation was 4.1% (18/435) in North-Central control group and 4.8% (265/5.496) in the general Polish population. However it was not associated with an increased risk of breast cancer. Conclusion Obtained results suggest that CHEK2 mutations could potentially contribute to the susceptibility to breast cancer. The germline mutations of CHEK2, especially the truncating ones confer low-penetrance breast cancer predisposition that contribute significantly to familial clustering of breast cancer at the population level. PMID:24713400

A risk of breast cancer in women - carriers of constitutional CHEK2 gene mutations, originating from the North - Central Poland.

PubMed

Bąk, Aneta; Janiszewska, Hanna; Junkiert-Czarnecka, Anna; Heise, Marta; Pilarska-Deltow, Maria; Laskowski, Ryszard; Pasińska, Magdalena; Haus, Olga

2014-04-08

Germline mutations of the CHEK2 gene have been reported to be associated with breast cancer. In this study, we analyzed the association of CHEK2 mutations with the risk of development of breast cancer in women of North-Central Poland. 420 women with breast cancer and 435 controls were tested for three protein truncating (IVS2 + 1G > A, 1100delC, del5395) and one missense (I157T) CHEK2 mutation. IVS2 + 1G > A and I157T mutations were identified by RFLP-PCR, 1100delC variant was analyzed using an ASO-PCR and del5395 mutation by multiplex-PCR. The statistical tests: the odds ratio (OR) and Fisher's exact test were used. In 33 out of 420 (7.9%) women consecutively diagnosed with breast cancer, we detected one of four analyzed CHEK2 mutations: I157T, 1100delC, IVS2 + 1G > A or del5395. Together they were not associated with the increased risk of breast cancer (North-Central control group: OR = 1.6, p = 0.124; the general Polish population: OR = 1.4, p = 0.109). This association was only seen for IVS2 + 1G > A mutation (OR = 3.0; p = 0.039). One of the three truncating CHEK2 mutations (IVS2 + 1G > A, 1100delC, del5395) was present in 9 of 420 women diagnosed with breast cancer (2.1%) and in 4 of 121 women (3.3%) with a history of breast cancer in a first- and/or second- degree relatives. Together they were associated with the increased risk of disease in these groups, compared to the general Polish population (OR = 2.1, p = 0.053 and OR = 3.2; p = 0.044, respectively). I157T mutation was detected in 25 of 420 women diagnosed with breast cancer (6.0%) and in 8 of 121 women (6.6%) with a history of breast cancer in first- and/or second- degree relatives. The prevalance of I157T mutation was 4.1% (18/435) in North-Central control group and 4.8% (265/5.496) in the general Polish population. However it was not associated with an increased risk of breast cancer. Obtained results suggest that CHEK2 mutations could potentially contribute to the susceptibility to breast cancer. The germline mutations of CHEK2, especially the truncating ones confer low-penetrance breast cancer predisposition that contribute significantly to familial clustering of breast cancer at the population level.

Prevalence of 185delAG and 5382insC mutations in BRCA1, and 6174delT in BRCA2 in women of Ashkenazi Jewish origin in southern Brazil

PubMed Central

Dillenburg, Crisle Vignol; Bandeira, Isabel Cristina; Tubino, Taiana Valente; Rossato, Luciana Grazziotin; Dias, Eleonora Souza; Bittelbrunn, Ana Cristina; Leistner-Segal, Sandra

2012-01-01

Certain mutations in BRCA1 and BRCA2 genes are frequent in the Ashkenazi Jewish population. Several factors contribute to this increased frequency, including consanguineous marriages and an event known as a “bottleneck”, which occurred in the past and caused a drastic reduction in the genetic variability of this population. Several studies were performed over the years in an attempt to elucidate the role of BRCA1 and BRCA2 genes in susceptibility to breast cancer. The aim of this study was to estimate the carrier frequency of certain common mutations in the BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) genes in an Ashkenazi Jewish population from Porto Alegre, Brazil. Molecular analyses were done by PCR followed by RFLP (ACRS). The carrier frequencies for BRCA1 185delAG and 5382insC were 0.78 and 0 respectively, and 0.4 for the BRCA2 6174deT mutation. These findings are similar to those of some prior studies but differ from others, possibly due to excluding individuals with a personal or family history of cancer. Our sample was drawn from the community group and included individuals with or without a family or personal history of cancer. Furthermore, increased dispersion among Ashkenazi subpopulations may be the result of strong genetic drift and/or admixture. It is therefore necessary to consider the effects of local admixture on the mismatch distributions of various Jewish populations. PMID:23055798

Prevalence of 185delAG and 5382insC mutations in BRCA1, and 6174delT in BRCA2 in women of Ashkenazi Jewish origin in southern Brazil.

PubMed

Dillenburg, Crisle Vignol; Bandeira, Isabel Cristina; Tubino, Taiana Valente; Rossato, Luciana Grazziotin; Dias, Eleonora Souza; Bittelbrunn, Ana Cristina; Leistner-Segal, Sandra

2012-07-01

Certain mutations in BRCA1 and BRCA2 genes are frequent in the Ashkenazi Jewish population. Several factors contribute to this increased frequency, including consanguineous marriages and an event known as a "bottleneck", which occurred in the past and caused a drastic reduction in the genetic variability of this population. Several studies were performed over the years in an attempt to elucidate the role of BRCA1 and BRCA2 genes in susceptibility to breast cancer. The aim of this study was to estimate the carrier frequency of certain common mutations in the BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) genes in an Ashkenazi Jewish population from Porto Alegre, Brazil. Molecular analyses were done by PCR followed by RFLP (ACRS). The carrier frequencies for BRCA1 185delAG and 5382insC were 0.78 and 0 respectively, and 0.4 for the BRCA2 6174deT mutation. These findings are similar to those of some prior studies but differ from others, possibly due to excluding individuals with a personal or family history of cancer. Our sample was drawn from the community group and included individuals with or without a family or personal history of cancer. Furthermore, increased dispersion among Ashkenazi subpopulations may be the result of strong genetic drift and/or admixture. It is therefore necessary to consider the effects of local admixture on the mismatch distributions of various Jewish populations.

Clinical relevance of CHEK2 and NBN mutations in the macedonian population.

PubMed

Kostovska, I Maleva; Jakimovska, M; Kubelka-Sabit, K; Karadjozov, M; Arsovski, A; Stojanovska, L; Plaseska-Karanfilska, D

2015-06-01

Clinical importance of the most common CHEK2 (IVS2+1 G>A, 1100delC, I157T and del5395) and NBN (R215W and 657del5) gene mutations for breast cancer development in Macedonian breast cancer patients is unknown. We performed a case-control study including 300 Macedonian breast cancer patients and 283 Macedonian healthy controls. Genotyping was done using a fast and highly accurate single-nucleotide primer extension method for the detection of five mutations in a single reaction. The detection of the del5395 was performed using an allele-specific duplex polymerase chain reaction (PCR) assay. We have found that mutations were more frequent in breast cancer patients (n = 13, 4.3%) than in controls (n = 5, 1.8%), although without statistical significance. Twelve patients were heterozygous for one of the analyzed mutations, while one patient had two mutations (NBN R215W and CHEK2 I157T). The most frequent variant was I157T, found in 10 patients and four controls (p = 0.176) and was found to be associated with familial breast cancer (p = 0.041). CHEK2 1100delC and NBN 657del5 were each found in one patient and not in the control group. CHEK2 IVS2+1G>A and del5395 were not found in our cohort. Frequencies of the studied mutations are low and they are not likely to represent alleles of clinical importance in the Macedonian population.

Hacia el consumo informado de tabaco en México: efecto de las advertencias con pictogramas en población fumadora

PubMed Central

Thrasher, James F; Pérez-Hernández, Rosaura; Arillo-Santillán, Edna; Barrientos-Gutiérrez, Inti

2015-01-01

Resumen Objetivo Evaluar el efecto de las advertencias sanitarias (AS) con pictogramas en las cajetillas de tabaco en adultos fumadores. Material y métodos Cohorte de fumadores con representatividad poblacional de siete ciudades mexi canas, antes (2010) y después (2011) de la implementación de AS con pictogramas (ASP). Para determinar el cambio en las variables sobre el impacto cognitivo y conductual de las advertencias, se estimaron modelos bivariados y ajustados de ecuaciones de estimación generalizada. En el Segundo levantamiento (2011), se estimaron modelos para determiner los factores que se asocian con el reporte de recordar cada advertencia que había entrado al mercado, además de los factores asociados con el autorreporte del impacto de cada advertencia vigente. Resultados Se observaron incrementos importantes de 2010 a 2011 en los conocimientos sobre los riesgos de fumar, los componentes tóxicos del tabaco y el número telefónico para recibir consejos sobre dejar de fumar. La recordación e impacto de las primeras advertencias con pictogramas parecen ser amplios y equitativos a través de la población fumadora. En comparación con 2010, un mayor nivel de ex fumadores entrevistados en 2011 reportaron que las advertencias habían influido mucho en dejar de fumar (RM=2.44, 95% IC 1.27–4.72). Conclusiones Las AS con pictogramas han logrado un impacto importante en el conocimiento y conducta, información relevante para la población y en tomadores de decisiones. PMID:22689162

Correctors of the Major Cystic Fibrosis Mutant Interact through Membrane-Spanning Domains.

PubMed

Laselva, Onofrio; Molinski, Steven; Casavola, Valeria; Bear, Christine E

2018-06-01

The most common cystic fibrosis causing mutation is deletion of phenylalanine at position 508 (F508del), a mutation that leads to protein misassembly with defective processing. Small molecule corrector compounds: VX-809 or Corr-4a (C4) partially restores processing of the major mutant. These two prototypical corrector compounds cause an additive effect on F508del/cystic fibrosis transmembrane conductance regulator (CFTR) processing, and hence were proposed to act through distinct mechanisms: VX-809 stabilizing the first membrane-spanning domain (MSD) 1, and C4 acting on the second half of the molecule [consisting of MSD2 and/or nucleotide binding domain (NBD) 2]. We confirmed the effect of VX-809 in enhancing the stability of MSD1 and showed that it also allosterically modulates MSD2 when coexpressed with MSD1. We showed for the first time that C4 stabilizes the second half of the CFTR protein through its action on MSD2. Given the allosteric effect of VX-809 on MSD2, we were prompted to test the hypothesis that the two correctors interact in the full-length mutant protein. We did see evidence supporting their interaction in the full-length F508del-CFTR protein bearing secondary mutations targeting domain:domain interfaces. Disruption of the MSD1:F508del-NBD1 interaction (R170G) prevented correction by both compounds, pointing to the importance of this interface in processing. On the other hand, stabilization of the MSD2:F508del-NBD1 interface (by introducing R1070W) led to a synergistic effect of the compound combination on the total abundance of both the immature and mature forms of the protein. Together, these findings suggest that the two correctors interact in stabilizing the complex of MSDs in F508del-CFTR. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

77 FR 2606 - Unblocking of Specially Designated Nationals and Blocked Persons Pursuant to Executive Order 12978

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-18

.... RENTERIA CAICEDO, Beatriz Eugenia, c/o INVERSIONES AGROINDUSTRIALES DEL OCCIDENTE LTDA., Bogota, Colombia... ILOVIN S.A., Bogota, Colombia; c/o INVERSIONES DEL PRADO ABDALA SAIEH Y CIA. S.C.A., Barranquilla...., Bogota, Colombia; c/o INVERSIONES DEL PRADO ABDALA SAIEH Y CIA. S.C.A., Barranquilla, Colombia; c/o KAREN...

Cost effectiveness of population based BRCA1 founder mutation testing in Sephardi Jewish women.

PubMed

Patel, Shreeya; Legood, Rosa; Evans, D Gareth; Turnbull, Clare; Antoniou, Antonis C; Menon, Usha; Jacobs, Ian; Manchanda, Ranjit

2018-04-01

Population-based BRCA1/BRCA2 founder-mutation testing has been demonstrated as cost effective compared with family history based testing in Ashkenazi Jewish women. However, only 1 of the 3 Ashkenazi Jewish BRCA1/BRCA2 founder mutations (185delAG[c.68_69delAG]), 5382insC[c.5266dupC]), and 6174delT[c.5946delT]) is found in the Sephardi Jewish population (185delAG[c.68_69delAG]), and the overall prevalence of BRCA mutations in the Sephardi Jewish population is accordingly lower (0.7% compared with 2.5% in the Ashkenazi Jewish population). Cost-effectiveness analyses of BRCA testing have not previously been performed at these lower BRCA prevalence levels seen in the Sephardi Jewish population. Here we present a cost-effectiveness analysis for UK and US populations comparing population testing with clinical criteria/family history-based testing in Sephardi Jewish women. A Markov model was built comparing the lifetime costs and effects of population-based BRCA1 testing, with testing using family history-based clinical criteria in Sephardi Jewish women aged ≥30 years. BRCA1 carriers identified were offered magnetic resonance imaging/mammograms and risk-reducing surgery. Costs are reported at 2015 prices. Outcomes include breast cancer, ovarian cancer, and excess deaths from heart disease. All costs and outcomes are discounted at 3.5%. The time horizon is lifetime, and perspective is payer. The incremental cost-effectiveness ratio per quality-adjusted life-year was calculated. Parameter uncertainty was evaluated through 1-way and probabilistic sensitivity analysis. Population testing resulted in gain in life expectancy of 12 months (quality-adjusted life-year = 1.00). The baseline discounted incremental cost-effectiveness ratio for UK population-based testing was £67.04/quality-adjusted life-year and for US population was $308.42/quality-adjusted life-year. Results were robust in the 1-way sensitivity analysis. The probabilistic sensitivity analysis showed 100% of simulations were cost effective at £20,000/quality-adjusted life-year UK and the $100,000/quality-adjusted life-year US willingness-to-pay thresholds. Scenario analysis showed that population testing remains cost effective in UK and US populations, even if premenopausal oophorectomy does not reduce breast cancer risk or if hormone replacement therapy compliance is nil. Population-based BRCA1 testing is highly cost effective compared with clinical criteria-driven approach in Sephardi Jewish women. This supports changing the paradigm to population-based BRCA testing in the Jewish population, regardless of Ashkenazi/Sephardi ancestry. Copyright © 2017 Elsevier Inc. All rights reserved.

Impaired Heme Binding and Aggregation of Mutant Cystathionine β-Synthase Subunits in Homocystinuria

PubMed Central

Janošík, Miroslav; Oliveriusová, Jana; Janošíková, Bohumila; Sokolová, Jitka; Kraus, Eva; Kraus, Jan P.; Kožich, Viktor

2001-01-01

During the past 20 years, cystathionine β-synthase (CBS) deficiency has been detected in the former Czechoslovakia with a calculated frequency of 1:349,000. The clinical manifestation was typical of homocystinuria, and about half of the 21 patients were not responsive to pyridoxine. Twelve distinct mutations were detected in 30 independent homocystinuric alleles. One half of the alleles carried either the c.833 T→C or the IVS11−2A→C mutation; the remaining alleles contained private mutations. The abundance of five mutant mRNAs with premature stop codons was analyzed by PCR-RFLP. Two mRNAs, c.828_931ins104 (IVS7+1G→A) and c.1226 G→A, were severely reduced in the cytoplasm as a result of nonsense-mediated decay. In contrast, the other three mRNAs—c.19_20insC, c.28_29delG, and c.210_235del26 (IVS1−1G→C)—were stable. Native western blot analysis of 14 mutant fibroblast lines showed a paucity of CBS antigen, which was detectable only in aggregates. Five mutations—A114V (c.341C→T), A155T (c.463G→A), E176K (c.526G→A), I278T (c.833T→C), and W409_G453del (IVS11−2A→C)—were expressed in Escherichia coli. All five mutant proteins formed substantially more aggregates than did the wild-type CBS, and no aggregates contained heme. These data suggest that abnormal folding, impaired heme binding, and aggregation of mutant CBS polypeptides may be common pathogenic mechanisms in CBS deficiency. PMID:11359213

Exome Sequencing Identifies a Founder Frameshift Mutation in an Alternative Exon of USH1C as the Cause of Autosomal Recessive Retinitis Pigmentosa with Late-Onset Hearing Loss

PubMed Central

Khateb, Samer; Zelinger, Lina; Ben-Yosef, Tamar; Crystal-Shalit, Ornit; Gross, Menachem; Banin, Eyal; Sharon, Dror

2012-01-01

We used a combined approach of homozygosity mapping and whole exome sequencing (WES) to search for the genetic cause of autosomal recessive retinitis pigmentosa (arRP) in families of Yemenite Jewish origin. Homozygosity mapping of two arRP Yemenite Jewish families revealed a few homozygous regions. A subsequent WES analysis of the two index cases revealed a shared homozygous novel nucleotide deletion (c.1220delG) leading to a frameshift (p.Gly407Glufs*56) in an alternative exon (#15) of USH1C. Screening of additional Yemenite Jewish patients revealed a total of 16 homozygous RP patients (with a carrier frequency of 0.008 in controls). Funduscopic and electroretinography findings were within the spectrum of typical RP. While other USH1C mutations usually cause Usher type I (including RP, vestibular dysfunction and congenital deafness), audiometric screening of 10 patients who are homozygous for c.1220delG revealed that patients under 40 years of age had normal hearing while older patients showed mild to severe high tone sensorineural hearing loss. This is the first report of a mutation in a known USH1 gene that causes late onset rather than congenital sensorineural hearing loss. The c.1220delG mutation of USH1C accounts for 23% of RP among Yemenite Jewish patients in our cohort. PMID:23251578

High resolution melting curve analysis targeting the HBB gene mutational hot-spot offers a reliable screening approach for all common as well as most of the rare beta-globin gene mutations in Bangladesh.

PubMed

Islam, Md Tarikul; Sarkar, Suprovath Kumar; Sultana, Nusrat; Begum, Mst Noorjahan; Bhuyan, Golam Sarower; Talukder, Shezote; Muraduzzaman, A K M; Alauddin, Md; Islam, Mohammad Sazzadul; Biswas, Pritha Promita; Biswas, Aparna; Qadri, Syeda Kashfi; Shirin, Tahmina; Banu, Bilquis; Sadya, Salma; Hussain, Manzoor; Sarwardi, Golam; Khan, Waqar Ahmed; Mannan, Mohammad Abdul; Shekhar, Hossain Uddin; Chowdhury, Emran Kabir; Sajib, Abu Ashfaqur; Akhteruzzaman, Sharif; Qadri, Syed Saleheen; Qadri, Firdausi; Mannoor, Kaiissar

2018-01-02

Bangladesh lies in the global thalassemia belt, which has a defined mutational hot-spot in the beta-globin gene. The high carrier frequencies of beta-thalassemia trait and hemoglobin E-trait in Bangladesh necessitate a reliable DNA-based carrier screening approach that could supplement the use of hematological and electrophoretic indices to overcome the barriers of carrier screening. With this view in mind, the study aimed to establish a high resolution melting (HRM) curve-based rapid and reliable mutation screening method targeting the mutational hot-spot of South Asian and Southeast Asian countries that encompasses exon-1 (c.1 - c.92), intron-1 (c.92 + 1 - c.92 + 130) and a portion of exon-2 (c.93 - c.217) of the HBB gene which harbors more than 95% of mutant alleles responsible for beta-thalassemia in Bangladesh. Our HRM approach could successfully differentiate ten beta-globin gene mutations, namely c.79G > A, c.92 + 5G > C, c.126_129delCTTT, c.27_28insG, c.46delT, c.47G > A, c.92G > C, c.92 + 130G > C, c.126delC and c.135delC in heterozygous states from the wild type alleles, implying the significance of the approach for carrier screening as the first three of these mutations account for ~85% of total mutant alleles in Bangladesh. Moreover, different combinations of compound heterozygous mutations were found to generate melt curves that were distinct from the wild type alleles and from one another. Based on the findings, sixteen reference samples were run in parallel to 41 unknown specimens to perform direct genotyping of the beta-thalassemia specimens using HRM. The HRM-based genotyping of the unknown specimens showed 100% consistency with the sequencing result. Targeting the mutational hot-spot, the HRM approach could be successfully applied for screening of beta-thalassemia carriers in Bangladesh as well as in other countries of South Asia and Southeast Asia. The approach could be a useful supplement of hematological and electrophortic indices in order to avoid false positive and false negative results.

Short communication: novel truncating mutations in the CFTR gene causing a severe form of cystic fibrosis in Italian patients.

PubMed

Lenarduzzi, S; Morgutti, M; Crovella, S; Coiana, A; Rosatelli, M C

2014-11-14

Cystic fibrosis (CF) is a common recessive genetic disease caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. More than 1800 different mutations have been described to date. Here, we report 3 novel mutations in CFTR in 3 Italian CF patients. To detect and identify 36 frequent mutations in Caucasians, we used the INNO-LiPA CFTR19 and INNO-LiPA CFTR17+Tn Update kits (Innogenetics; Ghent, Belgium). Our first analysis did not reveal both of the responsible mutations; thus, direct sequencing of the CFTR gene coding region was performed. The 3 patients were compound heterozygous. In one allele, the F508del (c.1521_1523delCTT, p.PHE508del) mutation in exon 11 was observed in each case. For the second allele, in patient No.1, direct sequencing revealed an 11-base pair deletion (GAGGCGATACT) in exon 14 (c.2236_2246del; pGlu746Alafs*29). In patient No. 2, direct sequencing revealed a nonsense mutation at nucleotide 3892 (c.3892G>T) in exon 24. In patient No. 3, direct sequencing revealed a deletion of cytosine in exon 27 (c.4296delC; p.Asn1432Lysfs*16). These 3 novel mutations indicate the production of a truncated protein, which consequently results in a non-functional polypeptide.

Role of Leptin Deficiency, Inefficiency, and Leptin Receptors in Obesity.

PubMed

Wasim, Muhammad; Awan, Fazli Rabbi; Najam, Syeda Sadia; Khan, Abdul Rehman; Khan, Haq Nawaz

2016-10-01

Leptin protein consists of 167 amino acids, which is mainly secreted from the white adipose tissue. This protein acts on the hypothalamic regions of the brain which control eating behavior, thus playing a significant role in maintaining body's metabolism. Leptin receptors belong to glycoprotein 130 (gp130) family of cytokine receptors and exist in six isoforms (LEPR a-f), and all the isoforms are encoded by LEPR gene; out of these isoforms, the LEPR-b receptor is the 'longest form,' and in most of the cases, mutations in this isoform cause severe obesity. Also, mutations in the leptin gene (LEP) or its receptors gene can lead to obesity. Some biochemical pathways affect the bioactivity of leptin and/or its receptors. To date, eleven pathogenic mutations have been reported in the LEP which are p.L72S, p.N103K, p.R105W, p.H118L, p.S141C, p.W121X c.104_106delTCA, c.135del3bp, c.398delG, c.481_482delCT, and c.163C>T. Different mutations in the LEPR have also been reported as c.2396-1 G>T, c.1675 G>A, p.P316T, etc. In some studies, where leptin was deficient, leptin replacement therapy has shown positive impact by preventing weight gain and obesity.

Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation

PubMed Central

Stefano, Daniela De; Villella, Valeria R; Esposito, Speranza; Tosco, Antonella; Sepe, Angela; Gregorio, Fabiola De; Salvadori, Laura; Grassia, Rosa; Leone, Carlo A; Rosa, Giuseppe De; Maiuri, Maria C; Pettoello-Mantovani, Massimo; Guido, Stefano; Bossi, Anna; Zolin, Anna; Venerando, Andrea; Pinna, Lorenzo A; Mehta, Anil; Bona, Gianni; Kroemer, Guido; Maiuri, Luigi; Raia, Valeria

2014-01-01

Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in CftrF508del homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the F508del-CFTR mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from F508del homozygous CF patients, and these effects persisted for 24 h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both in vivo, in mice, and in vitro, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 F508del-CFTR homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells in vivo, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of TNF/TNF-alpha (tumor necrosis factor) and CXCL8 (chemokine [C-X-C motif] ligand 8) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the F508del-CFTR mutation. PMID:25350163

A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathy.

PubMed

Li, Xiaobo; Hu, Zhengmao; Liu, Lei; Xie, Yongzhi; Zhan, Yajing; Zi, Xiaohong; Wang, Junling; Wu, Lixiang; Xia, Kun; Tang, Beisha; Zhang, Ruxu

2015-06-16

To identify the underlying genetic cause in a consanguineous Chinese family segregating distal hereditary motor neuropathy (dHMN) in an autosomal recessive pattern. We used whole-exome sequencing and homozygosity mapping to detect the genetic variant in 2 affected individuals of the consanguineous Chinese family with dHMN. RNA analysis of peripheral blood leukocytes and immunofluorescence and immunoblotting of stable cell lines were performed to support the pathogenicity of the identified mutation. We identified 3 shared novel homozygous variants in 3 shared homozygous regions of the affected individuals. Sequencing of these 3 variants in family members revealed the c.151+1G>T mutation in SIGMAR1 gene, which located in homozygous region spanning approximately 5.3 Mb at chromosome 9p13.1-p13.3, segregated with the dHMN phenotype. The mutation causes an alternative splicing event and generates a transcript variant with an in-frame deletion of 60 base pairs in exon 1 (c.92_151del), and results in an internally shortened protein σ1R(31_50del). The proteasomal inhibitor treatment increased the intracellular amount of σ1R(31_50del) and led to the formation of nuclear aggregates. Stable expressing σ1R(31_50del) induced endoplasmic reticulum stress and enhanced apoptosis. The homozygous c.151+1G>T mutation in SIGMAR1 caused a novel form of autosomal recessive dHMN in a Chinese consanguineous family. Endoplasmic reticulum stress may have a role in the pathogenesis of dHMN. © 2015 American Academy of Neurology.

46. C.P.S., photographer March 1936 MENDOCINO COUNTY, SECTION, HIGHWAY 1. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

46. C.P.S., photographer March 1936 MENDOCINO COUNTY, SECTION, HIGHWAY 1. MEN-1-J#135, 384+50 81TTC2, LOOKING SOUTH LANES FLAT, C.P.S., 36. - Redwood National & State Parks Roads, California coast from Crescent City to Trinidad, Crescent City, Del Norte County, CA

Aarskog-Scott syndrome: clinical update and report of nine novel mutations of the FGD1 gene.

PubMed

Orrico, A; Galli, L; Faivre, L; Clayton-Smith, J; Azzarello-Burri, S M; Hertz, J M; Jacquemont, S; Taurisano, R; Arroyo Carrera, I; Tarantino, E; Devriendt, K; Melis, D; Thelle, T; Meinhardt, U; Sorrentino, V

2010-02-01

Mutations in the FGD1 gene have been shown to cause Aarskog-Scott syndrome (AAS), or facio-digito-genital dysplasia (OMIM#305400), an X-linked disorder characterized by distinctive genital and skeletal developmental abnormalities with a broad spectrum of clinical phenotypes. To date, 20 distinct mutations have been reported, but little phenotypic data are available on patients with molecularly confirmed AAS. In the present study, we report on our experience of screening for mutations in the FGD1 gene in a cohort of 60 European patients with a clinically suspected diagnosis of AAS. We identified nine novel mutations in 11 patients (detection rate of 18.33%), including three missense mutations (p.R402Q; p.S558W; p.K748E), four truncating mutations (p.Y530X; p.R656X; c.806delC; c.1620delC), one in-frame deletion (c.2020_2022delGAG) and the first reported splice site mutation (c.1935+3A>C). A recurrent mutation (p.R656X) was detected in three independent families. We did not find any evidence for phenotype-genotype correlations between type and position of mutations and clinical features. In addition to the well-established phenotypic features of AAS, other clinical features are also reported and discussed. Copyright 2010 Wiley-Liss, Inc.

[The significance of pedigree genetic screening and rapid immunological parameters in the diagnosis of primary hemophagocytic lymphohistiocytosis].

PubMed

Zhang, J; Wang, Y N; Wang, J S; Wu, L; Wei, N; Fu, L; Gao, Z; Chen, J H; Pei, R J; Wang, Z

2016-07-01

To investigate the significance of pedigree genetic screening and rapid immunological parameters in the diagnosis of primary hemophagocytic lymphohistiocytosis (HLH). Four cases of primary HLH patients with PRF1, UNC13D and SH2D1A gene mutations were conducted pedigree investigation, including family genetic screening and detections of immunological parameters (NK cell activity, CD107a degranulation and expression of HLH related defective protein), to evaluate the significance of these different indicators in the diagnosis of primary HLH and explore their correlations. The DNA mutations of the four families included missense mutation c.T172C (p.S58P) and non- frameshift deletions c.1083_1094del (p.361_365del), missense mutation c.C1349T (p.T450M) and frameshift mutation c.1090_1091delCT (p.T364fsX93) in PRF1 gene, missense mutation c.G2588A (p.G863D) in UNC13D gene and hemizygous mutation c.32T>G (p.I11S) in SH2D1A gene. The patients and their family members presented decreased NK cell activities. Individuals who carried mutations of PRF1 gene and SH2D1A gene showed low expression of perforin (PRF1) and signaling lymphocytic activation molecule associated protein (SAP). And the patient with UNC13D gene mutation and his family member with identical mutation showed significant reducing cytotoxic degranulation function (expression of CD107a). Pedigree genetic screening and rapid detection of immunological parameters might play an important role in the diagnosis of primary HLH, and both of them had good consistency. As an efficient detection means, the rapid immunological detection indicators would provide reliable basis for the early diagnosis of the primary HLH.

The Potential Contribution of BRCA Mutations to Early Onset and Familial Breast Cancer in Uzbekistan.

PubMed

Abdikhakimov, Abdulla; Tukhtaboeva, Mukaddas; Adilov, Bakhtiyar; Turdikulova, Shahlo

2016-01-01

Breast cancer is the most common malignancy in women and affects approximately 1 out of 8 females in the US. Risk of developing breast cancer is strongly influenced by genetic factors. Germ-line mutations in BRCA1 and BRCA2 genes are associated with 5-10% of breast cancer incidence. To reduce the risk of developing cancer and to increase the likelihood of early detection, carriers of BRCA1 or BRCA2 mutations are offered surveillance programs and effective preventive medical interventions. Identification of founder mutations of BRCA1/2 in high risk communities can have a significant impact on the management of hereditary cancer at the level of the national healthcare systems, making genetic testing more affordable and cost-effective. BRCA1 and BRCA2 mutations in breast cancer patients have not been characterized in the Uzbek population. This pilot study aimed to investigate the contribution of BRCA1 and BRCA2 mutation to early onset and familial cases of breast cancer in Uzbekistan. A total of 67 patients with breast cancer and 103 age-matched disease free controls were included in this study. Utilizing SYBR Green based real-time allele-specific PCR, we have analyzed DNA samples of patients with breast cancer and disease free controls to identify the following BRCA1 and BRCA2 mutations: BRCA1 5382insC, BRCA1 4153delA, BRCA1 185delAG, BRCA1 300T>G, BRCA2 6174delT. Three unrelated samples (4.5%) were found to be positive for the heterozygous 5382insCBRCA1 mutation, representing a possible founder mutation in the Uzbek population, supporting the need for larger studies examining the contribution of this mutation to breast cancer incidence in Uzbekistan. We did not find BRCA1 4153delA, BRCA1 185delAG, BRCA1 300T>G, and BRCA2 6174delT mutations. This preliminary evidence suggests a potential contribution of BRCA1 5382insC mutation to breast cancer development in Uzbek population. Taking into account a high disease penetrance in carriers of BRCA1 mutation, it seems reasonable to recommend inclusion of the 5382insC mutation test in future research on the development of screening programs for breast cancer prevention in Uzbekistan.

PAX3 mutations and clinical characteristics in Chinese patients with Waardenburg syndrome type 1.

PubMed

Wang, Juan; Li, Shiqiang; Xiao, Xueshan; Wang, Panfeng; Guo, Xiangming; Zhang, Qingjiong

2010-06-22

To detect paired box gene 3 (PAX3) mutations and associated phenotypes in Chinese patients with Waardenburg syndrome type 1 (WS1). Five unrelated families with suspected WS1 were selected from our Genomic DNA Repository for Hereditary Eye Diseases. The coding and adjacent intronic regions of PAX3 were amplified by polymerase chain reaction and the amplicons were then analyzed by cycle sequencing. Variations detected were further evaluated in available family members as well as one hundred controls with heteroduplex-single strand conformational polymorphism (heteroduplex-SSCP) analysis and/or clone sequencing. Three novel and two known mutations in PAX3 were detected in five patients, respectively: c.567_586+17del (p.Asp189_Gln505delinsGluGlyGlyAlaLeuAlaGly), c.456_459dupTTCC (p.Ile154PhefsX162), c.795_800delCTGGTT (p.Trp266_Phe267del), c.799T>A (p.Phe267Ile), and c.667C>T (p.Arg223X). Two novel mutations proved to be de novo as their parents did not carry the mutations. All five patients with PAX3 mutations had dystopia canthorum and different iris color and fundi between their two eyes. However, none had white forelock, skin hypopigmentation, and deafness. Our findings expand the frequency and spectrum of PAX3 mutations and ethnic-related phenotypes in Chinese patients with WS1. De novo mutations in PAX3 have not been reported before.

PAX3 mutations and clinical characteristics in Chinese patients with Waardenburg syndrome type 1

PubMed Central

Wang, Juan; Li, Shiqiang; Xiao, Xueshan; Wang, Panfeng; Guo, Xiangming

2010-01-01

Purpose To detect paired box gene 3 (PAX3) mutations and associated phenotypes in Chinese patients with Waardenburg syndrome type 1 (WS1). Methods Five unrelated families with suspected WS1 were selected from our Genomic DNA Repository for Hereditary Eye Diseases. The coding and adjacent intronic regions of PAX3 were amplified by polymerase chain reaction and the amplicons were then analyzed by cycle sequencing. Variations detected were further evaluated in available family members as well as one hundred controls with heteroduplex-single strand conformational polymorphism (heteroduplex-SSCP) analysis and/or clone sequencing. Results Three novel and two known mutations in PAX3 were detected in five patients, respectively: c.567_586+17del (p.Asp189_Gln505delinsGluGlyGlyAlaLeuAlaGly), c.456_459dupTTCC (p.Ile154PhefsX162), c.795_800delCTGGTT (p.Trp266_Phe267del), c.799T>A (p.Phe267Ile), and c.667C>T (p.Arg223X). Two novel mutations proved to be de novo as their parents did not carry the mutations. All five patients with PAX3 mutations had dystopia canthorum and different iris color and fundi between their two eyes. However, none had white forelock, skin hypopigmentation, and deafness. Conclusions Our findings expand the frequency and spectrum of PAX3 mutations and ethnic-related phenotypes in Chinese patients with WS1. De novo mutations in PAX3 have not been reported before. PMID:20664692

Hereditary fructose intolerance: frequency and spectrum mutations of the aldolase B gene in a large patients cohort from France--identification of eight new mutations.

PubMed

Davit-Spraul, Anne; Costa, Catherine; Zater, Mokhtar; Habes, Dalila; Berthelot, Jacques; Broué, Pierre; Feillet, François; Bernard, Olivier; Labrune, Philippe; Baussan, Christiane

2008-08-01

We investigated the molecular basis of hereditary fructose intolerance (HFI) in 160 patients from 92 families by means of a PCR-based mutation screening strategy, consisting of restriction enzyme digestion and direct sequencing. Sixteen different mutations of the aldolase B (ALDOB) gene were identified in HFI patients. As in previous studies, p.A150P (64%), p.A175D (16%) and p.N335K (5%) were the most common mutated alleles, followed by p.R60X, p.A338V, c.360_363delCAAA (p.N120KfsX30), c.324G>A (p.K108K) and c.625-1G>A. Eight novel mutations were also identified in 10 families with HFI: a one-base deletion (c.146delT (p.V49GfsX27)), a small deletion (c.953del42bp), a small insertion (c.689ins TGCTAA (p.K230MfsX136)), one splice site mutation (c.112+1G>A), one nonsense mutation (c.444G>A (p.W148X)), and three missense mutations (c.170G>C (p.R57P), c.839C>A (p.A280P) and c.932T>C (p.L311P)). Our strategy allows to diagnose 75% of HFI patients using restriction enzymatic analysis and to enlarge the diagnosis to 97% of HFI patients when associated with direct sequencing.

A founder BRCA2 mutation in non-Afrikaner breast cancer patients of the Western Cape of South Africa.

PubMed

van der Merwe, N C; Hamel, N; Schneider, S-R; Apffelstaedt, J P; Wijnen, J T; Foulkes, W D

2012-02-01

Founder mutations in BRCA1 and BRCA2 have been reported in many different populations. We studied 105 Coloured and 16 Black Xhosa women residing in the Western Cape of South Africa diagnosed with breast cancer. We screened these patients using our standard panel of six previously reported SA Afrikaner and Ashkenazi Jewish BRCA1/2 mutations and identified only two Afrikaner mutations. Further screening by the protein truncation test (BRCA1 exon 11, and BRCA2 exons 10 and 11) revealed an additional four deleterious mutations (BRCA1 c.1504_ 1508del,p.Leu502AlafsX2, BRCA2 c.2826_2829del,p.Ile943LysfsX16, c.6447_6448dup,p.Lys2150IlefsX19 and c.5771_5774del,p.Ile1924Argfs X38). The latter, also known in Breast Cancer Information Core nomenclature as 5999del4, was identified in 4 of 105 (3.8%) Coloureds and 4 of 16 (25%) Xhosa women, which makes it a frequent founder mutation in the Western Cape Province. Although this mutation was previously reported to occur in the Netherlands, haplotype analysis indicated two distinct origins for the Dutch and South African mutations, excluding the possibility of a common Dutch ancestor and suggesting gene flow from the indigenous tribes such as the Xhosa to the Coloured population instead. Further studies to determine the carrier rate of this variant in the Xhosa and other SA populations are warranted. © 2011 John Wiley & Sons A/S.

Cerebral visual impairment and intellectual disability caused by PGAP1 variants.

PubMed

Bosch, Daniëlle G M; Boonstra, F Nienke; Kinoshita, Taroh; Jhangiani, Shalini; de Ligt, Joep; Cremers, Frans P M; Lupski, James R; Murakami, Yoshiko; de Vries, Bert B A

2015-12-01

Homozygous variants in PGAP1 (post-GPI attachment to proteins 1) have recently been identified in two families with developmental delay, seizures and/or spasticity. PGAP1 is a member of the glycosylphosphatidylinositol anchor biosynthesis and remodeling pathway and defects in this pathway are a subclass of congenital disorders of glycosylation. Here we performed whole-exome sequencing in an individual with cerebral visual impairment (CVI), intellectual disability (ID), and factor XII deficiency and revealed compound heterozygous variants in PGAP1, c.274_276del (p.(Pro92del)) and c.921_925del (p.(Lys308Asnfs*25)). Subsequently, PGAP1-deficient Chinese hamster ovary (CHO)-cell lines were transfected with either mutant or wild-type constructs and their sensitivity to phosphatidylinositol-specific phospholipase C (PI-PLC) treatment was measured. The mutant constructs could not rescue the PGAP1-deficient CHO cell lines resistance to PI-PLC treatment. In addition, lymphoblastoid cell lines (LCLs) of the affected individual showed no sensitivity to PI-PLC treatment, whereas the LCLs of the heterozygous carrier parents were partially resistant. In conclusion, we report novel PGAP1 variants in a boy with CVI and ID and a proven functional loss of PGAP1 and show, to our knowledge, for the first time this genetic association with CVI.

PubMed

Medina Arnaudo, Gisel Ivana

2017-09-08

Resumen: La valoración del Índice de Filtrado Glomerular (IFG) es fundamental para la selección de potenciales donantes renales. Para su medición existen métodos poco prácticos y complejos, por lo cual se han desarrollado ecuaciones de estimación del IFG. Objetivo: Evaluar el rendimiento diagnóstico de ecuaciones de estimación del IFG a partir de Creatinina y Cistatina C en una población de adultos sanos candidatos a donantes renales. Materiales y métodos: Se llevó a cabo un estudio transversal en 72 pacientes de ambos sexos de entre 18 y 75 años de edad, candidatos a donantes renales. Se les midió el IFG a través del clearance de Iotalamato no marcado (IFGm). Se evaluaron cuatro ecuaciones de estimación del FG (IFGe): MDRD, del estudio "Modification of Diet in Renal Disease"; CKD-EPI-Creatinina (CKD-EPI-CREAT) y CKD-EPI-Creatinina y Cistatina C (CKD-EPI-CREAT+CIS), desarrolladas por el grupo "Chronic Kidney Disease Epidemiology Collaboration"; y la que incluye Creatinina y Cistatina C propuesta por Stevens y col. (STEVENS-CREAT+CIS). Se analizó el desempeño de cada ecuación con respecto al IFGm. Resultados: Las ecuaciones CKD-EPI-CREAT+CIS, STEVENS-CREAT+CIS y CKD-EPI-CREAT mostraron ser más exactas (bias= 1,93; -0,71; -1,53 mL/min/1,73m2 respectivamente) que MDRD (bias= -10,36 mL/min/1,73m2). El mejor rendimiento diagnóstico lo mostró  el IFGe CKD-EPI-CREAT+CIS (LR(+)=9,8; "Positive Likelihood Ratios"), seguido por IFGe STEVENS-CREAT+CIS (LR(+)=4,7) y luego por IFGe CKD-EPI-CREAT (LR(+)=3,7). Discusión: Las ecuaciones CKD-EPI-CREAT+CIS, STEVENS-CREAT+CIS y CKD-EPI-CREAT demostraron tener un desempeño claramente superior a MDRD para estimar el IFG en la población estudiada.

The c.64_80del SMIM1 allele is segregating in the Hutterite population.

PubMed

Coghlan, Gail; Zelinski, Teresa

2016-04-01

The high-incidence red blood cell (RBC) antigen Vel is coded by SMIM1 (small-membrane molecule 1 gene), where a homozygous 17 base pair deletion underlies the majority of Vel- phenotypes. Because anti-Vel has been reported to cause severe hemolytic transfusion reactions and periodically hemolytic disease of the newborn and fetus, identification of individuals negative for Vel is clinically important. RBCs from the members of a large three-generation Hutterite family were serologically determined to be Vel+(w) . Genomic DNA from these family members was polymerase chain reaction amplified and analyzed for SMIM1 polymorphisms by either Sanger sequencing or restriction fragment length polymorphisms. SMIM1 genotyping was also conducted on DNA from an additional 104 Hutterites. All family members whose RBCs weakly expressed the Vel antigen were found to be heterozygous for the c.64_80del mutation in SMIM1. Of the 104 additional Hutterite samples, four were found to be heterozygous for the same SMIM1 mutation. After emigrating to the United States and Canada, the Hutterite population has expanded dramatically. Alleles that initially entered the population have been maintained within the population. The c.64_80del null allele of SMIM1 is one such allele, thus having implications for transfusion medicine and child or maternal health. © 2015 AABB.

45. C.P.S., photographer January 1936 MENDOCINO COUNTY, SECTION, HIGHWAY 1. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

45. C.P.S., photographer January 1936 MENDOCINO COUNTY, SECTION, HIGHWAY 1. MEN-I-J #132, 388+00 81TTC2, LOOKING SOUTH LANES FLAT, C.P.S., 1-36. - Redwood National & State Parks Roads, California coast from Crescent City to Trinidad, Crescent City, Del Norte County, CA

Clinical features of X linked juvenile retinoschisis in Chinese families associated with novel mutations in the RS1 gene.

PubMed

Li, Xiaoxin; Ma, Xiang; Tao, Yong

2007-06-07

To describe the clinical phenotype of X linked juvenile retinoschisis (XLRS) in 12 Chinese families with 11 different mutations in the XLRS1 (RS1) gene. Complete ophthalmic examinations were carried out in 29 affected males (12 probands), 38 heterozygous females carriers, and 100 controls. The coding regions of the RS1 gene that encodes retinoschisin were amplified by polymerase chain reaction and directly sequenced. Of the 29 male participants, 28 (96.6%) displayed typical foveal schisis. Eleven different RS1 mutations were identified in 12 families; four of these mutations, two frameshift mutations (26 del T of exon 1 and 488 del G of exon 5), and two missense mutations (Asp145His and Arg156Gly) of exon 5, had not been previously described. One non-disease-related polymorphism (NSP): 576C to T (Pro192Pro) change was also newly reported herein. We compared genotypes and observed more severe clinical features in families with the following mutations: frameshift mutation (26 del T) of exon 1, the splice donor site mutation (IVS1+2T to C),or Arg102Gln, Arg209His, and Arg213Gln mutations. Severe XLRS phenotypes are associated with the frameshift mutation 26 del T, splice donor site mutation (IVS1+2T to C), and Arg102Gln, Asp145His, Arg209His, and Arg213Gln mutations. The wide variability in the phenotype in Chinese patients with XLRS and different mutations in the RS1 gene is described. Identification of mutations in the RS1 gene and expanded information on clinical manifestations will facilitate early diagnosis, appropriate early therapy, and genetic counseling regarding the prognosis of XLRS.

Clinical features of X linked juvenile retinoschisis in Chinese families associated with novel mutations in the RS1 gene

PubMed Central

Ma, Xiang; Tao, Yong

2007-01-01

Purpose To describe the clinical phenotype of X linked juvenile retinoschisis (XLRS) in 12 Chinese families with 11 different mutations in the XLRS1 (RS1) gene. Methods Complete ophthalmic examinations were carried out in 29 affected males (12 probands), 38 heterozygous females carriers, and 100 controls. The coding regions of the RS1 gene that encodes retinoschisin were amplified by polymerase chain reaction and directly sequenced. Results Of the 29 male participants, 28 (96.6%) displayed typical foveal schisis. Eleven different RS1 mutations were identified in 12 families; four of these mutations, two frameshift mutations (26 del T of exon 1 and 488 del G of exon 5), and two missense mutations (Asp145His and Arg156Gly) of exon 5, had not been previously described. One non-disease-related polymorphism (NSP): 576C to T (Pro192Pro) change was also newly reported herein. We compared genotypes and observed more severe clinical features in families with the following mutations: frameshift mutation (26 del T) of exon 1, the splice donor site mutation (IVS1+2T to C),or Arg102Gln, Arg209His, and Arg213Gln mutations. Conclusions Severe XLRS phenotypes are associated with the frameshift mutation 26 del T, splice donor site mutation (IVS1+2T to C), and Arg102Gln, Asp145His, Arg209His, and Arg213Gln mutations. The wide variability in the phenotype in Chinese patients with XLRS and different mutations in the RS1 gene is described. Identification of mutations in the RS1 gene and expanded information on clinical manifestations will facilitate early diagnosis, appropriate early therapy, and genetic counseling regarding the prognosis of XLRS. PMID:17615541

TRANSMISIÓN VERTICAL DE HTLV-1 EN EL PERÚ

PubMed Central

Villaverde, Jorge Alarcón; Romaní, Franco Romaní; Torres, Silvia Montano; Zunt, Joseph R.

2012-01-01

La infección por el virus linfotrópico humano de células T tipo 1 (HTLV-1) ha sido descrita en muchas áreas del mundo, como en los países del Caribe, Japón, África, Oceanía y en Sudamérica. En la presente revisión definimos la endemicidad del HTLV-1 en el país, planteando cuatro criterios epidemiológicos. Luego discutimos el tema central de la revisión: la transmisión vertical del HTLV-1, que en nuestro país sería uno de los principales mecanismos de transmisión. Dentro del desarrollo de este aspecto en particular, presentamos una estimación de la tasa de transmisión vertical y los factores de riesgo asociados con la transmisión vertical sobre la base de una revisión exhaustiva de estudios nacionales y extranjeros. Con esta revisión pretendemos dar una primera aproximación al estudio de la trasmisión vertical de HTLV-1, un aspecto poco estudiado en nuestro medio. PMID:21537777

Analysis of Space Station Operations in the Space Debris Environment.

DTIC Science & Technology

1984-12-01

o, a Itmd, a Ithi , umco, s atpop, s tplo, a atpm d , aatphi , + expobj,dlo,dmd,dhi,nexplo,nexpuid,nexphi, colide , + objlo,objmd,objhi,cobjlo,cobjmd...tisoic, tiioc,flumco, + soivsl,soivsm, soivsh,numrun double precision c, colide ,rholo,rhomd, rhoh. equivalence(nset(l ),qset(l)) net-7 5000 ncrdr-5...del tlo,del tmd,del thi, + *1 tlo,altad,althi ,numco,satpop,satplo,aatpmd,satphi, + expobj,dlo,dad,dhi,nexplo,nexpudnexphi, colide , + objlo

Identification of a novel BRCA2 and CHEK2 A-C-G-C haplotype in Turkish patients affected with breast cancer.

PubMed

Haytural, Hazal; Yalcinkaya, Nazli; Akan, Gokce; Arikan, Soykan; Ozkok, Elif; Cakmakoglu, Bedia; Yaylim, Ilhan; Aydin, Makbule; Atalar, Fatmahan

2013-01-01

Many breast cancers are caused by certain rare and familial mutations in the high or moderate penetrance genes BRCA1, BRCA2 and CHEK2. The aim of this study was to examine the allele and genotype frequencies of seven mutations in BRCA1, BRCA2 and CHEK2 genes in breast cancer patients and to investigate their isolated and combined associations with breast cancer risk. We genotyped seven mutations in BRCA1, BRCA2 and CHEK2 genes and then analyzed single variations and haplotype associations in 106 breast cancer patients and 80 healthy controls. We found significant associations in the analyses of CHEK2- 1100delC (p=0.001) and BRCA1-5382insC (p=0.021) mutations in breast cancer patients compared to controls. The highest risk was observed among breast cancer patients carrying both CHEK2-1100delC and BRCA2- Met784Val mutations (OR=0.093; 95%CI 0.021-0.423; p=0.001). We identified one previously undescribed BRCA2 and a CHEK2 four-marker haplotype of A-C-G-C which was overrepresented (?2=7.655; p=0.0057) in the patient group compared to controls. In this study, we identified a previously undescribed BRCA2 and CHEK2 A-C-G-C haplotype in association with the breast cancer in our population. Our results further suggest that the CHEK2-1100delC mutation in combination with BRCA2-Met784Val may lead to an unexpected high risk which needs to be confirmed in larger cohorts in order to better understand their role in the development and prognosis of breast cancer.

Novel mutations in the TULP1 gene causing autosomal recessive retinitis pigmentosa.

PubMed

Paloma, E; Hjelmqvist, L; Bayés, M; García-Sandoval, B; Ayuso, C; Balcells, S; Gonzàlez-Duarte, R

2000-03-01

To assess the contribution of TULP1 to autosomal recessive retinitis pigmentosa (arRP). Fifteen exons of the gene were screened by single-strand conformation polymorphism analysis of 7 (of 49) arRP pedigrees showing cosegregation with TULP1 locus markers. In one of the seven families two allelic mutations, IVS4-2delAGA and c.937delC, were found in exons 5 and 10, respectively. Two novel mutations in TULP1 were found to be associated with arRP. That they both compromise the gene product supports their pathogenicity. This gene was present in no more than 2% of a panel of 49 Spanish families affected by arRP.

Magnetic Turbulence in Clusters of Galaxies

DTIC Science & Technology

2009-01-01

plasmas que nos permiten confrontar conceptos teóricos del origen del campo magnético con observaciones detalladas. La turbulencia magnética en...GALAXIES T. A. Enßlin,1 T. Clarke,2 C. Vogt,3 A. Waelkens,1 A. A. Schekochihin4 RESUMEN Los cúmulos de galaxias son grandes laboratorios de turbulencia en...éstos cúmulos puede ser estudiada a través de la emisión radio-sincrotrón del medio intra-cúmulo en forma de rélicas y halos de los cúmulos. El

Deletion of the late cornified envelope (LCE) 3B and 3C genes as a susceptibility factor for psoriasis

PubMed Central

de Cid, Rafael; Riveira-Munoz, Eva; Zeeuwen, Patrick L.J.M.; Robarge, Jason; Liao, Wilson; Dannhauser, Emma N.; Giardina, Emiliano; Stuart, Philip E.; Nair, Rajan; Helms, Cynthia; Escaramís, Georgia; Ballana, Ester; Martín-Ezquerra, Gemma; den Heijer, Martin; Kamsteeg, Marijke; Joosten, Irma; Eichler, Evan E.; Lázaro, Conxi; Pujol, Ramón M.; Armengol, Lluís; Abecasis, Gonçalo; Elder, James T.; Novelli, Giuseppe; Armour, John A.L.; Kwok, Pui; Bowcock, Anne; Schalkwijk, Joost; Estivill, Xavier

2011-01-01

Psoriasis is a common inflammatory skin disease with a prevalence of 2% to 3% in Caucasians1. In a genome-wide search for copy number variants (CNV) using a sample pooling approach we have identified a deletion comprising LCE3B and LCE3C, members of the late cornified envelope (LCE) gene cluster2. The absence of LCE3B and LCE3C (LCE3C-LCE3B-del) is significantly associated (p=1.38E-08) with risk of psoriasis in 2,831 samples from Spain, The Netherlands, Italy and the USA, and in a family-based study (p=5.4E-04). LCE3C-LCE3B-del is tagged by rs4112788 (r2=0.93), which is also strongly associated with psoriasis (p<6.6E-09). LCE3C-LCE3B-del shows epistatic effects with the HLA-Cw6 allele on the development of psoriasis in Dutch samples, and multiplicative effects in the other samples. LCE expression can be induced in normal epidermis by skin barrier disruption and is strongly expressed in psoriatic lesions, suggesting that compromised skin barrier function plays a role in psoriasis susceptibility. PMID:19169253

Mutation and new polymorphisms insight in introns 11 to 14a of CFTR gene of northern Iranian cystic fibrosis patients.

PubMed

Esmaeili Dooki, Mohammad Reza; Tabaripour, Reza; Rahimi, Razieh; Akhavan-Niaki, Haleh

2015-06-15

Cystic fibrosis (CF) is the most common autosomal recessive disease in Caucasians, caused by mutation in cystic fibrosis transmembrane conductance regulator (CFTR). The type and distribution of mutations vary widely between different countries and ethnic groups. We therefore aimed to perform a comprehensive analysis of the CFTR gene in northern Iranian CF patients. Forty northern Iranian CF patients were analyzed for mutations in introns 11 to 14a of their CFTR genes, using sequencing and reverse dot blot methods. Five normal subjects were also analyzed as normal control. One mutation and seven polymorphisms were identified. Of the eighty alleles studied, c.2043delG in exon 13 represented 12.5% of mutant alleles and was associated with two distinct haplotypes. rs1042077T>G, rs4148712delAT, rs4148711T>A and rs3808183 T>C with frequencies varying between 29.2% and 6.9% for the least common allele, as well as three new polymorphisms c.1680-224C>A (11.1%), c.2491-275T>G (14.1%) and c.2491-274C>G (35.9%) were detected. These findings suggest a founder effect for c.2043delG in the Middle East and will assist in genetic counseling, prenatal diagnosis and future screening of CF in Iran. Copyright © 2015 Elsevier B.V. All rights reserved.

Left-dominant arrhythmogenic cardiomyopathy in a large family: associated desmosomal or nondesmosomal genotype?

PubMed

Groeneweg, Judith A; van der Zwaag, Paul A; Jongbloed, Jan D H; Cox, Moniek G P J; Vreeker, Arnold; de Boer, Rudolf A; van der Heijden, Jeroen F; van Veen, Toon A B; McKenna, William J; van Tintelen, J Peter; Dooijes, Dennis; Hauer, Richard N W

2013-04-01

Arrhythmogenic cardiomyopathy (AC) is considered a predominantly right ventricular (RV) desmosomal disease. However, left-dominant forms due to desmosomal gene mutations, including PKP2 variant c.419C>T, have been described. Recently, a nondesmosomal phospholamban (PLN) mutation (c.40_42delAGA) has been identified, causing dilated cardiomyopathy and arrhythmias. To gain more insight into pathogenicity of the PKP2 variant c.419C>T by cosegregation analysis of the PKP2 variant c.419C>T vs the PLN mutation c.40_42delAGA. A Dutch family (13 family members, median age 49 years, range 34-71 years) with ventricular tachycardia underwent (1) meticulous phenotypic characterization and (2) screening of 5 desmosomal genes (PKP2, DSC2, DSG2, DSP, JUP) and PLN. Six family members fulfilled 2010 AC Task Force Criteria. Seven had signs of left ventricular (LV) involvement (inverted T waves in leads V4-V6, LV wall motion abnormalities and late enhancement, and reduced LV ejection fraction), including 6 family members with proven AC. The PKP2 variant c.419C>T was found as a single variant in 3 family members, combined with the PLN mutation c.40_42delAGA in 3 others. PLN mutation was found in 9 family members, including the 6 with AC and all 7 with LV involvement. The PLN mutation c.40_42delAGA was found as a single mutation in 6, combined with the PKP2 variant c.419C>T in 3 others. A low-voltage electrocardiogram was seen in 4 of 9 PLN mutation-positive subjects. None of the family members with the single PKP2 variant showed any sign of RV or LV involvement. The PLN mutation c.40_42delAGA cosegregates with AC and with electrocardiographic and structural LV abnormalities. In this family, there was no evidence of disease-causing contribution of the PKP2 variant c.419C>T. Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Mutant calreticulin knockin mice develop thrombocytosis and myelofibrosis without a stem cell self-renewal advantage.

PubMed

Li, Juan; Prins, Daniel; Park, Hyun Jung; Grinfeld, Jacob; Gonzalez-Arias, Carlos; Loughran, Stephen; Dovey, Oliver M; Klampfl, Thorsten; Bennett, Cavan; Hamilton, Tina L; Pask, Dean C; Sneade, Rachel; Williams, Matthew; Aungier, Juliet; Ghevaert, Cedric; Vassiliou, George S; Kent, David G; Green, Anthony R

2018-02-08

Somatic mutations in the endoplasmic reticulum chaperone calreticulin (CALR) are detected in approximately 40% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). Multiple different mutations have been reported, but all result in a +1-bp frameshift and generate a novel protein C terminus. In this study, we generated a conditional mouse knockin model of the most common CALR mutation, a 52-bp deletion. The mutant novel human C-terminal sequence is integrated into the otherwise intact mouse CALR gene and results in mutant CALR expression under the control of the endogenous mouse locus. CALR del/+ mice develop a transplantable ET-like disease with marked thrombocytosis, which is associated with increased and morphologically abnormal megakaryocytes and increased numbers of phenotypically defined hematopoietic stem cells (HSCs). Homozygous CALR del/del mice developed extreme thrombocytosis accompanied by features of MF, including leukocytosis, reduced hematocrit, splenomegaly, and increased bone marrow reticulin. CALR del/+ HSCs were more proliferative in vitro, but neither CALR del/+ nor CALR del/del displayed a competitive transplantation advantage in primary or secondary recipient mice. These results demonstrate the consequences of heterozygous and homozygous CALR mutations and provide a powerful model for dissecting the pathogenesis of CALR-mutant ET and PMF. © 2018 by The American Society of Hematology.

Hydrographic Measurements in the Western Arlboran Sea, October 1982.

DTIC Science & Technology

1984-04-01

about 1 km. Individual fixes based on the satellite system were accurate to about 0.5 km and on omega to about 2.0 km. 9 Table 3. Salinity Calibration...Activity Technical Note 224. 100 p. Cano, C. and F.F. de Castillejo (1972). Contribucion al Conocimiento del Mar de Alboran: III. Variaciones del

Validation of an instrument for evaluating health care services to ostomized people.

PubMed

Moraes, Juliano Teixeira; Amaral, Carlos Faria Santos; Borges, Eline Lima; Ribeiro, Mauro Souza; Guimarães, Eliete Albano Azevedo

2016-12-08

to develop and validate an array of analysis and judgment for the evaluation of Health Care Services of people with stomas. cross-sectional study in 28 health facilities in the state of Minas Gerais. A descriptive analysis of the instrument and a study of its psychometric properties were performed. We used the Delphi technique for the validation of content and appearance. A psychometric analysis was carried out through the study of the reliability and validity of the measures obtained with the instrument. it was possible to construct an array analysis and judgment with 16 components (with scores from zero to five) grouped according to size and structure and process considered essential to evaluate the service. The results achieved in the reliability for structure and process, through the Cronbach alpha coefficient (α = 0.771 and α = 0.809, respectively), and the validity of content and construct demonstrated good internal consistency and satisfactory validity. An exploratory factor analysis indicated the item "main activity performed in the unit" as a limitation of the scale. the study provides a new tool for the evaluation of structure and process of Health Care Services of a Person with a stoma. desenvolver e validar uma matriz de análise e julgamento para a avaliação de Serviços de Atenção à Saúde da Pessoa Estomizada. estudo seccional em 28 unidades de saúde do estado de Minas Gerais. Foi realizada uma análise descritiva do instrumento e um estudo das suas propriedades psicométricas. Para a validação de conteúdo e de aparência foi utilizada a técnica Delphi. A análise psicométrica foi realizada por meio do estudo da confiabilidade e validade das medidas obtidas com o instrumento. foi possível construir uma matriz de análise e julgamento com 16 componentes (pontuados com escores de zero a cinco) agrupados de acordo com as dimensões estrutura e processo considerados fundamentais para a avaliação do serviço. Os resultados alcançados para a confiabilidade para estrutura e processo, por meio do Coeficiente alfa de Cronbach (α = 0,771 e α = 0,809 respectivamente), e validades de conteúdo e de construto, demonstraram boa consistência interna e satisfatória validade. A análise fatorial exploratória apontou o item "principal atividade realizada na unidade" como limitação da escala. o estudo disponibiliza nova ferramenta para a avaliação de estrutura e processo do Serviço de Atenção à Saúde da Pessoa Ostomizada. desarrollar y validar una matriz de análisis y juzgamiento para la evaluación de Servicios de Atención a la Salud de la Persona Ostomizada. estudio seccional en 28 unidades de salud del estado de Minas Gerais. Fue realizado un análisis descriptivo del instrumento y un estudio de sus propiedades psicométricas. Para la validación de contenido y de apariencia fue utilizada la técnica Delphi. El análisis psicométrico fue realizada por medio del estudio de la confiabilidad y validez de las medidas obtenidas con el instrumento. fue posible construir una matriz de análisis y juzgamiento con 16 componentes (evaluados con puntajes de cero a cinco) agrupados de acuerdo con las dimensiones estructura y proceso considerados fundamentales para la evaluación del servicio. Los resultados alcanzados para la confiabilidad para estructura y proceso, por medio del Coeficiente Alfa de Cronbach (α = 0,771 y α = 0,809 respectivamente), y validez de contenido y de constructo, demostraron buena consistencia interna y satisfactoria validez. El análisis factorial exploratória apuntó el ítem "principal actividad realizada en la unidad" como limitación de la escala. el estudio suministra una nueva herramienta para la evaluación de estructura y proceso del Servicio de Atención a la Salud de la Persona Ostomizada.

Observaciones de fulguraciones en rayos X duros

NASA Astrophysics Data System (ADS)

Rovira, M. G.; Mandrini, C. H.

El objetivo principal de la investigación de las fulguraciones solares es el descubrimiento del proceso responsable de la impredecible, rápida y enorme, liberación de energía que ocurre en ellas. Las evidencias observacionales más claras de esta liberación son la emisión de rayos X y microondas. En particular, la detección de la emisión de rayos X duros (energías entre decenas y centenas de keV) es uno de los elementos de diagnóstico utilizados para comprender los mecanismos de aceleración y transporte de los electrones energéticos que, hoy es aceptado, son los que en su interacción con la atmósfera solar generan los rayos X observados. En 1991 se puso en órbita el Compton Gamma Ray Observatory (CGRO) uno de cuyos instrumentos observa las fulguraciones solares en el rango de energías 15 <= E <= 300 keV con una resolución temporal de 0.064 seg. En este trabajo analizamos, usando la Técnica de la Transformada Discreta en Onditas, algunos de los casos registrados para intentar separar y parametrizar las componentes de distinta escala de tiempo que se superponen durante la fase impulsiva de una fulguración. Discutimos nuestros resultados en términos de las características del mecanismo de liberación de energía.

Phenotype, Genotype, and Drug Resistance in Subtype C HIV-1 Infection.

PubMed

Derache, Anne; Wallis, Carole L; Vardhanabhuti, Saran; Bartlett, John; Kumarasamy, Nagalingeswaran; Katzenstein, David

2016-01-15

Virologic failure in subtype C is characterized by high resistance to first-line antiretroviral (ARV) drugs, including efavirenz, nevirapine, and lamivudine, with nucleoside resistance including type 2 thymidine analog mutations, K65R, a T69del, and M184V. However, genotypic algorithms predicting resistance are mainly based on subtype B viruses and may under- or overestimate drug resistance in non-B subtypes. To explore potential treatment strategies after first-line failure, we compared genotypic and phenotypic susceptibility of subtype C human immunodeficiency virus 1 (HIV-1) following first-line ARV failure. AIDS Clinical Trials Group 5230 evaluated patients failing an initial nonnucleoside reverse-transcriptase inhibitor (NNRTI) regimen in Africa and Asia, comparing the genotypic drug resistance and phenotypic profile from the PhenoSense (Monogram). Site-directed mutagenesis studies of K65R and T69del assessed the phenotypic impact of these mutations. Genotypic algorithms overestimated resistance to etravirine and rilpivirine, misclassifying 28% and 32%, respectively. Despite K65R with the T69del in 9 samples, tenofovir retained activity in >60%. Reversion of the K65R increased susceptibility to tenofovir and other nucleosides, while reversion of the T69del showed increased resistance to zidovudine, with little impact on other NRTI. Although genotype and phenotype were largely concordant for first-line drugs, estimates of genotypic resistance to etravirine and rilpivirine may misclassify subtype C isolates compared to phenotype. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Exome sequencing identifies complex I NDUFV2 mutations as a novel cause of Leigh syndrome.

PubMed

Cameron, Jessie M; MacKay, Nevena; Feigenbaum, Annette; Tarnopolsky, Mark; Blaser, Susan; Robinson, Brian H; Schulze, Andreas

2015-09-01

Two siblings with hypertrophic cardiomyopathy and brain atrophy were diagnosed with Complex I deficiency based on low enzyme activity in muscle and high lactate/pyruvate ratio in fibroblasts. Whole exome sequencing results of fibroblast gDNA from one sibling was narrowed down to 190 SNPs or In/Dels in 185 candidate genes by selecting non-synonymous coding sequence base pair changes that were not present in the SNP database. Two compound heterozygous mutations were identified in both siblings in NDUFV2, encoding the 24 kDa subunit of Complex I. The intronic mutation (c.IVS2 + 1delGTAA) is disease causing and has been reported before. The other mutation is novel (c.669_670insG, p.Ser224Valfs*3) and predicted to cause a pathogenic frameshift in the protein. Subsequent investigation of 10 probands with complex I deficiency from different families revealed homozygosity for the intronic c.IVS2 + 1delGTAA mutation in a second, consanguineous family. In this family three of five siblings were affected. Interestingly, they presented with Leigh syndrome but no cardiac involvement. The same genotype had been reported previously in a two families but presenting with hypertrophic cardiomyopathy, trunk hypotonia and encephalopathy. We have identified NDUFV2 mutations in two families with Complex I deficiency, including a novel mutation. The diagnosis of Leigh syndrome expands the clinical phenotypes associated with the c.IVS2 + 1delGTAA mutation in this gene. Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Hearing-loss-associated gene detection in neonatal intensive care unit.

PubMed

Yang, S M; Liu, Ying; Liu, C; Yin, A H; Wu, Y F; Zheng, X E; Yang, H M; Yang, J

2018-02-01

To investigate the frequency and mutation spectrum of hearing loss-associated gene mutation in Neonatal Intensive Care Unit (NICU). Neonates (n=2305) admitted to NICU were enrolled in this study. Nine prominent hearing loss-associated genes, GJB2 (35 del G, 176 del 16,235 del C, 299 del AT), GJB3 (538 C > T), SLC26A4 (IVS7-2A > G, 2168 A > G) and mtDNA 12S rRNA(1555 A > G, 1494 C > T), were detected. There were 73 cases hearing-loss-associated gene mutation among 2305 cases, the mutation frequency was 3.1%, with 40 cases GJB2 (235del C) mutation (54.8%), 6 cases GJB2 (299 del AT) mutation (8.2%), 21 cases SLC26A4 (IVS 7-2 A > G) mutation (28.7%), 4 cases SLC26A4 (2168 A > G) mutation (5.5%), 2 cases of GJB2 (235del C) combined SLC26A4 (IVS 7-2 A > G, 2168 A > G) mutation (2.8%). Among 73 gene mutation cases, preterm neonates presented in 18 cases, accounting for 24.7% (18/73); hyperbilirubinemia in 13 cases, accounting for 17.8% (13/73); Torch Syndrome in 15 cases, with 12 cases CMV, 2 cases rubella, 1 case toxoplasm, respectively, totally accounting for 20.54% (15/73); neonatal pneumonia in 12 cases, accounting for 16.4% (12/73); birth asphyxia in 5 cases, accounting for 6.9% (5/73); sepsis in 5 cases, accounting for 6.9% (5/73); others in 5 cases, accounting for 6.8% (5/73) . The frequency of hearing loss-associated gene mutation was higher in NICU.There were hearing loss-associated gene mutations in the NICU, suggesting this mutation may complicate with perinatal high-risk factors.

Reduced-Function SLC22A1 Polymorphisms Encoding Organic Cation Transporter 1 and Glycemic Response to Metformin: A GoDARTS Study

PubMed Central

Zhou, Kaixin; Donnelly, Louise A.; Kimber, Charlotte H.; Donnan, Peter T.; Doney, Alex S.F.; Leese, Graham; Hattersley, Andrew T.; McCarthy, Mark I.; Morris, Andrew D.; Palmer, Colin N.A.; Pearson, Ewan R.

2009-01-01

OBJECTIVE Metformin is actively transported into the liver by the organic cation transporter (OCT)1 (encoded by SLC22A1). In 12 normoglycemic individuals, reduced-function variants in SLC22A1 were shown to decrease the ability of metformin to reduce glucose excursion in response to oral glucose. We assessed the effect of two common loss-of-function polymorphisms in SLC22A1 on metformin response in a large cohort of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS The Diabetes Audit and Research in Tayside Scotland (DARTS) database includes prescribing and biochemistry information and clinical phenotypes of all patients with diabetes within Tayside, Scotland, from 1992 onwards. R61C and 420del variants of SLC22A1 were genotyped in 3,450 patients with type 2 diabetes who were incident users of metformin. We assessed metformin response by modeling the maximum A1C reduction in 18 months after starting metformin and investigated whether a treatment target of A1C <7% was achieved. Sustained metformin effect on A1C between 6 and 42 months was also assessed, as was the time to metformin monotherapy failure. Covariates were SLC22A1 genotype, BMI, average drug dose, adherence, and creatinine clearance. RESULTS A total of 1,531 patients were identified with a definable metformin response. R61C and 420del variants did not affect the initial A1C reduction (P = 0.47 and P = 0.92, respectively), the chance of achieving a treatment target (P = 0.83 and P = 0.36), the average A1C on monotherapy up to 42 months (P = 0.44 and P = 0.75), or the hazard of monotherapy failure (P = 0.85 and P = 0.56). CONCLUSIONS The SLC22A1 loss-of-function variants, R61C and 420del, do not attenuate the A1C reduction achieved by metformin in patients with type 2 diabetes. PMID:19336679

Pneumatocele selar a tensión: Reporte de un caso y revisión de la literatura

PubMed Central

Campero, Álvaro; Ajler, Pablo; Goldschmidt, Ezequiel; Bendersky, Damián; Campero, Abraham

2012-01-01

Introducción: El neumoencéfalo a tensión luego de la cirugía transesfenoidal es poco común. En la literatura existen pocos casos reportados en los cuales el aire se encuentra localizado exclusivamente en las regiones selar y supraselar, constituyendo un pneumatocele selar. En este artículo se describe un caso inusual de pneumatocele selar a tensión de presentación tardía. Descripción del caso: Una mujer de 57 años consultó por hemianopsia bitemporal. Previamente, ya se le había realizado una cirugía transnasal por un adenoma hipofisario y se le había colocado una derivación lumbo-peritoneal por la presencia de una fístula de líquido cefalorraquídeo. Además, se le había realizado una resección transcraneal de un componente intracavernoso del tumor y radiocirugía debido a la agresividad del mismo. Se llevó a cabo una resonancia magnética que demostró un pneumatocele selar y supraselar. Intervención: Se realizó un abordaje transciliar. La región selar estaba encapsulada por tejido cicatrizal debido a los procedimientos previos. Se abrió la cicatriz y el aire fue evacuado. Posteriormente, el piso selar fue cerrado con grasa y cola de fibrina. Despuós del procedimiento, su campo visual retornó a la normalidad. Un año después de su última cirugía, continua asintomática. Conclusión: El pneumatocele selar y supraselar a tensión es un hallazgo extremadamente raro luego de una cirugía transesfenoidal. Su manifestaciónw clínica sería la alteración visual debida a la compresión inferior de la vía óptica. El pneumatocele selar a tensión debe ser evacuado en un corto plazo. PMID:23596554

[Mutation analysis of seven patients with Waardenburg syndrome].

PubMed

Hao, Ziqi; Zhou, Yongan; Li, Pengli; Zhang, Quanbin; Li, Jiao; Wang, Pengfei; Li, Xiangshao; Feng, Yong

2016-06-01

To perform genetic analysis for 7 patients with Waardenburg syndrome. Potential mutation of MITF, PAX3, SOX10 and SNAI2 genes was screened by polymerase chain reaction and direct sequencing. Functions of non-synonymous polymorphisms were predicted with PolyPhen2 software. Seven mutations, including c.649-651delAGA (p.R217del), c.72delG (p.G24fs), c.185T>C (p.M62T), c.118C>T (p.Q40X), c.422T>C (p.L141P), c.640C>T (p.R214X) and c.28G>T(p.G43V), were detected in the patients. Among these, four mutations of the PAX3 gene (c.72delG, c.185T>C, c.118C>T and c.128G>T) and one SOX10 gene mutation (c.422T>C) were not reported previously. Three non-synonymous SNPs (c.185T>C, c.128G>T and c.422T>C) were predicted as harmful. Genetic mutations have been detected in all patients with Waardenburg syndrome.

Analysis of a RECQL splicing mutation, c.1667_1667+3delAGTA, in breast cancer patients and controls from Central Europe.

PubMed

Bogdanova, Natalia; Pfeifer, Katja; Schürmann, Peter; Antonenkova, Natalia; Siggelkow, Wulf; Christiansen, Hans; Hillemanns, Peter; Park-Simon, Tjoung-Won; Dörk, Thilo

2017-04-01

RECQL is a DNA helicase required for genomic stability. Two studies have recently identified RECQL as a novel breast cancer susceptibility gene. The most common RECQL mutation, the 4 bp-deletion c.1667_1667+3delAGTA, was five-fold enriched in Polish breast cancer patients, but the exact magnitude of the risk is uncertain. We investigated two hospital-based breast cancer case-control series from Belarus and Germany, respectively, comprising a total of 2596 breast cancer patients and 2132 healthy females. The mutation was found in 9 cases and 6 controls, with an adjusted Odds Ratio 1.23 (95% CI 0.44-3.47; p = 0.69) in the combined analysis. Among the cases, heterozygosity for c.1667_1667+3delAGTA was linked with estrogen-receptor positive breast cancer. There was no significant difference in age at diagnosis between carriers and non-carriers, and only one of the carriers reported a first-degree family history. Meta-analysis with the initial study from Poland suggests an about two-fold increase in risk for this mutation (OR 2.51; 95% CI 1.13-5.57, p = 0.02). Altogether, the data indicate that RECQL* c.1667_1667+3delAGTA is not a high-risk mutation for breast cancer though it could represent a moderate-risk breast cancer susceptibility allele. Further studies will be required to determine the clinical significance of testing for this RECQL mutation.

Reframing HIV care: putting people at the centre of antiretroviral delivery

PubMed Central

Duncombe, Chris; Rosenblum, Scott; Hellmann, Nicholas; Holmes, Charles; Wilkinson, Lynne; Biot, Marc; Bygrave, Helen; Hoos, David; Garnett, Geoff

2015-01-01

The delivery of HIV care in the initial rapid scale-up of HIV care and treatment was based on existing clinic-based models, which are common in highly resourced settings and largely undifferentiated for individual needs. A new framework for treatment based on variable intensities of care tailored to the specific needs of different groups of individuals across the cascade of care is proposed here. Service intensity is characterised by four delivery components: (i) types of services delivered, (ii) location of service delivery, (iii) provider of health services and (iv) frequency of health services. How these components are developed into a service delivery framework will vary across countries and populations, with the intention being to improve acceptability and care outcomes. The goal of getting more people on treatment before they become ill will necessitate innovative models of delivering both testing and care. As HIV programmes expand treatment eligibility, many people entering care will not be ‘patients’ but healthy, active and productive members of society 1. To take the framework to scale, it will be important to: (i) define which individuals can be served by an alternative delivery framework; (ii) strengthen health systems that support decentralisation, integration and task shifting; (iii) make the supply chain more robust; and (iv) invest in data systems for patient tracking and for programme monitoring and evaluation. La délivrance des soins du VIH dans le déploiement initial rapide des soins et du traitement du VIH a été basée sur des modèles existants dans les cliniques, qui sont courants dans les régions bénéficiant d’importantes ressources et largement indifférenciées pour les besoins individuels. Un nouveau cadre est proposé ici pour le traitement basé selon les intensités variables de soins, adaptés aux besoins spécifiques des différents groupes de personnes à travers la cascade de soins. L’intensité des services est caractérisée par quatre éléments de délivrance: (1) les types de services délivrés, (2) l’emplacement de la délivrance des services, (3) Les prestataires des services de santé et (4) la fréquence des services de santé. La façon dont ces éléments sont développés dans un cadre de prestation de services peut varier selon les pays et les populations, l’intention étant d’améliorer les résultats d’acceptabilité et des soins. Le but d’obtenir plus de personnes sous traitement avant qu’ils ne tombent malades nécessitera des modèles innovateurs de prestation à la fois pour dépistage et pour les soins. Comme les programmes VIH étendent l’éligibilité au traitement, beaucoup de gens qui entrent dans les soins ne seront pas des “malades- mais des éléments sains de la société, actifs et productifs. Afin de tenir le cadre à l’échelle, il sera important de: (1) définir les individus qui peuvent être traités par un cadre alternatif de prestation, (2) renforcer les systèmes de santé qui soutiennent la décentralisation, l’intégration et le transfert des tâches; (3) rendre la chaîne d’approvisionnement plus robuste et (4) investir dans des systèmes de données pour le suivi des patients et pour le suivi et l’évaluation du programme. Los servicios de atención del VIH durante el inicio de la primera etapa de rápida expansión del tratamiento y cuidados del VIH estaban basados en modelos clínicos existentes, comunes en lugares con abundancia de recursos y poco diferenciados en cuanto a necesidades individuales. Aquí se propone un nuevo marco para el tratamiento basado en intensidades variables de cuidados, hecho a medida según las necesidades específicas de los diferentes grupos de individuos a lo largo del tratamiento. La intensidad del servicio se caracteriza por cuatro componentes de entrega: (1) tipología de los servicios ofrecidos, (2) lugar de entrega de los servicios, (3) proveedor de los servicios sanitarios, y (4) frecuencia de los servicios sanitarios. El cómo estos componentes conforman un marco de entrega de servicios variará según el país y la población, con la intención de mejorar la aceptabilidad y los resultados de los cuidados. El objetivo de conseguir que más personas reciban tratamiento antes de que enfermen requerirá de modelos innovadores en la oferta tanto de pruebas para detección como de los cuidados. A medida que los programas para el VIH expandan los criterios de elegibilidad para el tratamiento, muchas de las personas que comiencen a recibir cuidados no serán “pacientes- sino miembros sanos, activos y productivos de la sociedad. Con el fin de expandir la escala de esta estructura, sería importante: (1) definir cuales individuos pueden ser atendidos dentro de un marco de entrega de servicios alternativo; (2) fortalecer los sistemas sanitarios que apoyan la descentralización, integración y delegación de funciones; (3) robustecer la cadena de proveedores; e (4) invertir en sistemas de datos para el seguimiento de pacientes y para la monitorización y evaluación de programas. PMID:25583302

Developmental endothelial locus-1 modulates platelet-monocyte interactions and instant blood-mediated inflammatory reaction in islet transplantation.

PubMed

Kourtzelis, Ioannis; Kotlabova, Klara; Lim, Jong-Hyung; Mitroulis, Ioannis; Ferreira, Anaisa; Chen, Lan-Sun; Gercken, Bettina; Steffen, Anja; Kemter, Elisabeth; Klotzsche-von Ameln, Anne; Waskow, Claudia; Hosur, Kavita; Chatzigeorgiou, Antonios; Ludwig, Barbara; Wolf, Eckhard; Hajishengallis, George; Chavakis, Triantafyllos

2016-04-01

Platelet-monocyte interactions are strongly implicated in thrombo-inflammatory injury by actively contributing to intravascular inflammation, leukocyte recruitment to inflamed sites, and the amplification of the procoagulant response. Instant blood-mediated inflammatory reaction (IBMIR) represents thrombo-inflammatory injury elicited upon pancreatic islet transplantation (islet-Tx), thereby dramatically affecting transplant survival and function. Developmental endothelial locus-1 (Del-1) is a functionally versatile endothelial cell-derived homeostatic factor with anti-inflammatory properties, but its potential role in IBMIR has not been previously addressed. Here, we establish Del-1 as a novel inhibitor of IBMIR using a whole blood-islet model and a syngeneic murine transplantation model. Indeed, Del-1 pre-treatment of blood before addition of islets diminished coagulation activation and islet damage as assessed by C-peptide release. Consistently, intraportal islet-Tx in transgenic mice with endothelial cell-specific overexpression of Del-1 resulted in a marked decrease of monocytes and platelet-monocyte aggregates in the transplanted tissues, relative to those in wild-type recipients. Mechanistically, Del-1 decreased platelet-monocyte aggregate formation, by specifically blocking the interaction between monocyte Mac-1-integrin and platelet GPIb. Our findings reveal a hitherto unknown role of Del-1 in the regulation of platelet-monocyte interplay and the subsequent heterotypic aggregate formation in the context of IBMIR. Therefore, Del-1 may represent a novel approach to prevent or mitigate the adverse reactions mediated through thrombo-inflammatory pathways in islet-Tx and perhaps other inflammatory disorders involving platelet-leukocyte aggregate formation.

Reciprocal Effects on Neurocognitive and Metabolic Phenotypes in Mouse Models of 16p11.2 Deletion and Duplication Syndromes.

PubMed

Arbogast, Thomas; Ouagazzal, Abdel-Mouttalib; Chevalier, Claire; Kopanitsa, Maksym; Afinowi, Nurudeen; Migliavacca, Eugenia; Cowling, Belinda S; Birling, Marie-Christine; Champy, Marie-France; Reymond, Alexandre; Herault, Yann

2016-02-01

The 16p11.2 600 kb BP4-BP5 deletion and duplication syndromes have been associated with developmental delay; autism spectrum disorders; and reciprocal effects on the body mass index, head circumference and brain volumes. Here, we explored these relationships using novel engineered mouse models carrying a deletion (Del/+) or a duplication (Dup/+) of the Sult1a1-Spn region homologous to the human 16p11.2 BP4-BP5 locus. On a C57BL/6N inbred genetic background, Del/+ mice exhibited reduced weight and impaired adipogenesis, hyperactivity, repetitive behaviors, and recognition memory deficits. In contrast, Dup/+ mice showed largely opposite phenotypes. On a F1 C57BL/6N × C3B hybrid genetic background, we also observed alterations in social interaction in the Del/+ and the Dup/+ animals, with other robust phenotypes affecting recognition memory and weight. To explore the dosage effect of the 16p11.2 genes on metabolism, Del/+ and Dup/+ models were challenged with high fat and high sugar diet, which revealed opposite energy imbalance. Transcriptomic analysis revealed that the majority of the genes located in the Sult1a1-Spn region were sensitive to dosage with a major effect on several pathways associated with neurocognitive and metabolic phenotypes. Whereas the behavioral consequence of the 16p11 region genetic dosage was similar in mice and humans with activity and memory alterations, the metabolic defects were opposite: adult Del/+ mice are lean in comparison to the human obese phenotype and the Dup/+ mice are overweight in comparison to the human underweight phenotype. Together, these data indicate that the dosage imbalance at the 16p11.2 locus perturbs the expression of modifiers outside the CNV that can modulate the penetrance, expressivity and direction of effects in both humans and mice.

The high frequency of GJB2 gene mutation c.313_326del14 suggests its possible origin in ancestors of Lithuanian population.

PubMed

Mikstiene, Violeta; Jakaitiene, Audrone; Byckova, Jekaterina; Gradauskiene, Egle; Preiksaitiene, Egle; Burnyte, Birute; Tumiene, Birute; Matuleviciene, Ausra; Ambrozaityte, Laima; Uktveryte, Ingrida; Domarkiene, Ingrida; Rancelis, Tautvydas; Cimbalistiene, Loreta; Lesinskas, Eugenijus; Kucinskas, Vaidutis; Utkus, Algirdas

2016-02-19

Congenital hearing loss (CHL) is diagnosed in 1 - 2 newborns in 1000, genetic factors contribute to two thirds of CHL cases in industrialised countries. Mutations of the GJB2 gene located in the DFNB1 locus (13q11-12) are a major cause of CHL worldwide. The aim of this cross-sectional study was to assess the contribution of the DFNB1 locus containing the GJB2 and GJB6 genes in the development of early onset hearing loss in the affected group of participants, to determine the population-specific mutational profile and DFNB1-related HL burden in Lithuanian population. Clinical data were obtained from a collection of 158 affected participants (146 unrelated probands) with early onset non-syndromic HL. GJB2 and GJB6 gene sequencing and GJB6 gene deletion testing were performed. The data of GJB2 and GJB6 gene sequencing in 98 participants in group of self-reported healthy Lithuanian inhabitants were analysed. Statistic summary, homogeneity tests, and logistic regression analysis were used for the assessment of genotype-phenotype correlation. Our findings show 57.5% of affected participants with two pathogenic GJB2 gene mutations identified. The most prevalent GJB2 mutations were c.35delG, p. (Gly12Valfs*2) (rs80338939) and c.313_326del14, p. (Lys105Glyfs*5) (rs111033253) with allele frequencies 64.7% and 28.3% respectively. GJB6 gene mutations were not identified in the affected group of participants. The statistical analysis revealed significant differences between GJB2(-) and GJB2(+) groups in disease severity (p = 0.001), and family history (p = 0.01). The probability of identification of GJB2 mutations in patients with various HL characteristics was estimated. The carrier rate of GJB2 gene mutations - 7.1% (~1 in 14) was identified in the group of healthy participants and a high frequency of GJB2-related hearing loss was estimated in our population. The results show a very high proportion of GJB2-positive individuals in the research group affected with sensorineural HL. The allele frequency of c.35delG mutation (64.7 %) is consistent with many previously published studies in groups of affected individuals of Caucasian populations. The high frequency of the c.313_326del14 (28.3 % of pathogenic alleles) mutation in affected group of participants was an unexpected finding in our study suggesting not only a high frequency of carriers of this mutation in our population but also its possible origin in Lithuanian ancestors. The high frequency of carriers of the c.313_326del14 mutation in the entire Lithuanian population is supported by it being identified twice in the ethnic Lithuanian group of healthy participants (a frequency 2.0 % of carriers in the study group). Analysis of the allele frequency of GJB2 gene mutations revealed a high proportion of c. 313_326del14 (rs111033253) mutations in the GJB2-positive group suggesting its possible origin in Lithuanian forebears. The high frequency of carriers of GJB2 gene mutations in the group of healthy participants corresponds to the substantial frequency of GJB2-associated HL in Lithuania. The observations of the study indicate the significant contribution of GJB2 gene mutations to the pathogenesis of the disorder in the Lithuanian population and will contribute to introducing principles to predict the characteristics of the disease in patients.

Identification of a novel COL1A1 frameshift mutation, c.700delG, in a Chinese osteogenesis imperfecta family

PubMed Central

Wang, Xiran; Pei, Yu; Dou, Jingtao; Lu, Juming; Li, Jian; Lv, Zhaohui

2015-01-01

Osteogenesis imperfecta (OI) is a family of genetic disorders associated with bone loss and fragility. Mutations associated with OI have been found in genes encoding the type I collagen chains. People with OI type I often produce insufficient α1-chain type I collagen because of frameshift, nonsense, or splice site mutations in COL1A1 or COL1A2. This report is of a Chinese daughter and mother who had both experienced two bone fractures. Because skeletal fragility is predominantly inherited, we focused on identifying mutations in COL1A1 and COL1A2 genes. A novel mutation in COL1A1, c.700delG, was detected by genomic DNA sequencing in the mother and daughter, but not in their relatives. The identification of this mutation led to the conclusion that they were affected by mild OI type I. Open reading frame analysis indicated that this frameshift mutation would truncate α1-chain type I collagen at residue p263 (p.E234KfsX264), while the wild-type protein would contain 1,464 residues. The clinical data were consistent with the patients’ diagnosis of mild OI type I caused by haploinsufficiency of α1-chain type I collagen. Combined with previous reports, identification of the novel mutation COL1A1-c.700delG in these patients suggests that additional genetic and environmental factors may influence the severity of OI. PMID:25983617

PEPCK-C reexpression in the liver counters neonatal hypoglycemia in Pck1 del/del mice, unmasking role in non-gluconeogenic tissues.

PubMed

Semakova, Jana; Hyroššová, Petra; Méndez-Lucas, Andrés; Cutz, Ernest; Bermudez, Jordi; Burgess, Shawn; Alcántara, Soledad; Perales, José C

2017-02-01

Whole body cytosolic phosphoenolpyruvate carboxykinase knockout (PEPCK-C KO) mice die early after birth with profound hypoglycemia therefore masking the role of PEPCK-C in adult, non-gluconeogenic tissues where it is expressed. To investigate whether PEPCK-C deletion in the liver was critically responsible for the hypoglycemic phenotype, we reexpress this enzyme in the liver of PEPCK-C KO pups by early postnatal administration of PEPCK-C-expressing adenovirus. This maneuver was sufficient to partially rescue hypoglycemia and allow the pups to survive and identifies the liver as a critical organ, and hypoglycemia as the critical pathomechanism, leading to early postnatal death in the whole-body PEPCK-C knockout mice. Pathology assessment of survivors also suggest a possible role for PEPCK-C in lung maturation and muscle metabolism.

Modelo semi-empírico de protuberancia solar a partir del diagnóstico de densidades

NASA Astrophysics Data System (ADS)

Cirigliano, D.; Vial, J. C.; Rovira, M.

A partir de la observación del espectro del quintuplete de C III alrededor de 1175 Å, se ha realizado el diagnóstico de la densidad y presión electrónica, basado en el cálculo del cociente de las intensidades observadas. Una vez establecida la densidad electrónica, y con el cálculo de las velocidades Doppler, hemos investigado el flujo de masa en la protuberancia en función de la temperatura. Estableciendo como hipótesis la conservación del número de partículas que ingresan y salen del cuerpo de la protuberancia, se investiga la variación del área de un tubo de flujo semi-empírico en función de la temperatura. A partir de dicho diagnóstico, se examina el comportamiento del radio del tubo magnético en función de la temperatura, los que dan cuenta de la abertura de las líneas de campo magnético que confinan el plasma y de la divergencia del campo magnético en diferentes alturas de la atmósfera solar.

Coinheritance of a novel mutation on the HBA1 gene: c.187delG (p.W62fsX66) [codon 62 (-G) (α1)] with the α212 patchwork allele and Hb S [β6(A3)Glu→Val, GAG>GTG; HBB: c.20A>T].

PubMed

Scheps, Karen G; De Paula, Silvia M; Bitsman, Alicia R; Freigeiro, Daniel H; Basack, F Nora; Pennesi, Sandra P; Varela, Viviana

2013-01-01

We describe a novel frameshift mutation on the HBA1 gene (c.187delG), causative of α-thalassemia (α-thal) in a Black Cuban family with multiple sequence variants in the HBA genes and the Hb S [β6(A3)Glu→Val, GAG>GTG; HBB: c.20A>T] mutation. The deletion of the first base of codon 62 resulted in a frameshift at amino acid 62 with a putative premature termination codon (PTC) at amino acid 66 on the same exon (p.W62fsX66), which most likely triggers nonsense mediated decay of the resulting mRNA. This study also presents the first report of the α212 patchwork allele in Latin America and the description of two new sequence variants in the HBA2 region (c.-614G>A in the promoter region and c.95+39 C>T on the first intron).

Descripción del coronógrafo a ser instalado en Argentina (MICA)

NASA Astrophysics Data System (ADS)

Stenborg, G.; Francile, C.; Schwenn, R.; Epple, A.; Rovira, M.

El ``Coronógrafo de espejo para Argentina'' es un telescopio solar terrestre a ser colocado en el Observatorio Astronómico Félix Aguilar (El Leoncito), antes de finalizar 1996, como parte de un programa de ciencia bilateral entre Alemania y Argentina. Eclipses fotográficos de alta resolución han revelado que la corona solar es altamente estructurada y variable. De hecho, está contínuamente deformada y moldeada por los movimientos convectivos de los extremos de los arcos magnéticos en la fotosfera, estando, en muchas oportunidades, afectada por explosivas liberaciones de energía. MICA, en conjunción con otros telescopios solares espaciales y terrestres, tratará de contribuir al entendimiento de cuestiones fundamentales de la física solar. Entre ellas: cómo la corona está siendo calentada, dónde y cómo el viento solar es acelerado, qué causa los transitorios coronales, etc. Para ello investigará la distribución de los parámetros del plasma y su evolución con el tiempo, la estructura espacial de la corona en fina y gran escala, procesos que ocurren en los transitorios coronales y factores que los disparan, etc. Para responder a estas cuestiones MICA observará la atmósfera solar por sobre el limbo entre 1.1 y 2 radios solares aproximadamente, usando un nuevo tipo de sistema coronográfico que permite suprimir el brillo del disco solar suficientemente bien, tomando las imágenes con una cámara CCD de 1024x1024 pixels, codificada en 12 bits, pudiendo el mismo ser operado en forma remota. En la presente exposición describiremos las características del instrumento, cómo será controlado y qué esperamos observar basados en las imágenes obtenidas por los telescopios de similares características LASCO C1 a bordo del SOHO y PICO (ubicado en el Observatorio de Pic du Midi, Francia).

Estructura y química del suelo en un bosque de Castilla elastica en el carso del norte de Puerto Rico: resultados de una calicata

Treesearch

Christian A. Viera Martinez; Oscar Abelleira; Ariel E. Lugo

2008-01-01

We dug a soil pit of 1m x 1m x 1m in a forest dominated by Castilla elastica, a tree for shade coffee introduced in the karst of northern Puerto Rico. We found four soil horizons (designation notes in parenthesis) (A) organic soil matter (E) mineral soil leachate (B) aerobic mineral soil, and (C) saturated soil. The total storage of soil organic matter was 143 Mg/ha....

Maple Syrup Urine Disease in Cypriot Families: Identification of Three Novel Mutations and Biochemical Characterization of the p.Thr211Met Mutation in the E1α Subunit

PubMed Central

Georgiou, Theodoros; Chuang, Jacinta L.; Wynn, R. Max; Stylianidou, Goula; Korson, Mark; Chuang, David T.

2009-01-01

We report five mutations, three of them novel, responsible for maple syrup urine disease in four unrelated Cypriot families. The five children studied are the first cases of classic maple syrup urine disease to be reported among Cypriots. The first novel mutation identified is a single-base deletion in exon 6 of the Elα gene (c.718delG), which leads to a frameshift after Ala240 and to a stop codon 89 residues further downstream. The other two novel mutations identified are in the Elβ subunit: a two-base deletion in exon 6, c.662_663delCC, which leads to a frameshift after Ala221 and creates a stop codon 17 residues further downstream, as well as a splice mutation, IVS3[+3]delA, which results in the skipping of exon 3. The two known mutations identified are in the Elα gene: the G > C transversion at the 3′-splice acceptor site, (IVS5-1G > C), which results in the deletion of the entire exon 6, and the missense mutation in exon 5 (c.632C > T), which corresponds to a p.Thr211Met substitution. The p.Thr211Met substitution is located in a potassium-ion pocket in the E1 component required for stability of the bound cofactor thiamine diphosphate. The mutant E1 protein harboring the p.Thr211Met substitution was shown unable to bind thiamine diphosphate, leading to undetectable E1 activity. PMID:19715473

Mutations in the ADAR1 gene in Chinese families with dyschromatosis symmetrica hereditaria.

PubMed

Zhang, G L; Shi, H J; Shao, M H; Li, M; Mu, H J; Gu, Y; Du, X F; Xie, P

2013-01-04

We investigated 2 Chinese families with dyschromatosis symmetrica hereditaria (DSH) and search for mutations in the adenosine deaminase acting on RNA1 (ADAR1) gene in these 2 pedigrees. We performed a mutation analysis of the ADAR1 gene in 2 Chinese families with DSH and reviewed all articles published regarding ADAR1 mutations reported since 2003 by using PubMed. By direct sequencing, a 2-nucleotide AG deletion, 2099-2100delAG, was found in family 1, and a C→T mutation was identified at nucleotide 1420 that changed codon 474 from arginine to a translational termination codon in family 2. Two different pathogenic mutations were identified, c.2099-2100delAG and c.1420C>T, the former being a novel mutation, and the latter previously reported in 3 other families with DSH. To date, a total of 110 mutations in the ADAR1 gene have been reported, and 10 of them were recurrent; the mutations R474X, R1083C, R1096X, and R1155W might be the DSH-related hotspots.

Evaluation of the need for routine clinical testing of PALB2 c.1592delT mutation in BRCA negative Northern Finnish breast cancer families.

PubMed

Haanpää, Maria; Pylkäs, Katri; Moilanen, Jukka S; Winqvist, Robert

2013-08-13

Testing for mutations in the BRCA1 and BRCA2 genes among high-risk breast cancer patients has become a routine practice among clinical geneticists. Unfortunately, however, the genetic background of a majority of the cases coming to the clinics remains currently unexplained, making genetic counseling rather challenging. In recent years it has become evident world-wide that also women carrying a heterozygous germline mutation in PALB2 are at significantly increased risk of getting breast cancer. We have previously studied the clinical as well as biological impact of the PALB2 c.1592delT founder mutation occurring in about 1% of Finnish breast cancer patients unselected for their family history of disease, and our results demonstrated a 40% increased breast cancer risk by age 70 for female mutation carriers. Thus, this relatively common mutation in PALB2 is associated with a high risk of developing breast cancer. The aim of the current study was to analyze whether female index individuals of breast cancer families who had tested negative for germline mutations in BRCA1/BRCA2 as part of genetic counseling services should be offered mutation testing for PALB2 c.1592delT. The study cohort consisted of altogether 223 individuals who had contacted the Department of Clinical Genetics at the Oulu University Hospital in Finland between the years 1997 and 2011 for counseling on hereditary breast and/or ovarian cancer risk. 101 of them met our inclusion criteria. Of these, 10 persons were now deceased, but 6 of them had participated in one of our previous studies on PALB2. Seventy (77%) of the remaining 91 persons responded positively to our study invitation. Chart review of updated pedigree data led to the exclusion of 14 further individuals not meeting the selection criteria. Of the 56 alive affected female individuals screened for PALB2 c.1592delT, altogether two (3.6%) tested positive for this mutation. In addition, of the previously tested but now deceased 6 persons eligible for the current study, one more mutation carrier was observed. Therefore, overall 4.8% (3/62) of the tested individuals belonging to the Northern Finnish 1997-2011 study cohort turned out to be carriers of the PALB2 c.1592delT allele. Given the potential benefits versus harms of this testing, the result of our study suggest that PALB2 c.1592delT should be a routine part of the genetic counseling protocol for Finnish high-risk breast cancer cases tested negative for mutations in BRCA1/BRCA2.

77 FR 14594 - Additions to the Identifying Information for an Individual Previously Designated Pursuant to the...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-12

..., Colombia; c/o INVERPUNTO DEL VALLE S.A., Cali, Colombia; c/o INVERSIONES CIFUENTES Y CIA. S. EN C...., Bogota, Colombia; c/o INVERPUNTO DEL VALLE S.A., Cali, Colombia; c/o INVERSIONES CIFUENTES Y CIA. S. EN C...

PDGFRα promoter polymorphisms and expression patterns influence risk of development of imatinib-induced thrombocytopenia in chronic myeloid leukemia: A study from India.

PubMed

Guru, Sameer Ahmad; Mir, Rashid; Bhat, Musadiq; Najar, Imtiyaz; Zuberi, Mariyam; Sumi, Mamta; Masroor, Mirza; Gupta, Naresh; Saxena, Alpana

2017-10-01

Platelet-derived growth factor receptor has been implicated in many malignant and non-malignant diseases. Platelet-derived growth factor receptor-α is a tyrosine kinase and a side target for imatinib, a revolutionary drug for the treatment of chronic myeloid leukemia that has dramatically improved the survival of chronic myeloid leukemia patients. Given the importance of platelet-derived growth factor receptor in platelet development and its inhibition by imatinib, it was intriguing to analyze the role of platelet-derived growth factor receptor-α in relation to imatinib treatment in the development of imatinib-induced thrombocytopenia in chronic myeloid leukemia patients. We hypothesized that two known functional polymorphisms, +68GA insertion/deletion and -909C/A, in the promoter region of the platelet-derived growth factor receptor-α gene may affect the susceptibility of chronic myeloid leukemia patients receiving imatinib treatment to the development of thrombocytopenia. A case-control study was conducted among a cohort of chronic myeloid leukemia patients admitted to the Lok Nayak Hospital, New Delhi, India. A set of 100 patients of chronic myeloid leukemia in chronic phase and 100 age- and sex-matched healthy controls were studied. After initiation of imatinib treatment, the hematological response of chronic myeloid leukemia patients was monitored regularly for 2 years, in which the development of thrombocytopenia was the primary end point. Platelet-derived growth factor receptor-α promoter polymorphisms +68GA ins/del and -909C/A were studied by allele-specific polymerase chain reaction. Platelet-derived growth factor receptor-α messenger RNA expression was evaluated by quantitative real-time polymerase chain reaction. The messenger RNA expression results were expressed as 2 -Δct ± standard deviation. The distribution of +68GA ins/del promoter polymorphism genotypes differed significantly between the thrombocytopenic and non-thrombocytopenic chronic myeloid leukemia patient groups (p < 0.0001). Moreover, +68GA del/del and ins/del genotypes in imatinib-treated chronic myeloid leukemia patients were associated with an increased risk of developing thrombocytopenia, with odds ratios 6.5 (95% confidence interval = 2.02-0.89, p = 0.001) and 6.0 (95% confidence interval = 2.26-15.91, p = 0.0002), respectively. Similarly, -909C/A promoter polymorphism genotype distribution also differed significantly between thrombocytopenic and non-thrombocytopenic chronic myeloid leukemia patient groups (p = 0.02), and a significantly increased risk of imatinib-induced thrombocytopenia was associated with -909C/A polymorphism mutant homozygous (AA) genotypes the odds ratio being 7.7 (95% confidence interval 1.50 to 39.91, p = 0.009). However, no significant risk of imatinib-induced thrombocytopenia was found to be associated with heterozygous genotype (-909C/A) with odds ratio 1.9 (95% confidence interval = 0.86-4.56, p = 1.14). Platelet-derived growth factor receptor-α messenger RNA expression was significantly higher in chronic myeloid leukemia patients compared to controls (p = 0.008). Moreover, patients with imatinib-induced thrombocytopenia had a significantly lower platelet-derived growth factor receptor-α messenger RNA expression, compared to patients without thrombocytopenia (p = 0.01). A differential expression of platelet-derived growth factor receptor-α messenger RNA was observed with respect to different +68 GA ins/del and -909C/A polymorphism genotypes. The +68GA deletion allele and -909A allele were significantly associated with lower expression of platelet-derived growth factor receptor-α messenger RNA. The platelet-derived growth factor receptor-α +68GA del/del, +68GA ins/del, and -909AA genotypes are associated with an increased risk of developing thrombocytopenia in imatinib-treated chronic myeloid leukemia patients. A significantly lower platelet-derived growth factor receptor-α messenger RNA expression accompanies the +68GA deletion allele in an allele dose-dependent manner. Platelet-derived growth factor receptor-α -909AA genotype is also associated with lower expression of platelet-derived growth factor receptor-α. The downregulation of platelet-derived growth factor receptor-α expression may play a causative role in imatinib-induced thrombocytopenia, a common side effect, in the subset of chronic myeloid leukemia patients with platelet-derived growth factor receptor-α +68 GA ins/del, +68 GA del/del, and -909C/A genotypes.

A composite six bp in-frame deletion in the melanocortin 1 receptor (MC1R) gene is associated with the Japanese brindling coat colour in rabbits (Oryctolagus cuniculus).

PubMed

Fontanesi, Luca; Scotti, Emilio; Colombo, Michela; Beretti, Francesca; Forestier, Lionel; Dall'Olio, Stefania; Deretz, Séverine; Russo, Vincenzo; Allain, Daniel; Oulmouden, Ahmad

2010-07-01

In the domestic rabbit (Oryctolagus cuniculus), classical genetic studies have identified five alleles at the Extension locus: ED (dominant black), ES (steel, weaker version of ED), E (wild type, normal extension of black), eJ(Japanese brindling, mosaic distribution of black and yellow) and e (non-extension of black, yellow/red with white belly). Sequencing almost the complete coding sequence (CDS) of the rabbit MC1R gene, we recently identified two in-frame deletions associated with dominant black (c.280_285del6; alleles ED or ES) and recessive red (c.304_333del30; allele e) coat colours. It remained to characterize the eJallele whose phenotypic effect is similar to the Orange and Sex-linked yellow loci of cat and Syrian hamster. We sequenced the whole CDS in 25 rabbits of different coat colours including 10 Japanese and 10 Rhinelander (tricolour) rabbits and identified another 6 bp-in frame deletion flanked by a G > A transition in 5' (c.[124G>A;125_130del6]) that was present in all animals with Japanese brindling coat colour and pattern. These mutations eliminate two amino acids in the first transmembrane domain and, in addition, cause an amino acid substitution at position 44 of the wild type sequence. Genotyping 371 rabbits of 31 breeds with different coat colour this allele (eJ) was present in homozygous state in Japanese, Rhinelander and Dutch tricolour rabbits only (except one albino rabbit). Rabbits with eJ/eJ genotype were non fixed at the non-agouti mutation we previously identified in the ASIP gene. Segregation in F1 and F2 families confirmed the order of dominance already determined by classical genetic experiments with a possible dose effect evident comparing eJ/eJ and eJ/e animals. MC1R mRNA was expressed in black hair skin regions only. The c.[124A;125_130del6] allele may be responsible for a MC1R variant determining eumelanin production in the black areas. However, the mechanism determining the presence of both red and black hairs in the same animal seems more complex. Expression analyses of the c.[124A;125_130del6] allele suggest that MC1R transcription may be regulated epigenetically in rabbits with the Japanese brindling phenotype. Further studies are needed to clarify this issue.

A novel germline PALB2 deletion in Polish breast and ovarian cancer patients.

PubMed

Dansonka-Mieszkowska, Agnieszka; Kluska, Anna; Moes, Joanna; Dabrowska, Michalina; Nowakowska, Dorota; Niwinska, Anna; Derlatka, Pawel; Cendrowski, Krzysztof; Kupryjanczyk, Jolanta

2010-02-02

PALB2 protein was recently identified as a partner of BRCA1 and BRCA2 which determines their proper function in DNA repair. Initially, the entire coding sequence of the PALB2 gene with exon/intron boundaries was evaluated by the PCR-SSCP and direct sequencing methods on 70 ovarian carcinomas. Sequence variants of interest were further studied on enlarged groups of ovarian carcinomas (total 339 non-consecutive ovarian carcinomas), blood samples from 334 consecutive sporadic and 648 consecutive familial breast cancer patients, and 1310 healthy controls from central Poland. Ten types of sequence variants were detected, and among them four novel polymorphisms: c.2996+58T>C in intron 9; c.505C>A (p.L169I), c.618T>G (p.L206L), both in exon 4; and c.2135C>T (A712V) in exon 5 of the PALB2 gene. Another two polymorphisms, c.212-58A>C and c.2014G>C (E672Q) were always detected together, both in cancer (7.5% of patients) and control samples (4.9% of controls, p = 0.2). A novel germline truncating mutation, c.509_510delGA (p.R170fs) was found in exon 4: in 2 of 339 (0.6%) unrelated ovarian cancer patients, in 4 of 648 (0.6%) unrelated familial breast cancer patients, and in 1 of 1310 controls (0.08%, p = 0.1, p = 0.044, respectively). One ovarian cancer patient with the PALB2 mutation had also a germline nonsense mutation of the BRCA2 gene. The c.509_510delGA is a novel PALB2 mutation that increases the risk of familial breast cancer. Occurrence of the same PALB2 alteration in seven unrelated women suggests that c.509_510delGA (p.R170fs) is a recurrent mutation for Polish population.

The first Japanese patient with mandibular hypoplasia, deafness, progeroid features and lipodystrophy diagnosed via POLD1 mutation detection.

PubMed

Okada, Asami; Kohmoto, Tomohiro; Naruto, Takuya; Yokota, Ichiro; Kotani, Yumiko; Shimada, Aki; Miyamoto, Yoko; Takahashi, Rizu; Goji, Aya; Masuda, Kiyoshi; Kagami, Shoji; Imoto, Issei

2017-01-01

Mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome is a rare autosomal dominant disorder caused by heterozygous POLD1 mutations. To date, 13 patients affected by POLD1 mutation-caused MDPL have been described. We report a clinically undiagnosed 11-year-old male who noted joint contractures at 6 years of age. Targeted exome sequencing identified a known POLD1 mutation [NM_002691.3:c.1812_1814del, p.(Ser605del)] that diagnosed him as the first Japanese/East Asian MDPL case.

CYP1A2 polymorphisms, occupational and environmental exposures and risk of bladder cancer.

PubMed

Pavanello, Sofia; Mastrangelo, Giuseppe; Placidi, Donatella; Campagna, Marcello; Pulliero, Alessandra; Carta, Angela; Arici, Cecilia; Porru, Stefano

2010-07-01

Cytochrome P4501A2 (CYP1A2) is a key enzyme for activation of bladder carcinogens. Polymorphisms in the 5'-noncoding promoter region of CYP1A2 gene [mainly -2467T/delT(rs35694136) and -163C/A(rs762551)], are crucial in modifying CYP1A2 activity in smokers. Within the framework of a hospital-based case/control study, we investigated the relationship between CYP1A2 polymorphisms, occupational/environmental exposures and bladder cancer (BC) risk. The study population included 185 BC cases and 180 non-cancer controls, all Caucasian males. Data were collected on lifetime smoking, coffee drinking, dietary habits and lifetime occupation, with particular reference to exposure to aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs). A case-only design was applied to study the interaction between CYP1A2 -2467T/delT (or -163C/A) and occupational and environmental factors. Multiple logistic regression showed a significantly increased risk among heavy smokers (> or =50 packyears; OR 5.6, 95% CI: 2.5-12.5) and heavy coffee drinkers (>5 cups/day; OR 3.1, 95% CI: 1.2-7.9). Exposure to AAs showed a significant trend of BC risk with increasing cumulative exposure (CE) (P = 0.04), with heavy smoking as possible confounder. A decreased risk was noted for large leaf vegetable consumption, with significant trend from <1/month to >3 times/week (P = 0.008). The case-only analysis showed an interaction between -2467T/delT and tobacco smoking >25 packyears (P = 0.04); no interaction was detected between such polymorphisms and coffee consumption, dietary habits and occupational exposure to AAs. No effects were shown with -163C/A genotype as well as no overall effect of CYP1A2 by itself on BC risk. This is the first study suggesting that CYP1A2 -2467T/delT modifies the effect of cigarette smoking on BC risk.

Stellar Mixing: I. Formalism

NASA Technical Reports Server (NTRS)

Canuto, V .M.

2011-01-01

In this paper we use the Reynolds stress models (RSM) to derive algebraic expressions for the following variables: a) heat fluxes; b) J.l fluxes; and c) momentum fluxes. These relations, which are fully 3D, include: 1) stable and unstable stratification, represented by the Brunt-Vaislila frequency, N(exp 2) =-g/H(sub p_(del - del(sub ad))(1 - RI(sub mu)); 2) double diffusion, salt-fingers, and semi-convection, represented by the density ratio R(sub mu) = del(sub mu)/(del - del(sub ad)); 3) shear (differential rotation), represented by the mean squared shear Sigma(exp 2) or by the Richardson number, Ri =N(exp 2)Sigma(exp -2); 4) radiative losses represented by a Peclet number, Pe; 5) a complete analytical solution of the ID version of the model. In general, the model requires the solution of two differential equations for the eddy kinetic energy K and its rate of dissipation, epsilon. In the local and stationary cases, when production equals dissipation, the model equations are all algebraic.

Estudio teórico del CO2. Orbitales de valencia y del ``core''

NASA Astrophysics Data System (ADS)

Olalla Gutiérrez, E.

Hemos calculado las intensidades de las transiciones E1 a los miembros de las series de Rydberg con origen en los orbitales ``no enlazantes'' del dióxido de carbono, especie de conocida relevancia atmosférica. Se han computado, asimismo, los continuos de fotoionización correspondientes a los distintos canales de ionización, representándolos como densidad espectral de fuerza de oscilador frente a la energía del fotón incidente; mostramos los resultados df/dE para la fotoionización total de esta especie en el intervalo 15-60 eV. Todos los cálculos se han llevado a cabo mediante la formulación Molecular del Método de los Orbitales de Defecto Cuántico, MQDO [1,2]. La calidad de los resultados que presentamos se ha evaluado en base a la comparación con los datos, tanto experimentales como teóricos, disponibles en la bibliografía. El acuerdo encontrado es altamente satisfactorio

Four Novel p.N385K, p.V36A, c.1033–1034insT and c.1417–1418delCT Mutations in the Sphingomyelin Phosphodiesterase 1 (SMPD1) Gene in Patients with Types A and B Niemann-Pick Disease (NPD)

PubMed Central

Manshadi, Masoumeh Dehghan; Kamalidehghan, Behnam; Keshavarzi, Fatemeh; Aryani, Omid; Dadgar, Sepideh; Arastehkani, Ahoora; Tondar, Mahdi; Ahmadipour, Fatemeh; Meng, Goh Yong; Houshmand, Massoud

2015-01-01

Background: Types A and B Niemann-Pick disease (NPD) are autosomal-recessive lysosomal storage disorders caused by the deficient activity of acid sphingomyelinase due to mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. Methods: In order to determine the prevalence and distribution of SMPD1 gene mutations, the genomic DNA of 15 unrelated Iranian patients with types A and B NPD was examined using PCR, DNA sequencing and bioinformatics analysis. Results: Of 8 patients with the p.G508R mutation, 5 patients were homozygous, while the other 3 were heterozygous. One patient was heterozygous for both the p.N385K and p.G508R mutations. Another patient was heterozygous for both the p.A487V and p.G508R mutations. Two patients (one homozygous and one heterozygous) showed the p.V36A mutation. One patient was homozygous for the c.1033–1034insT mutation. One patient was homozygous for the c.573delT mutation, and 1 patient was homozygous for the c.1417–1418delCT mutation. Additionally, bioinformatics analysis indicated that two new p.V36A and p.N385K mutations decreased the acid sphingomyelinase (ASM) protein stability, which might be evidence to suggest the pathogenicity of these mutations. Conclusion: with detection of these new mutations, the genotypic spectrum of types A and B NPD is extended, facilitating the definition of disease-related mutations. However, more research is essential to confirm the pathogenic effect of these mutations. PMID:25811928

Non-native Conformers of Cystic Fibrosis Transmembrane Conductance Regulator NBD1 Are Recognized by Hsp27 and Conjugated to SUMO-2 for Degradation.

PubMed

Gong, Xiaoyan; Ahner, Annette; Roldan, Ariel; Lukacs, Gergely L; Thibodeau, Patrick H; Frizzell, Raymond A

2016-01-22

A newly identified pathway for selective degradation of the common mutant of the cystic fibrosis transmembrane conductance regulator (CFTR), F508del, is initiated by binding of the small heat shock protein, Hsp27. Hsp27 collaborates with Ubc9, the E2 enzyme for protein SUMOylation, to selectively degrade F508del CFTR via the SUMO-targeted ubiquitin E3 ligase, RNF4 (RING finger protein 4) (1). Here, we ask what properties of CFTR are sensed by the Hsp27-Ubc9 pathway by examining the ability of NBD1 (locus of the F508del mutation) to mimic the disposal of full-length (FL) CFTR. Similar to FL CFTR, F508del NBD1 expression was reduced 50-60% by Hsp27; it interacted preferentially with the mutant and was modified primarily by SUMO-2. Mutation of the consensus SUMOylation site, Lys(447), obviated Hsp27-mediated F508del NBD1 SUMOylation and degradation. As for FL CFTR and NBD1 in vivo, SUMO modification using purified components in vitro was greater for F508del NBD1 versus WT and for the SUMO-2 paralog. Several findings indicated that Hsp27-Ubc9 targets the SUMOylation of a transitional, non-native conformation of F508del NBD1: (a) its modification decreased as [ATP] increased, reflecting stabilization of the nucleotide-binding domain by ligand binding; (b) a temperature-induced increase in intrinsic fluorescence, which reflects formation of a transitional NBD1 conformation, was followed by its SUMO modification; and (c) introduction of solubilizing or revertant mutations to stabilize F508del NBD1 reduced its SUMO modification. These findings indicate that the Hsp27-Ubc9 pathway recognizes a non-native conformation of mutant NBD1, which leads to its SUMO-2 conjugation and degradation by the ubiquitin-proteasome system. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Molecular defects leading to human complement component C6 deficiency in an African-American family

PubMed Central

Zhu, Z-B; Totemchokchyakarn, K; Atkinson, T P; Volanakis, J E

1998-01-01

Complement component C6 deficiency (C6D) was diagnosed in a 16-year-old African-American male with meningococcal meningitis. The patient's father and two brothers also had C6D, but gave no history of meningitis or other neisserial infection. By using exon-specific polymerase chain reaction (PCR)/single-strand conformation polymorphism as a screening step and nucleotide sequencing of target exons, we determined that the proband was a compound heterozygote for two C6 gene mutations. The first, 1195delC located in exon 7, is a novel mutation, while the second, 1936delG in exon 12, has been described before to cause C6D in an unrelated African-American individual. Both mutations result in premature termination codons and C6 null alleles. Allele-specific PCR indicated that the proband's two brothers also inherited the 1195delC mutation from their heterozygous mother and the 1936delG mutation from their homozygous father. PMID:9472666

Toll-like receptor 4-positive macrophages protect mice from Pasteurella pneumotropica-induced pneumonia

NASA Technical Reports Server (NTRS)

Hart, Marcia L.; Mosier, Derek A.; Chapes, Stephen K.

2003-01-01

This study investigates Toll-like receptor 4 (TLR4)-positive macrophages in early recognition and clearance of pulmonary bacteria. TLR4 is a trans-membrane receptor that is the primary recognition molecule for lipopolysaccharide of gram-negative bacteria. The TLR4(Lps-del) mouse strains C57BL10/ScN (B10) and STOCK Abb(tm1) TLR4(Lps-del) Slc11a1(s)(B10 x C2D) are susceptible to pulmonary infections and develop pneumonia when naturally or experimentally infected by the opportunistic bacterium Pasteurella pneumotropica. Since these mice have the TLR4(Lps-del) genotype, we hypothesized that reconstitution of mice with TLR4-positive macrophages would provide resistance to this bacterium. A cultured macrophage cell line (C2D macrophages) and bone marrow cells from C2D mice were adoptively transferred to B10 and B10 x C2D mice by intraperitoneal injection. C2D macrophages increased B10 and B10 x C2D mouse resistance to P. pneumotropica. In C2D-recipient mice there was earlier transcription of tumor necrosis factor alpha and chemokines JE and macrophage inflammatory protein 2 (MIP-2) in the lungs of B10 and B10 x C2D mice, and there was earlier transcription of KC and MIP-1alpha in B10 x C2D mice. In addition, the course of inflammation following experimental Pasteurella challenge was altered in C2D recipients. C2D macrophages also protected B10 x C2D mice, which lack CD4(+) T cells. These data indicate that macrophages are critical for pulmonary immunity and can provide host resistance to P. pneumotropica. This study indicates that TLR4-positive macrophages are important for early recognition and clearance of pulmonary bacterial infections.

Calibración del retardo ionosférico en observaciones astrométricas y geodésicas a partir de observaciones GPS

NASA Astrophysics Data System (ADS)

Brunini, C.; Kleusberg, A.; Arias, E. F.; de Biasi, M. S.

Los parámetros astrométricos y geodésicos de precisión se determinan hoy mediante la observación con técnicas espaciales (VLBI, GPS y LSR). Las técnicas VLBI y GPS operan en la banda de microondas y en ella la ionósfera terrestre es dispersiva. Las señales que provienen de las radiofuentes y de los satélites atraviesan la ionósfera, donde el índice de refracción difiere de la unidad en una cantidad que es proporcional a la densidad de electrones libres e inversamente proporcional al cuadrado de la frecuencia de la onda portadora. Actualmente el International GPS Service for Geodynamics (IGS) mantiene operacional una red global integrada por más de 50 estaciones equipadas con receptores GPS de alta performance; las observaciones diarias son accesibles a los usuarios mediante ftp. La posibilidad de utilizar estas observaciones en un monitoreo continuo de la ionósfera fue señalada por diversos autores, razón por la cual en los últimos años se ha invertido un significativo esfuerzo en la producción de mapas ionosféricos regionales y globales. En el presente trabajo se utilizan 28 estaciones cuyas observaciones mapean la mayor parte de la ionósfera global. Los resultados obtenidos demuestran la posibilidad de obtener mapas ionosféricos globales con una resolución de medio día y con una precisión de (1.5 nseg (rms)). Dichos mapas proveen valores medios globales para el intervalo ajustado. Los residuos del ajuste por mínimos cuadrados constituyen una señal a partir de la cual pueden estudiarse mejor las variaciones geográficas de la ionósfera y las componentes estadísticas de su variación temporal.

Prevalence of Escherichia coli O157:H7 From House Flies (Diptera: Muscidae) and Dairy Samples in North Central Florida1.

PubMed

Burrus, Roxanne G; Hogsette, Jerome A; Kaufman, Phillip E; Maruniak, James E; Simonne, Amy H; Mai, Volker

2017-05-01

La detección de Escherichia coli O157:H7 en las lecherías es importante para mejorar la seguridad de los productos lácteos, y se ha llevado a cabo principalmente mediante el aislamiento de las bacterias a partir de las muestras de estiércol. Sin embargo, los componentes biliares presentes en el estiércol complica la identificación genética utilizando la técnica del PCR, y el aislamiento microbiológico se dificulta por la presencia de bacterias competidoras que comparten características microbiológicas similares. El aislamiento de E. coli O157:H7 a partir de la mosca doméstica evita las dificultades asociadas con el estiércol del ganado. El aislamiento de patógenos a partir de las moscas domésticas proporciona información adicional sobre el potencial impacto epidemiológico de la dispersión de la mosca doméstica en la distribución de patógenos, ya que las moscas domésticas se dispersan desde las lecherías donde la E. coli O157:H7 existe en forma endémica en el ganado. En este estudio, se encontró que las moscas domésticas son 2,6 veces más sensibles para la detección de E. coli O157:H7 en las lecherías. Las moscas son más fáciles de capturar y manejar que el estiércol, y deberían ser utilizadas en cualquier ensayo para detectar E. coli O157:H7 en las lecherías y otros establecimientos. Published by Oxford University Press on behalf of Entomological Society of America 2016. This work is written by US Government employees and is in the public domain in the US.

Analysis of HFE and non-HFE gene mutations in Brazilian patients with hemochromatosis.

PubMed

Bittencourt, Paulo Lisboa; Marin, Maria Lúcia Carnevale; Couto, Cláudia Alves; Cançado, Eduardo Luiz Rachid; Carrilho, Flair José; Goldberg, Anna Carla

2009-01-01

Approximately one-half of Brazilian patients with hereditary hemochromatosis (HH) are neither homozygous for the C282Y mutation nor compound heterozygous for the H63D and C282Y mutations that are associated with HH in Caucasians. Other mutations have been described in the HFE gene as well as in genes involved in iron metabolism, such as transferrin receptor 2 (TfR2) and ferroportin 1 (SCL40A1). To evaluate the role of HFE, TfR2 and SCL40A1 mutations in Brazilian subjects with HH. Nineteen male subjects (median age 42 [range: 20-72] years) with HH were evaluated using the Haemochromatosis StripAssay A. This assay is capable of detecting twelve HFE mutations, which are V53M, V59M, H63D, H63H, S65C, Q127H, P160delC, E168Q, E168X, W169X, C282Y and Q283, four TfR2 mutations, which are E60X, M172K, Y250X, AVAQ594-597del, and two SCL40A1 mutations, which are N144H and V162del. In our cohort, nine (47%) patients were homozygous for the C282Y mutation, two (11%) were heterozygous for the H63D mutation, and one each (5%) was either heterozygous for C282Y or compound heterozygous for C282Y and H63D. No other mutations in the HFE, TfR2 or SCL40A1 genes were observed in the studied patients. One-third of Brazilian subjects with the classical phenotype of HH do not carry HFE or other mutations that are currently associated with the disease in Caucasians. This observation suggests a role for other yet unknown mutations in the aforementioned genes or in other genes involved in iron homeostasis in the pathogenesis of HH in Brazil.

78 FR 47489 - Unblocking of Specially Designated Nationals and Blocked Persons Pursuant to the Foreign...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-05

...; c/o INVERPUNTO DEL VALLE S.A., Cali, Colombia; c/o INVERSIONES CIFUENTES Y CIA. S. EN C., Medellin...: INVERPUNTO DEL VALLE S.A.; Linked To: INVERSIONES CIFUENTES Y CIA. S. EN C.; Linked To: LE CLAUDE, S.A. DE C...

A lesson from a reported pathogenic variant in Peutz-Jeghers syndrome: a case report.

PubMed

Tan, Hu; Wei, Xianda; Yang, Pu; Huang, Yanru; Li, Haoxian; Liang, Desheng; Wu, Lingqian

2017-07-01

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder characterized by mucocutaneous hyperpigmentation, gastrointestinal (GI) hamartmatous polyps, and an increased risk of various malignancies. Pathogenic variants in the LKB1 tumor suppressor gene (also known as STK11) are the major cause of PJS. In this study, compound heterozygous variants of LKB1, c.890G > A/ c.1062C > G and del(exon1)/ c.1062C > G, were identified in two sporadic Chinese PJS cases respectively. Although all these three variants had been related to the autosomal dominant PJS in previous studies, all evidences collected in this study including de novo data, segregation data, population data, in-silico data, and functional data indicated that del(exon1) and c.890G > A are pathogenic in these two PJS families rather than c.1062C > G. This finding would contribute to genetic counseling for individuals carrying the variant c.1062C > G with or without PJS phenotypes. Moreover, this finding reminds genetic counselors that it is necessary to reevaluate the pathogenicity of reported variants in a known Mendelian disorder in order to avoid a misleading decision.

Genetic aberrations in multiple myeloma characterized by cIg-FISH: a Brazilian context

PubMed Central

Segges, P.; Braggio, E.; Minnicelli, C.; Hassan, R.; Zalcberg, I.R.; Maiolino, A.

2016-01-01

Genetic abnormalities are critical prognostic factors for patients diagnosed with multiple myeloma (MM). This retrospective, multicenter study aimed to contribute with the genetic and clinical characterization of MM patients in a country with continental dimensions such as Brazil. Genetic abnormalities were assessed by cIg-fluorescent in situ hybridization (cIg-FISH) in a series of 152 MM patients (median age 55 years, 58.5% men). Overall, genetic abnormalities were detected in 52.7% (80/152) of patients. A 14q32 rearrangement was detected in 33.5% (n=51), including t(11;14), t(4;14) and t(14;16) in 18.4, 14.1, and 1% of cases, respectively. del(13q) was identified in 42.7% (n=65) of patients, of whom 49.2% (32/65) presented a concomitant 14q32 rearrangement. del(17p) had a frequency of 5.2% (n=8). del(13q) was associated with high plasma cell burden (≥50%, P=0.02), and del(17p) with advanced ISS stages (P=0.05) and extramedullary disease (P=0.03). t(4;14) was associated with advanced Durie-Salmon stages (P=0.008), renal insufficiency (P=0.01) and was more common in patients over 60 years old. This study reports similar frequencies of genetic abnormalities to most series worldwide, whereas the t(14;16) and del(17p), two high risk factors for newly diagnosed patients, exhibited lower frequencies. Our results expand the knowledge on the molecular features of MM in Brazil, a country where innovative therapies that could overcome a poor prognosis for some genetic abnormalities are not always available. PMID:27074166

Genetic aberrations in multiple myeloma characterized by cIg-FISH: a Brazilian context.

PubMed

Segges, P; Braggio, E; Minnicelli, C; Hassan, R; Zalcberg, I R; Maiolino, A

2016-01-01

Genetic abnormalities are critical prognostic factors for patients diagnosed with multiple myeloma (MM). This retrospective, multicenter study aimed to contribute with the genetic and clinical characterization of MM patients in a country with continental dimensions such as Brazil. Genetic abnormalities were assessed by cIg-fluorescent in situ hybridization (cIg-FISH) in a series of 152 MM patients (median age 55 years, 58.5% men). Overall, genetic abnormalities were detected in 52.7% (80/152) of patients. A 14q32 rearrangement was detected in 33.5% (n=51), including t(11;14), t(4;14) and t(14;16) in 18.4, 14.1, and 1% of cases, respectively. del(13q) was identified in 42.7% (n=65) of patients, of whom 49.2% (32/65) presented a concomitant 14q32 rearrangement. del(17p) had a frequency of 5.2% (n=8). del(13q) was associated with high plasma cell burden (≥50%, P=0.02), and del(17p) with advanced ISS stages (P=0.05) and extramedullary disease (P=0.03). t(4;14) was associated with advanced Durie-Salmon stages (P=0.008), renal insufficiency (P=0.01) and was more common in patients over 60 years old. This study reports similar frequencies of genetic abnormalities to most series worldwide, whereas the t(14;16) and del(17p), two high risk factors for newly diagnosed patients, exhibited lower frequencies. Our results expand the knowledge on the molecular features of MM in Brazil, a country where innovative therapies that could overcome a poor prognosis for some genetic abnormalities are not always available.

Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline CHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma

PubMed Central

Reisle, Caralyn; Martin, Lee Ann; Alwelaie, Yazeed; Mungall, Karen L.; Ch'ng, Carolyn; Thomas, Ruth; Ng, Tony; Yip, Stephen; J. Lim, Howard; Sun, Sophie; Young, Sean S.; Karsan, Aly; Zhao, Yongjun; Mungall, Andrew J.; Moore, Richard A.; J. Renouf, Daniel; Gelmon, Karen; Ma, Yussanne P.; Hayes, Malcolm; Laskin, Janessa; Marra, Marco A.; Schrader, Kasmintan A.; Jones, Steven J. M.

2017-01-01

We describe a woman with the known pathogenic germline variant CHEK2:c.1100delC and synchronous diagnoses of both pelvic genital type leiomyosarcoma (LMS) and metastatic invasive ductal breast carcinoma. CHEK2 (checkpoint kinase 2) is a tumor-suppressor gene encoding a serine/threonine-protein kinase (CHEK2) involved in double-strand DNA break repair and cell cycle arrest. The CHEK2:c.1100delC variant is a moderate penetrance allele resulting in an approximately twofold increase in breast cancer risk. Whole-genome and whole-transcriptome sequencing were performed on the leiomyosarcoma and matched blood-derived DNA. Despite the presence of several genomic hits within the double-strand DNA damage pathway (CHEK2 germline variant and multiple RAD51B somatic structural variants), tumor profiling did not show an obvious DNA repair deficiency signature. However, even though the LMS displayed clear malignant features, its genomic profiling revealed several characteristics classically associated with leiomyomas including a translocation, t(12;14), with one breakpoint disrupting RAD51B and the other breakpoint upstream of HMGA2 with very high expression of HMGA2 and PLAG1. This is the first report of LMS genomic profiling in a patient with the germline CHEK2:c.1100delC variant and an additional diagnosis of metastatic invasive ductal breast carcinoma. We also describe a possible mechanistic relationship between leiomyoma and LMS based on genomic and transcriptome data. Our findings suggest that RAD51B translocation and HMGA2 overexpression may play an important role in LMS oncogenesis. PMID:28514723

Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline CHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma.

PubMed

Thibodeau, My Linh; Reisle, Caralyn; Zhao, Eric; Martin, Lee Ann; Alwelaie, Yazeed; Mungall, Karen L; Ch'ng, Carolyn; Thomas, Ruth; Ng, Tony; Yip, Stephen; J Lim, Howard; Sun, Sophie; Young, Sean S; Karsan, Aly; Zhao, Yongjun; Mungall, Andrew J; Moore, Richard A; J Renouf, Daniel; Gelmon, Karen; Ma, Yussanne P; Hayes, Malcolm; Laskin, Janessa; Marra, Marco A; Schrader, Kasmintan A; Jones, Steven J M

2017-09-01

We describe a woman with the known pathogenic germline variant CHEK2 :c.1100delC and synchronous diagnoses of both pelvic genital type leiomyosarcoma (LMS) and metastatic invasive ductal breast carcinoma. CHEK2 (checkpoint kinase 2) is a tumor-suppressor gene encoding a serine/threonine-protein kinase (CHEK2) involved in double-strand DNA break repair and cell cycle arrest. The CHEK2 :c.1100delC variant is a moderate penetrance allele resulting in an approximately twofold increase in breast cancer risk. Whole-genome and whole-transcriptome sequencing were performed on the leiomyosarcoma and matched blood-derived DNA. Despite the presence of several genomic hits within the double-strand DNA damage pathway ( CHEK2 germline variant and multiple RAD51B somatic structural variants), tumor profiling did not show an obvious DNA repair deficiency signature. However, even though the LMS displayed clear malignant features, its genomic profiling revealed several characteristics classically associated with leiomyomas including a translocation, t(12;14), with one breakpoint disrupting RAD51B and the other breakpoint upstream of HMGA2 with very high expression of HMGA2 and PLAG1 This is the first report of LMS genomic profiling in a patient with the germline CHEK2 :c.1100delC variant and an additional diagnosis of metastatic invasive ductal breast carcinoma. We also describe a possible mechanistic relationship between leiomyoma and LMS based on genomic and transcriptome data. Our findings suggest that RAD51B translocation and HMGA2 overexpression may play an important role in LMS oncogenesis. © 2017 Thibodeau et al.; Published by Cold Spring Harbor Laboratory Press.

55. E.M.C., photographer July 3, 1936 HUMBOLDT COUNTY, SECTION J, ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

55. E.M.C., photographer July 3, 1936 HUMBOLDT COUNTY, SECTION J, HIGHWAY 1. 1-HUM-I-J #80, BITUMULS PORTION OF EXPERIMENTAL SECTION, E.M.C, 7-3-36. BACK READS: C/PROCESSING STABILIZING BITUMULS WITH BLADE AFTER BEING PROCESSED WITH SPRING TOOTH HARROW. Stamped office copy. - Redwood National & State Parks Roads, California coast from Crescent City to Trinidad, Crescent City, Del Norte County, CA

Dual Inhibition of PI3K/Akt and mTOR by the Dietary Antioxidant, Delphinidin, Ameliorates Psoriatic Features In Vitro and in an Imiquimod-Induced Psoriasis-Like Disease in Mice

PubMed Central

Adhami, Vaqar M.; Esnault, Stephane; Sechi, Mario; Siddiqui, Imtiaz A.; Satyshur, Kenneth A.; Syed, Deeba N.; Dodwad, Shah-Jahan M.; Chaves-Rodriquez, Maria-Ines; Longley, B. Jack; Wood, Gary S.

2017-01-01

Abstract Aim: The treatment of psoriasis remains elusive, underscoring the need for identifying novel disease targets and mechanism-based therapeutic approaches. We recently reported that the PI3K/Akt/mTOR pathway that is frequently deregulated in many malignancies is also clinically relevant for psoriasis. We also provided rationale for developing delphinidin (Del), a dietary antioxidant for the management of psoriasis. This study utilized high-throughput biophysical and biochemical approaches and in vitro and in vivo models to identify molecular targets regulated by Del in psoriasis. Results: A kinome-level screen and Kds analyses against a panel of 102 human kinase targets showed that Del binds to three lipid (PIK3CG, PIK3C2B, and PIK3CA) and six serine/threonine (PIM1, PIM3, mTOR, S6K1, PLK2, and AURKB) kinases, five of which belong to the PI3K/Akt/mTOR pathway. Surface plasmon resonance and in silico molecular modeling corroborated Del's direct interactions with three PI3Ks (α/c2β/γ), mTOR, and p70S6K. Del treatment of interleukin-22 or TPA-stimulated normal human epidermal keratinocytes (NHEKs) significantly inhibited proliferation, activation of PI3K/Akt/mTOR components, and secretion of proinflammatory cytokines and chemokines. To establish the in vivo relevance of these findings, an imiquimod (IMQ)-induced Balb/c mouse psoriasis-like skin model was employed. Topical treatment of Del significantly decreased (i) hyperproliferation and epidermal thickness, (ii) skin infiltration by immune cells, (iii) psoriasis-related cytokines/chemokines, (iv) PI3K/Akt/mTOR pathway activation, and (v) increased differentiation when compared with controls. Innovation and Conclusion: Our observation that Del inhibits key kinases involved in psoriasis pathogenesis and alleviates IMQ-induced murine psoriasis-like disease suggests a novel PI3K/AKT/mTOR pathway modulator that could be developed to treat psoriasis. Antioxid. Redox Signal. 26, 49–69. PMID:27393705

Spectrum and Frequency of the GJB2 Gene Pathogenic Variants in a Large Cohort of Patients with Hearing Impairment Living in a Subarctic Region of Russia (the Sakha Republic)

PubMed Central

Posukh, Olga L.; Teryutin, Fedor M.; Solovyev, Aisen V.; Klarov, Leonid A.; Romanov, Georgii P.; Gotovtsev, Nyurgun N.; Kozhevnikov, Andrey A.; Kirillina, Elena V.; Sidorova, Oksana G.; Vasilyevа, Lena M.; Fedotova, Elvira E.; Morozov, Igor V.; Bondar, Alexander A.; Solovyevа, Natalya A.; Kononova, Sardana K.; Rafailov, Adyum M.; Sazonov, Nikolay N.; Alekseev, Anatoliy N.; Tomsky, Mikhail I.; Dzhemileva, Lilya U.; Khusnutdinova, Elza K.; Fedorova, Sardana A.

2016-01-01

Pathogenic variants in the GJB2 gene, encoding connexin 26, are known to be a major cause of hearing impairment (HI). More than 300 allelic variants have been identified in the GJB2 gene. Spectrum and allelic frequencies of the GJB2 gene vary significantly among different ethnic groups worldwide. Until now, the spectrum and frequency of the pathogenic variants in exon 1, exon 2 and the flanking intronic regions of the GJB2 gene have not been described thoroughly in the Sakha Republic (Yakutia), which is located in a subarctic region in Russia. The complete sequencing of the non-coding and coding regions of the GJB2 gene was performed in 393 patients with HI (Yakuts—296, Russians—51, mixed and other ethnicities—46) and in 187 normal hearing individuals of Yakut (n = 107) and Russian (n = 80) populations. In the total sample (n = 580), we revealed 12 allelic variants of the GJB2 gene, 8 of which were recessive pathogenic variants. Ten genotypes with biallelic recessive pathogenic variants in the GJB2 gene (in a homozygous or a compound heterozygous state) were found in 192 out of 393 patients (48.85%). We found that the most frequent GJB2 pathogenic variant in the Yakut patients was c.-23+1G>A (51.82%) and that the second most frequent was c.109G>A (2.37%), followed by c.35delG (1.64%). Pathogenic variants с.35delG (22.34%), c.-23+1G>A (5.31%), and c.313_326del14 (2.12%) were found to be the most frequent among the Russian patients. The carrier frequencies of the c.-23+1G>A and с.109G>A pathogenic variants in the Yakut control group were 10.20% and 2.80%, respectively. The carrier frequencies of с.35delG and c.101T>C were identical (2.5%) in the Russian control group. We found that the contribution of the GJB2 gene pathogenic variants in HI in the population of the Sakha Republic (48.85%) was the highest among all of the previously studied regions of Asia. We suggest that extensive accumulation of the c.-23+1G>A pathogenic variant in the indigenous Yakut population (92.20% of all mutant chromosomes in patients) and an extremely high (10.20%) carrier frequency in the control group may indicate a possible selective advantage for the c.-23+1G>A carriers living in subarctic climate. PMID:27224056

[Cytochrome c oxydase-deficient Leigh syndrome with homozygous mutation in SURF1 gene].

PubMed

Monnot, S; Chabrol, B; Cano, A; Pellissier, J F; Collignon, P; Montfort, M F; Paquis-Flucklinger, V

2005-05-01

Leigh syndrome is a heterogeneous disorder, usually due to a defect in oxidative metabolism. Mutations in SURF1 gene have been identified in patients with cytochrome c oxidase deficiency. We report a homozygous splice site deletion [516-2_516-1delAG] in a young girl presenting with cytochrome c oxidase-deficient Leigh syndrome. Identification of molecular defect is indispensable for genetic counselling and prenatal diagnosis.

Department of Defense HIV/AIDS Prevention Program (DHAPP): 2006 Annual Report

DTIC Science & Technology

2007-01-01

The Comité Central de Prevención y Control del VIH /SIDA de las Fuerzas Armadas y Po- licía Nacional del Perú (COPRECOS) is a gov- B A C K G R O U N D...military populations; STIs; oppor- tunistic infections; combined therapy for HIV and tuber- culosis co-infections; VIH , HTLV-1, HCV, HBV co- infections

Patient survival and tumor characteristics associated with CHEK2:p.I157T - findings from the Breast Cancer Association Consortium.

PubMed

Muranen, Taru A; Blomqvist, Carl; Dörk, Thilo; Jakubowska, Anna; Heikkilä, Päivi; Fagerholm, Rainer; Greco, Dario; Aittomäki, Kristiina; Bojesen, Stig E; Shah, Mitul; Dunning, Alison M; Rhenius, Valerie; Hall, Per; Czene, Kamila; Brand, Judith S; Darabi, Hatef; Chang-Claude, Jenny; Rudolph, Anja; Nordestgaard, Børge G; Couch, Fergus J; Hart, Steven N; Figueroa, Jonine; García-Closas, Montserrat; Fasching, Peter A; Beckmann, Matthias W; Li, Jingmei; Liu, Jianjun; Andrulis, Irene L; Winqvist, Robert; Pylkäs, Katri; Mannermaa, Arto; Kataja, Vesa; Lindblom, Annika; Margolin, Sara; Lubinski, Jan; Dubrowinskaja, Natalia; Bolla, Manjeet K; Dennis, Joe; Michailidou, Kyriaki; Wang, Qin; Easton, Douglas F; Pharoah, Paul D P; Schmidt, Marjanka K; Nevanlinna, Heli

2016-10-03

P.I157T is a CHEK2 missense mutation associated with a modest increase in breast cancer risk. Previously, another CHEK2 mutation, the protein truncating c.1100delC has been associated with poor prognosis of breast cancer patients. Here, we have investigated patient survival and characteristics of breast tumors of germ line p.I157T carriers. We included in the analyses 26,801 European female breast cancer patients from 15 studies participating in the Breast Cancer Association Consortium. We analyzed the association between p.I157T and the clinico-pathological breast cancer characteristics by comparing the p.I157T carrier tumors to non-carrier and c.1100delC carrier tumors. Similarly, we investigated the p.I157T associated risk of early death, breast cancer-associated death, distant metastasis, locoregional relapse and second breast cancer using Cox proportional hazards models. Additionally, we explored the p.I157T-associated genomic gene expression profile using data from breast tumors of 183 Finnish female breast cancer patients (ten p.I157T carriers) (GEO: GSE24450). Differential gene expression analysis was performed using a moderated t test. Functional enrichment was investigated using the DAVID functional annotation tool and gene set enrichment analysis (GSEA). The tumors were classified into molecular subtypes according to the St Gallen 2013 criteria and the PAM50 gene expression signature. P.I157T was not associated with increased risk of early death, breast cancer-associated death or distant metastasis relapse, and there was a significant difference in prognosis associated with the two CHEK2 mutations, p.I157T and c.1100delC. Furthermore, p.I157T was associated with lobular histological type and clinico-pathological markers of good prognosis, such as ER and PR expression, low TP53 expression and low grade. Gene expression analysis suggested luminal A to be the most common subtype for p.I157T carriers and CDH1 (cadherin 1) target genes to be significantly enriched among genes, whose expression differed between p.I157T and non-carrier tumors. Our analyses suggest that there are fundamental differences in breast tumors of CHEK2:p.I157T and c.1100delC carriers. The poor prognosis associated with c.1100delC cannot be generalized to other CHEK2 mutations.

Expanding the Phenotypic and Genotypic Landscape of Autoimmune Polyendocrine Syndrome Type 1.

PubMed

Orlova, Elizaveta M; Sozaeva, Leila S; Kareva, Maria A; Oftedal, Bergithe E; Wolff, Anette S B; Breivik, Lars; Zakharova, Ekaterina Y; Ivanova, Olga N; Kämpe, Olle; Dedov, Ivan I; Knappskog, Per M; Peterkova, Valentina A; Husebye, Eystein S

2017-09-01

Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene and characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency. Comprehensive characterizations of large patient cohorts are rare. To perform an extensive clinical, immunological, and genetic characterization of a large nationwide Russian APS-1 cohort. Clinical components were mapped by systematic investigations, sera were screened for autoantibodies associated with APS-1, and AIRE mutations were characterized by Sanger sequencing. We identified 112 patients with APS-1, which is, to the best of our knowledge, the largest cohort described to date. Careful phenotyping revealed several additional and uncommon phenotypes such as cerebellar ataxia with pseudotumor, ptosis, and retinitis pigmentosa. Neutralizing autoantibodies to interferon-ω were found in all patients except for one. The major Finnish mutation c.769C>T (p.R257*) was the most frequent and was present in 72% of the alleles. Altogether, 19 different mutations were found, of which 9 were unknown: c.38T>C (p.L13P), c.173C>T (p.A58V), c.280C>T (p.Q94*), c.554C>G (p.S185*), c.661A>T (p.K221*), c.821del (p.Gly274Afs*104), c.1195G>C (p.A399P), c.1302C>A (p.C434*), and c.1497del (p.A500Pfs*21). The spectrum of phenotypes and AIRE mutation in APS-1 has been expanded. The Finnish major mutation is the most common mutation in Russia and is almost as common as in Finland. Assay of interferon antibodies is a robust screening tool for APS-1. Copyright © 2017 Endocrine Society

Polymorphisms of glutathione S-transferase π 1 and toll-like receptors 2 and 9: Association with breast cancer susceptibility

PubMed Central

AL-HARRAS, MOHAMMAD F.; HOUSSEN, MAHA E.; SHAKER, MOHAMED E.; FARAG, KAMEL; FAROUK, OMAR; MONIR, REHAN; EL-MAHDY, RASHA; ABO-HASHEM, EKBAL M.

2016-01-01

Polymorphisms in antioxidant enzymes and innate immune receptors have been implicated in the development of various types of cancer. The present study aimed to investigate whether polymorphisms of glutathione S-transferase π 1 (GSTP1) and toll-like receptors (TLRs) 2 and 9 are associated with susceptibility to breast cancer among females. The study was conducted on 72 Egyptian female patients with breast cancer, along with 100 healthy volunteers. Polymorphisms of GSTP1 (codon 105 Ile/Val) and TLR9 rs187084 (1237T/C) genes were assessed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, while the −196 to −174 deletion/insertion (del/ins) polymorphism of TLR2 was detected by PCR. The results indicated a decrease in GSTP1 Val allele frequency in breast cancer patients compared with healthy controls, at rates of 22.9 vs. 32.5%, respectively. In addition, the breast cancer group demonstrated a decreased TLR9 C allele frequency compared with the control group, at rates of 36.1 vs. 51.5%, respectively (P=0.0047). A non-significant difference was detected in the frequency of the TLR2 −196 to −174 del allele in breast cancer patients when compared to normal controls. In conclusion, these results suggested that the GSTP1 Val and TLR9 1237C alleles, but not TLR2 −196 to −174 del, are likely to be associated with breast cancer development among females. PMID:26998146

Polymorphisms of glutathione S-transferase π 1 and toll-like receptors 2 and 9: Association with breast cancer susceptibility.

PubMed

Al-Harras, Mohammad F; Houssen, Maha E; Shaker, Mohamed E; Farag, Kamel; Farouk, Omar; Monir, Rehan; El-Mahdy, Rasha; Abo-Hashem, Ekbal M

2016-03-01

Polymorphisms in antioxidant enzymes and innate immune receptors have been implicated in the development of various types of cancer. The present study aimed to investigate whether polymorphisms of glutathione S-transferase π 1 (GSTP1) and toll-like receptors (TLRs) 2 and 9 are associated with susceptibility to breast cancer among females. The study was conducted on 72 Egyptian female patients with breast cancer, along with 100 healthy volunteers. Polymorphisms of GSTP1 (codon 105 Ile/Val) and TLR9 rs187084 (1237T/C) genes were assessed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, while the -196 to -174 deletion/insertion (del/ins) polymorphism of TLR2 was detected by PCR. The results indicated a decrease in GSTP1 Val allele frequency in breast cancer patients compared with healthy controls, at rates of 22.9 vs. 32.5%, respectively. In addition, the breast cancer group demonstrated a decreased TLR9 C allele frequency compared with the control group, at rates of 36.1 vs. 51.5%, respectively (P=0.0047). A non-significant difference was detected in the frequency of the TLR2 -196 to -174 del allele in breast cancer patients when compared to normal controls. In conclusion, these results suggested that the GSTP1 Val and TLR9 1237C alleles, but not TLR2 -196 to -174 del, are likely to be associated with breast cancer development among females.

HSP90, HSPA8, HIF-1 alpha and HSP70-2 polymorphisms in breast cancer: a case-control study.

PubMed

Zagouri, Flora; Sergentanis, Theodoros N; Gazouli, Maria; Tsigginou, Alexandra; Dimitrakakis, Constantine; Papaspyrou, Irene; Eleutherakis-Papaiakovou, Evaggelos; Chrysikos, Dimosthenis; Theodoropoulos, George; Zografos, George C; Antsaklis, Aris; Dimopoulos, Athanassios-Meletios; Papadimitriou, Christos A

2012-12-01

This case control study aims to investigate the role of HSP90 Gln488His (C > G), HSP70-2 P1/P2, HIF-1 alpha C1772T and HSPA8 intronic 1541-1542delGT polymorphisms as potential risk factors and/or prognostic markers for breast cancer. 113 consecutive incident cases of histologically confirmed ductal breast cancer and 124 healthy cases were recruited. The above mentioned polymorphisms were genotyped; multivariate logistic regression was performed. HSP90 GG (His/His) genotype was associated with elevated breast cancer risk. Similarly, the allele dose-response model pointed to increase in breast cancer risk per G allele. HSP70-2 P1/P2, HSPA8 intronic 1541-1542delGT and HIF-1 alpha polymorphisms were not associated with breast cancer risk, as evidenced by the dose-response allele models. The positive association between HSP90 G allele and breast cancer risk seemed to pertain to both premenopausal and postmenopausal women. With respect to survival analysis, none of the aforementioned polymorphisms was associated with either disease-free survival or overall survival. HSP90α Gln488His polymorphism seems to be a risk factor for breast cancer. On the other hand, our study did not point to excess risk conferred by HSPA8 1541-1542delGT, Hsp70-2 P1/P2 and HIF-1α C1772T.

Rapid Detection Method for the Four Most Common CHEK2 Mutations Based on Melting Profile Analysis.

PubMed

Borun, Pawel; Salanowski, Kacper; Godlewski, Dariusz; Walkowiak, Jaroslaw; Plawski, Andrzej

2015-12-01

CHEK2 is a tumor suppressor gene, and the mutations affecting the functionality of the protein product increase cancer risk in various organs. The elevated risk, in a significant percentage of cases, is determined by the occurrence of one of the four most common mutations in the CHEK2 gene, including c.470T>C (p.I157T), c.444+1G>A (IVS2+1G>A), c.1100delC, and c.1037+1538_1224+328del5395 (del5395). We have developed and validated a rapid and effective method for their detection based on high-resolution melting analysis and comparative-high-resolution melting, a novel approach enabling simultaneous detection of copy number variations. The analysis is performed in two polymerase chain reactions followed by melting analysis, without any additional reagents or handling other than that used in standard high-resolution melting. Validation of the method was conducted in a group of 103 patients with diagnosed breast cancer, a group of 240 unrelated patients with familial history of cancer associated with the CHEK2 gene mutations, and a 100-person control group. The results of the analyses for all three groups were fully consistent with the results from other methods. The method we have developed improves the identification of the CHEK2 mutation carriers, reduces the cost of such analyses, as well as facilitates their implementation. Along with the increased efficiency, the method maintains accuracy and reliability comparable to other more labor-consuming techniques.

CHEK2 1100DELC germline mutation: a frequency study in hereditary breast and colon cancer Brazilian families.

PubMed

Abud, Jamile; Koehler-Santos, Patricia; Ashton-Prolla, Patricia; Prolla, João Carlos

2012-12-01

CHEK2 encodes a cell cycle checkpoint kinase that plays an important role in the DNA damage repair pathway, activated mainly by ATM (Ataxia Telangiectasia Mutated) in response to double-stranded DNA breaks. A germline mutation in CHEK2, 1100delC, has been described as a low penetrance allele in a significant number of families with breast and colorectal cancer in certain countries and is also associated with increased risk of contralateral breast cancer in women previously affected by the disease. About 5%-10% of all breast and colorectal cancers are associated with hereditary predisposition and its recognition is of great importance for genetic counseling and cancer risk management. Here, we have assessed the frequency of the CHEK2 1100delC mutation in the germline of 59 unrelated Brazilian individuals with clinical criteria for the hereditary breast and colorectal cancer syndrome. A long-range PCR strategy followed by gene sequencing was used. The 1100delC mutation was encountered in the germline of one (1.7%) individual in this high risk cohort. This indicates that the CHEK2 1100delC is not commonly encountered in Brazilian families with multiple diagnoses of breast and colorectal cancer. These results should be confirmed in a larger series of families and further testing should be undertaken to investigate the molecular mechanisms underlying the hereditary breast and colorectal cancer phenotype.

A chemical corrector modifies the channel function of F508del-CFTR.

PubMed

Kim Chiaw, Patrick; Wellhauser, Leigh; Huan, Ling Jun; Ramjeesingh, Mohabir; Bear, Christine E

2010-09-01

The deletion of Phe-508 (F508del) constitutes the most prevalent cystic fibrosis-causing mutation. This mutation leads to cystic fibrosis transmembrane conductance regulator (CFTR) misfolding and retention in the endoplasmic reticulum and altered channel activity in mammalian cells. This folding defect can however be partially overcome by growing cells expressing this mutant protein at low (27 degrees C) temperature. Chemical "correctors" have been identified that are also effective in rescuing the biosynthetic defect in F508del-CFTR, thereby permitting its functional expression at the cell surface. The mechanism of action of chemical correctors remains unclear, but it has been suggested that certain correctors [including 4-cyclohexyloxy-2-(1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl)-quinazoline (VRT-325)] may act to promote trafficking by interacting directly with the mutant protein. To test this hypothesis, we assessed the effect of VRT-325 addition on the channel activity of F508del-CFTR after its surface expression had been "rescued" by low temperature. It is noteworthy that short-term pretreatment with VRT-325 [but not with an inactive analog, 4-hydroxy-2-(1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl)-quinazoline (VRT-186)], caused a modest but significant inhibition of cAMP-mediated halide flux. Furthermore, VRT-325 decreased the apparent ATP affinity of purified and reconstituted F508del-CFTR in our ATPase activity assay, an effect that may account for the decrease in channel activity by temperature-rescued F508del-CFTR. These findings suggest that biosynthetic rescue mediated by VRT-325 may be conferred (at least in part) by direct modification of the structure of the mutant protein, leading to a decrease in its ATP-dependent conformational dynamics. Therefore, the challenge for therapy discovery will be the design of small molecules that bind to promote biosynthetic maturation of the major mutant without compromising its activity in vivo.

Contemporary Records of the (1492) Ensisheim Fall

NASA Astrophysics Data System (ADS)

Levi, F. A.; Levi-Donati, G. R.

1992-07-01

On the occasion of the five-hundredth anniversary of the Ensisheim (LL6) stone (November 16, 1492), five rare documents on this fall are presented: 1) Anonymous, Annali del Convento di S. Domenico. (in Italian) Manuscript n. 1151, Biblioteca Com. "Augusta", Perugia. 2) Eusebii Pamphili C. (1570) Chronicon. Petri, Basilea. (in Latin). 3) Lycosthenes (Wolffhart) C. (1557) Prodigiorum ac ostentorum Chronicon. Petri, Basilea. (in Latin). 4) Sansovino F. (1582) Cronologia del Mondo. Salicato, Vinegia. (in Italian). 5) Schedel H. (1492) Liber Chronicarum cum figuris et ymagi(ni)bus ab inicio mu(n)di. Koberger, Nuremberga. (in Latin).

Sensitivity to systemic therapy for metastatic breast cancer in CHEK2 1100delC mutation carriers.

PubMed

Kriege, Mieke; Jager, Agnes; Hollestelle, Antoinette; Berns, Els M J J; Blom, Jannet; Meijer-van Gelder, Marion E; Sieuwerts, Anieta M; van den Ouweland, Ans; Collée, J Margriet; Kroep, Judith R; Martens, John W M; Hooning, Maartje J; Seynaeve, Caroline

2015-10-01

The role of CHEK2 in DNA repair by homologous recombination suggests that CHEK2-associated breast cancer (BC) patients might be more sensitive to chemotherapy inducing double-strand DNA breaks, but results hereon are lacking. We compared the sensitivity to first-line chemotherapy and endocrine therapy between CHEK2 1100delC and non-CHEK2 metastatic breast cancer (MBC) patients. Sixty-two CHEK2 1100delC MBC patients were selected from three cohorts genotyped for CHEK2 1100delC (one non-BRCA1/2 cohort and two sporadic cohorts). Controls were 62 non-CHEK2 MBC patients, matched for age at and year of primary BC diagnosis, and year of metastatic disease. Objective response rate (complete and partial response) to, and progression-free survival (PFS) and overall survival (OS) after start of first-line chemotherapy and endocrine therapy were compared between CHEK2 and non-CHEK2 patients. Median age at BC diagnosis was 46 and 51 years at MBC diagnosis. First-line chemotherapy consisted of anthracycline-based chemotherapy (n = 73), taxanes (n = 16), CMF(-like) chemotherapy (n = 33) and taxane/anthracycline regimens (n = 2). CHEK2 and non-CHEK2 patients had a comparable objective response rate (44 vs. 52 %). Also, PFS and OS after start of chemotherapy were comparable between both patient groups (hazard ratio 0.91; 95 % confidence interval 0.63-1.30 and 1.03; 95 % CI 0.71-1.49, respectively). Thirty-six CHEK2 and 32 non-CHEK2 patients received first-line endocrine therapy (mainly tamoxifen) for MBC. No significant differences were observed in objective response rate to, and PFS and OS after start of endocrine therapy. No differential efficacy of chemotherapy and endocrine therapy given for MBC was observed in CHEK2 versus non-CHEK2 patients.

Formación estelar y AGNs en los entornos de quasars

NASA Astrophysics Data System (ADS)

Coldwell, G.; García Lambas, D.

En este trabajo utilizamos las galaxias del catálogo 2dF (2dF public 100K data release) y muestras de quasars tomados del catálogo Verón-Cetty & Verón (2001) para estudiar la naturaleza de estas galaxias en los entornos de quasars con redshift en el rango 0.1< z < 0.2. Estudiamos la distribución de índices espectrales, η, de galaxias a distintas distancias proyectadas de quasars y con diferencias de velocidad radial Δ V <= 500 km s-1. Por comparación, realizamos el mismo análisis en una muestra de galaxias random del catálogo 2dF y en una muestra de cúmulos Abell con similar distribución de redshift que los quasars. Los resultados indican que existe una gran fracción de galaxias con fuertes líneas de emisión, eta > 3.5, en los entornos de quasars comparado con la fracción presente en las vecindades de galaxias típicas del 2dF. Analizamos las distribuciones de luminosidad para estas galaxias (eta > 3.5) encontrando un exceso de galaxias mas luminosas que M ˜ -19.5 en las vecindades de quasars, indicativo de la posible presencia de AGNs. Por otro lado, estimamos la tasa de formación estelar promedio para objetos a distintas distancias de quasars, galaxias y cúmulos de galaxias detectando una actividad de formacion estelar significativamente alta dentro de 1.5 Mpc h-1 de quasars con respecto a las galaxias del 2dF. Estos resultados proveen evidencia de un particular entorno de galaxias alrededor de Quasars.

SnoRNA Snord116 (Pwcr1/MBII-85) Deletion Causes Growth Deficiency and Hyperphagia in Mice

PubMed Central

Ding, Feng; Li, Hong Hua; Zhang, Shengwen; Solomon, Nicola M.; Camper, Sally A.; Cohen, Pinchas; Francke, Uta

2008-01-01

Prader-Willi syndrome (PWS) is the leading genetic cause of obesity. After initial severe hypotonia, PWS children become hyperphagic and morbidly obese, if intake is not restricted. Short stature with abnormal growth hormone secretion, hypogonadism, cognitive impairment, anxiety and behavior problems are other features. PWS is caused by lack of expression of imprinted genes in a ∼4 mb region of chromosome band 15q11.2. Our previous translocation studies predicted a major role for the C/D box small nucleolar RNA cluster SNORD116 (PWCR1/HBII-85) in PWS. To test this hypothesis, we created a ∼150 kb deletion of the >40 copies of Snord116 (Pwcr1/MBII-85) in C57BL/6 mice. Snord116del mice with paternally derived deletion lack expression of this snoRNA. They have early-onset postnatal growth deficiency, but normal fertility and lifespan. While pituitary structure and somatotrophs are normal, liver Igf1 mRNA is decreased. In cognitive and behavior tests, Snord116del mice are deficient in motor learning and have increased anxiety. Around three months of age, they develop hyperphagia, but stay lean on regular and high-fat diet. On reduced caloric intake, Snord116del mice maintain their weight better than wild-type littermates, excluding increased energy requirement as a cause of hyperphagia. Normal compensatory feeding after fasting, and ability to maintain body temperature in the cold indicate normal energy homeostasis regulation. Metabolic chamber studies reveal that Snord116del mice maintain energy homeostasis by altered fuel usage. Prolonged mealtime and increased circulating ghrelin indicate a defect in meal termination mechanism. Snord116del mice, the first snoRNA deletion animal model, reveal a novel role for a non-coding RNA in growth and feeding regulation. PMID:18320030

78 FR 62948 - Unblocking of Specially Designated Nationals and Blocked Persons Pursuant to Executive Order 12978

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-22

... AGROPECUARIA DEL SUR LTDA., Bogota, Colombia; c/o INVERSIONES AGROINDUSTRIALES DEL OCCIDENTE LTDA., Bogota, Colombia; c/o AGROPECUARIA LINDARAJA S.A., Cali, Colombia; c/o INVERSIONES BRASILAR S.A., Bogota, Colombia...

"Estudio tribologico de aceros para moldes. Aplicacion al moldeo por inyeccion de polibutilentereftalato reforzado con fibra de vidrio"

NASA Astrophysics Data System (ADS)

Martinez Mateo, Isidoro Jose

Mould materials for injection moulding of polymers and polymer-matrix composites represent a relevant industrial economic sector due to the large quantity of pieces and components processed. The material selection for mould manufacturing, its composition and heat treatment, the hardening procedures and machining and finishing processes determine the service performance and life of the mould. In the first part of the present study, the relationship between the hardness and microstructure and the wear resistance of mould steels from large blocks has been studied by pin-on-disc tests, studying the main wear mechanisms. In order to determine the surface damage on mould steels under real injection conditions, different commercial steels have been studied by measuring the variation of surface roughness with the number of injected pieces with different reinforcement percentages and different mould geometries, by using optical profilometry and scanning electron microscopy techniques. It was important to determine the variation of surface roughness of the moulded pieces with the number of injection operations. The materials used were polybutyleneterephthalate pure and reinforced with either 20% or 50% glass fibre. For the different mould designs, the evolution of the glass fibre orientation with injection flow has been determined by image analysis and related to roughness changes and surface damage, both of the composite parts and of the mould steel surface. Finally, the abrasion resistance of the composite parts has been studied by scratch tests as a function of the number of injected parts and of the scratch direction with respect to injection flow and glass fibre orientation. Los materiales para moldes de inyeccion de polimeros y materiales compuestos representan un sector economicamente muy relevante debido al gran aumento del numero de componentes fabricados a partir de materiales polimericos obtenidos mediante moldeo por inyeccion. La seleccion del material para la fabricacion del molde, tienen una gran influencia sobre su comportamiento en servicio a lo largo de la vida util del molde. En la primera parte del presente estudio, a partir de ensayos punzon sobre disco, se ha determinado la relacion entre la resistencia al desgaste y la dureza de aceros para moldes obtenidos a partir de bloques de gran espesor, estudiando los principales mecanismos de desgaste que tienen lugar. A continuacion, con el fin de determinar el dano superficial que sufren los aceros para moldes en condiciones reales de inyeccion, se han estudiado distintos tipos de aceros utilizados comercialmente en moldes de inyeccion de polimeros y materiales compuestos, seleccionando las condiciones de operacion para determinar la variacion de la rugosidad superficial del acero en funcion del material inyectado, del numero de operaciones sucesivas de inyeccion y de la orientacion del flujo de inyeccion, mediante tecnicas de perfilometria optica y microscopia electronica de barrido. Ademas del dano superficial sufrido por el acero con el numero de piezas inyectadas, tambien se ha determinado la evolucion de la rugosidad superficial de los materiales inyectados, polibutilentereftalato (PBT) puro y materiales compuestos derivados de PBT por adicion de un 20 o un 50% en peso de fibra de vidrio. En el caso de las piezas inyectadas, se ha caracterizado su microestructura en funcion del flujo de inyeccion y de la densidad de fibra, se han determinado sus propiedades termicas y dinamico-mecanicas, asi como la variacion de la rugosidad superficial de las piezas inyectadas con el numero de operaciones de inyeccion y con la geometria de las distintas secciones de las piezas. Finalmente, se ha evaluado la resistencia a la abrasion de PBT reforzado con un 50% de fibra, en funcion del numero de piezas inyectadas y de la direccion de rayado con respecto a la orientacion del flujo de inyeccion.

Dinámica y crecimiento de los granos de polvo en la nebulosa protoplanetaria

NASA Astrophysics Data System (ADS)

de La Fuente Marcos, Carlos

2001-06-01

En el escenario estándar de la formación planetaria, los planetesimales (cuerpos de tamaño kilométrico) crecen a partir de granos de polvo, similares a los interestelares, embebidos en un disco gaseoso denominado nebulosa protoplanetaria. Durante esta etapa, los movimientos del gas pueden tener gran influencia en la dinámica y el crecimiento de los granos de polvo, dado que el flujo kepleriano del gas frena el movimiento de los mismos haciendo que caigan hacia el Sol, y la turbulencia inhibe la inestabilidad gravitacional de la capa de polvo. Aunque se acepta que los planetesimales fueron los elementos constituyentes de los planetas, todavía se desconoce cómo se produjo la formación de los mismos. Por esta razón, en los estudios más recientes, existe un renovado interés por comprender mejor la evolución de la capa de polvo inmersa en el disco gaseoso de la Nebulosa. El gas que fluye en el disco puede engendrar estructuras carentes de simetría axial, como por ejemplo ondas espirales y vórtices, a partir de gran variedad de mecanismos de excitación e inestabilidad. En 1995, Barge y Sommeria pusieron de manifiesto que la existencia de vórtices gaseosos persistentes en la nebulosa solar tendría importantes consecuencias sobre la formación de los planetesimales y el posterior crecimiento de los planetas gigantes. La investigación desarrollada en esta Tesis analiza la relación entre el polvo y el gas debida al acoplamiento por fricción dinámica entre ambos; en concreto, se estudia el efecto del flujo medio del gas sobre la dinámica de las partículas de polvo. El primer objetivo es investigar en profundidad los procesos de captura y crecimiento de los granos de polvo dentro de un vórtice y su posible relevancia en cuanto a la formación de los planetesimales. El segundo objetivo es la exploración de los efectos de ondas espirales propagándose en el disco gaseoso sobre la dinámica y el crecimiento de las partículas. La presencia de líneas de corriente no circulares perturba significativamente el movimiento de las partículas alrededor del Sol e incrementa su vida media en la Nebulosa. El flujo medio del gas se modela de forma simple, analizándose la dinámica y el crecimiento de las partículas mediante simulaciones numéricas. Al incrementarse la vida media y la densidad superficial de las partículas sólidas, los mecanismos de confinamiento derivados de la presencia de vórtices y ondas espirales actuan sobre el material sólido de la Nebulosa (mediante agregación colisional o inestabilidades gravitacionales) de manera mucho más eficiente que la previamente considerada. Esto ofrece nuevas posibilidades para la formación de planetesimales y núcleos de planetas gigantes, y puede explicar la formación rápida de planetas extrasolares gigantes. Además, esta Tesis analiza la respuesta de las partículas, en un disco protoplanetario con un radio de 100 UA en torno a una estrella de tipo solar, al campo gravitatorio derivado de la presencia de dos estrellas compañeras ligadas en una órbita relativamente elongada (300-1600 UA). Para llevar a cabo este análisis, se han realizado una serie de simulaciones numéricas de configuraciones jerárquicas coplanares utilizando un programa FORTRAN que integra directamente las ecuaciones del movimiento con el objeto de modelar la presencia de las fuerzas gravitacionales y viscosas. El disco protoplanetario masivo se encuentra en torno a una de las componentes de la binaria. La evolución temporal del subdisco de polvo depende directamente de la naturaleza (directa o retrógrada) de la revolución relativa de la compañera estelar, y de la temperatura y la masa del disco circunestelar.

Maize x Teosinte Hybrid Cobs Do Not Prevent Crop Gene Introgression.

PubMed

Chavez, Nancy B; Flores, Jose J; Martin, Joseph; Ellstrand, Norman C; Guadagnuolo, Roberto; Heredia, Sylvia; Welles, Shana R

2012-06-01

Maize x Teosinte Hybrid Cobs Do Not Prevent Crop Gene Introgression. Whether introgression from crops to wild relatives can occur is an important component of transgene risk assessment. In the case of maize, which co-occurs with its wild relative teosinte in Mexico, the possibility of introgression has been controversial. Maize is cross-compatible with teosinte, and spontaneous hybridization is known to occur. Some scientists have hypothesized that the maize x teosinte cob infructescence will prevent progeny dispersal, thus preventing introgression. Motivated by a prior study where we found maize x teosinte hybrid fruits naturally dispersed under field conditions, we tested whether hybrid cobs hold their fruits as tightly as maize cobs. We found the force required to detach hybrid fruits was substantially and significantly less than that for maize. Consequently, we expect that introgression of transgenes from maize into teosinte in Mexico should occur largely unimpeded by the hybrid cob.La mazorca o elote híbrido de maíz x teocintle no impide la introgresión de genes transgénicos provenientes del cultivo. La introgresión entre el maíz cultivado y el maíz silvestre, o teocintle, es un componente importante en la evaluación ambiental relacionada con los riesgos de la introducción de genes transgénicos. La posibilidad de introgresión entre el maíz domesticado y el teocintle ha sido un tema controversial, en particular en México, donde maíz y teocintle coexisten. El maíz es compatible con el teocintle y la hibridización espontánea ocurre entre ellos. Algunos científicos han planteado como hipótesis que al cruzar el maíz con teocintle, la estructura interna de la infrutescencia que sujeta los frutos conocida como la mazorca de maíz o el elote, impide la dispersión de la progenie evitando que la introgresión ocurra. Los resultados de un estudio previo evidencian la dispersión de los frutos híbridos del maíz x teocintle en condiciones naturales. Motivados por estos resultados, hemos decidido investigar si la mazorca o el elote de las infrutescencias del híbrido sujetan los frutos con una fuerza comparable o mayor a la del maíz. Nuestras mediciones implican que la fuerza necesaria para liberar los frutos híbridos son substancial y significativamente menores que aquellas necesarias para desprender los frutos del maíz. Como conclusión sugerimos que en México, la mazorca o el elote no representan una barrera que impida la introgresión de los genes transgénicos del maíz al teocintle.

The first Japanese patient with mandibular hypoplasia, deafness, progeroid features and lipodystrophy diagnosed via POLD1 mutation detection

PubMed Central

Okada, Asami; Kohmoto, Tomohiro; Naruto, Takuya; Yokota, Ichiro; Kotani, Yumiko; Shimada, Aki; Miyamoto, Yoko; Takahashi, Rizu; Goji, Aya; Masuda, Kiyoshi; Kagami, Shoji; Imoto, Issei

2017-01-01

Mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome is a rare autosomal dominant disorder caused by heterozygous POLD1 mutations. To date, 13 patients affected by POLD1 mutation-caused MDPL have been described. We report a clinically undiagnosed 11-year-old male who noted joint contractures at 6 years of age. Targeted exome sequencing identified a known POLD1 mutation [NM_002691.3:c.1812_1814del, p.(Ser605del)] that diagnosed him as the first Japanese/East Asian MDPL case. PMID:28791128

Novel genetic risk variants for pediatric celiac disease.

PubMed

Balasopoulou, Angeliki; Stanković, Biljana; Panagiotara, Angeliki; Nikčevic, Gordana; Peters, Brock A; John, Anne; Mendrinou, Effrosyni; Stratopoulos, Apostolos; Legaki, Aigli Ioanna; Stathakopoulou, Vasiliki; Tsolia, Aristoniki; Govaris, Nikolaos; Govari, Sofia; Zagoriti, Zoi; Poulas, Konstantinos; Kanariou, Maria; Constantinidou, Nikki; Krini, Maro; Spanou, Kleopatra; Radlovic, Nedeljko; Ali, Bassam R; Borg, Joseph; Drmanac, Radoje; Chrousos, George; Pavlovic, Sonja; Roma, Eleftheria; Zukic, Branka; Patrinos, George P; Katsila, Theodora

2016-10-24

Celiac disease is a complex chronic immune-mediated disorder of the small intestine. Today, the pathobiology of the disease is unclear, perplexing differential diagnosis, patient stratification, and decision-making in the clinic. Herein, we adopted a next-generation sequencing approach in a celiac disease trio of Greek descent to identify all genomic variants with the potential of celiac disease predisposition. Analysis revealed six genomic variants of prime interest: SLC9A4 c.1919G>A, KIAA1109 c.2933T>C and c.4268_4269delCCinsTA, HoxB6 c.668C>A, HoxD12 c.418G>A, and NCK2 c.745_746delAAinsG, from which NCK2 c.745_746delAAinsG is novel. Data validation in pediatric celiac disease patients of Greek (n = 109) and Serbian (n = 73) descent and their healthy counterparts (n = 111 and n = 32, respectively) indicated that HoxD12 c.418G>A is more prevalent in celiac disease patients in the Serbian population (P < 0.01), while NCK2 c.745_746delAAinsG is less prevalent in celiac disease patients rather than healthy individuals of Greek descent (P = 0.03). SLC9A4 c.1919G>A and KIAA1109 c.2933T>C and c.4268_4269delCCinsTA were more abundant in patients; nevertheless, they failed to show statistical significance. The next-generation sequencing-based family genomics approach described herein may serve as a paradigm towards the identification of novel functional variants with the aim of understanding complex disease pathobiology.

Role of genetic polymorphisms in NFKB-mediated inflammatory pathways in response to primary chemoradiation therapy for rectal cancer.

PubMed

Dzhugashvili, Maia; Luengo-Gil, Ginés; García, Teresa; González-Conejero, Rocío; Conesa-Zamora, Pablo; Escolar, Pedro Pablo; Calvo, Felipe; Vicente, Vicente; Ayala de la Peña, Francisco

2014-11-01

To investigate whether polymorphisms of genes related to inflammation are associated with pathologic response (primary endpoint) in patients with rectal cancer treated with primary chemoradiation therapy (PCRT). Genomic DNA of 159 patients with locally advanced rectal cancer treated with PCRT was genotyped for polymorphisms rs28362491 (NFKB1), rs1213266/rs5789 (PTGS1), rs5275 (PTGS2), and rs16944/rs1143627 (IL1B) using TaqMan single nucleotide polymorphism genotyping assays. The association between each genotype and pathologic response (poor response vs complete or partial response) was analyzed using logistic regression models. The NFKB1 DEL/DEL genotype was associated with pathologic response (odds ratio [OR], 6.39; 95% confidence interval [CI], 0.78-52.65; P=.03) after PCRT. No statistically significant associations between other polymorphisms and response to PCRT were observed. Patients with the NFKB1 DEL/DEL genotype showed a trend for longer disease-free survival (log-rank test, P=.096) and overall survival (P=.049), which was not significant in a multivariate analysis that included pathologic response. Analysis for 6 polymorphisms showed that patients carrying the haplotype rs28362491-DEL/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G (13.7% of cases) had a higher response rate to PCRT (OR, 8.86; 95% CI, 1.21-64.98; P=.034) than the reference group (rs28362491-INS/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G). Clinically significant (grade ≥2) acute organ toxicity was also more frequent in patients with that same haplotype (OR, 4.12; 95% CI, 1.11-15.36; P=.037). Our results suggest that genetic variation in NFKB-related inflammatory pathways might influence sensitivity to primary chemoradiation for rectal cancer. If confirmed, an inflammation-related radiogenetic profile might be used to select patients with rectal cancer for preoperative combined-modality treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dzhugashvili, Maia; Department of Radiation Oncology, Madrid Oncology Institute; Luengo-Gil, Ginés

Purpose: To investigate whether polymorphisms of genes related to inflammation are associated with pathologic response (primary endpoint) in patients with rectal cancer treated with primary chemoradiation therapy (PCRT). Methods and Materials: Genomic DNA of 159 patients with locally advanced rectal cancer treated with PCRT was genotyped for polymorphisms rs28362491 (NFKB1), rs1213266/rs5789 (PTGS1), rs5275 (PTGS2), and rs16944/rs1143627 (IL1B) using TaqMan single nucleotide polymorphism genotyping assays. The association between each genotype and pathologic response (poor response vs complete or partial response) was analyzed using logistic regression models. Results: The NFKB1 DEL/DEL genotype was associated with pathologic response (odds ratio [OR], 6.39; 95%more » confidence interval [CI], 0.78-52.65; P=.03) after PCRT. No statistically significant associations between other polymorphisms and response to PCRT were observed. Patients with the NFKB1 DEL/DEL genotype showed a trend for longer disease-free survival (log-rank test, P=.096) and overall survival (P=.049), which was not significant in a multivariate analysis that included pathologic response. Analysis for 6 polymorphisms showed that patients carrying the haplotype rs28362491-DEL/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G (13.7% of cases) had a higher response rate to PCRT (OR, 8.86; 95% CI, 1.21-64.98; P=.034) than the reference group (rs28362491-INS/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G). Clinically significant (grade ≥2) acute organ toxicity was also more frequent in patients with that same haplotype (OR, 4.12; 95% CI, 1.11-15.36; P=.037). Conclusions: Our results suggest that genetic variation in NFKB-related inflammatory pathways might influence sensitivity to primary chemoradiation for rectal cancer. If confirmed, an inflammation-related radiogenetic profile might be used to select patients with rectal cancer for preoperative combined-modality treatment.« less

TGF{beta}1 polymorphisms and late clinical radiosensitivity in patients treated for gynecologic tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ruyck, Kim de; Van Eijkeren, Marc; Claes, Kathleen

2006-07-15

Purpose: To investigate the association between six transforming growth factor {beta}1 gene (TGF{beta}1) polymorphisms (-1.552delAGG, -800G>A, -509C>T, Leu10Pro, Arg25Pro, Thr263Ile) and the occurrence of late normal tissue reactions after gynecologic radiotherapy (RT). Methods and Materials: Seventy-eight women with cervical or endometrial cancer and 140 control individuals were included in the study. According to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAEv3.0) scale, 25 patients showed late adverse RT reactions (CTC2+), of whom 11 had severe complications (CTC3+). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), single base extension and genotyping assays were performed to examine the polymorphic sites inmore » TGF{beta}1. Results: Homozygous variant -1.552delAGG, -509TT, and 10Pro genotypes were associated with the risk of developing late severe RT reactions. Triple (variant) homozygous patients had a 3.6 times increased risk to develop severe RT reactions (p = 0.26). Neither the -800A allele, nor the 25Pro allele or the 263Ile allele were associated with clinical radiosensitivity. There was perfect linkage disequilibrium (LD) between the -1.552delAGG and the -509C>T polymorphisms, and tight LD between the -1.552/-509 and the Leu10Pro polymorphisms. Haplotype analysis revealed two major haplotypes but could not distinguish radiosensitive from nonradiosensitive patients. Conclusions: The present study shows that homozygous variant TGF{beta}1 -1.552delAGG, -509TT, and 10Pro genotypes may be associated with severe clinical radiosensitivity after gynecologic RT.« less

AGXT Gene Mutations and Prevalence of Primary Hyperoxaluria Type 1 in Moroccan Population.

PubMed

Boualla, Lamiae; Tajir, Mariam; Oulahiane, Najat; Lyahyai, Jaber; Laarabi, Fatima Zahra; Chafai Elalaoui, Siham; Soulami, Kenza; Ait Ouamar, Hassan; Sefiani, Abdelaziz

2015-11-01

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder caused by deficiency of alanine glyoxylate aminotransferase, due to a defect in the AGXT gene. Several mutations in this gene have been reported and some of them have been observed in multiple populations. The aim of our study was to analyze the mutations causing PH1 in the Moroccan population and to estimate its prevalence in Morocco. Molecular studies of 29 unrelated Moroccan patients with PH were performed by direct sequencing of all exons of the AGXT gene. In addition, to estimate the prevalence of PH1, we screened for the recurrent p.Ile244Thr mutation in 250 unrelated Moroccan newborns using real-time polymerase chain reaction. Four pathogenic mutations were detected in 25 unrelated patients. The c.731T>C (p.Ile244Thr) was the most frequent mutation with a frequency of 84%. The other three mutations were c.33delC, c.976delG, and c.331C>T. The prevalence of the PH1 mutation among Moroccans was then estimated to range from 1/7267 to 1/6264. PH1 is one of the most prevalent genetic diseases in the Moroccan population and is probably underdiagnosed. Front line genetic testing for PH1 in Morocco should be initiated using an assay for the recurrent p.Ile244Thr mutation. This strategy would provide a useful tool for precocious diagnosis of presymptomatic individuals and to prevent their rapid progression to renal failure.

Effectiveness of personalized face-to-face and telephone nursing counseling interventions for cardiovascular risk factors: a controlled clinical trial.

PubMed

Vílchez Barboza, Vivian; Klijn, Tatiana Paravic; Salazar Molina, Alide; Sáez Carrillo, Katia Lorena

2016-08-08

to evaluate the effect and gender differences of an innovative intervention involving in-person and telephone nursing counseling to control cardiovascular risk factors (arterial hypertension, dyslipidemia, and overweight), improve health-related quality of life and strengthen self-efficacy and social support in persons using the municipal health centers' cardiovascular health program. a randomized controlled clinical trial involving participants randomized into the intervention group who received traditional consultation plus personalized and telephone nursing counseling for 7 months (n = 53) and the control group (n = 56). The study followed the Consolidated Standards of Reporting Trials Statement. women in the intervention group presented a significant increase in the physical and mental health components compared to the control group, with decreases in weight, abdominal circumference, total cholesterol, low-density lipoprotein cholesterol, and the atherogenic index. The effects attributable to the intervention in the men in the intervention group were increased physical and emotional roles and decreased systolic and diastolic pressure, waist circumference, total cholesterol, low-density lipoprotein cholesterol, atherogenic index, cardiovascular risk factor, and 10-year coronary risk. this intervention is an effective strategy for the control of three cardiovascular risk factors and the improvement of health-related quality of life. evaluar efecto y diferencias por sexo de una intervención innovadora "Consejería de Enfermería Personalizada y Telefónica", dirigida al control de factores de riesgo cardiovascular (hipertensión arterial, dislipidemia y sobrepeso) y al mejoramiento de la calidad de vida relacionada con la salud, fortaleciendo la autoeficacia y el apoyo social en personas usuarias del programa de salud cardiovascular de los Centros de Salud Municipales de Concepción. ensayo clínico controlado aleatoriamente y selección aleatoria de participantes; grupo intervención con consulta tradicional más consejería de enfermería personalizada y telefónica durante 7 meses (n=53); y grupo control (n=56); siguiendo la declaración del Consolidated Standards of Reporting Trials. mujeres del grupo intervención, presentaron aumento significativo con respecto al grupo control, en componentes de salud física y mental; disminución de: peso, circunferencia abdominal, colesterol total, colesterol lipoproteínas de baja densidad e índice de aterogenicidad. En hombres del grupo intervención se reflejó como efectos atribuibles a la intervención: 1) aumento en dimensiones del rol físico y emocional; 2) disminución: presión sistólica y diastólica, circunferencia abdominal, colesterol total, colesterol lipoproteínas de baja densidad, índice de aterogenicidad, factor de riesgo cardiovascular y riesgo coronario a 10 años. esta intervención es una estrategia efectiva para el control de tres factores de riesgo cardiovascular y mejoría de calidad de vida relacionada con la salud. avaliar o efeito e as diferenças por sexo de uma intervenção inovadora: o aconselhamento personalizado e por telefone em enfermagem, visando o controle de fatores de risco cardiovascular (hipertensão arterial, dislipidemia e sobrepeso) e a melhora na qualidade de vida relacionada à saúde, fortalecendo a autoeficácia e o apoio social a pessoas que usam o programa de saúde cardiovascular de Centros Municipais de Saúde. ensaio clínico controlado e randomizado, participantes randomizados, grupo de intervenção: consulta tradicional mais aconselhamento personalizado e por telefone em enfermagem por 7 meses (n = 53); e grupo de controle (n = 56); seguindo a declaração Consolidated Standards of Reporting Trials Statement. mulheres do grupo intervenção apresentaram um aumento significativo, em relação ao grupo controle, nos componentes de saúde mental e física, com diminuição do peso, circunferência abdominal, colesterol total, colesterol de lipoproteínas de baixa densidade e índice aterogênico. Em homens do grupo intervenção, os efeitos atribuíveis à intervenção foram: aumentos nos papeis físicos e emocionais, com diminuições na pressão sistólica e diastólica, circunferência abdominal, colesterol total, colesterol de lipoproteínas de baixa densidade, índice aterogênico, fator de risco cardiovascular e risco coronariano em 10 anos. essa intervenção é uma estratégia eficaz para o controle dos três fatores de risco cardiovascular e a melhora da qualidade de vida relacionada à saúde.

77 FR 63420 - Unblocking of Specially Designated Nationals and Blocked Persons Pursuant to Executive Order 12978

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-16

... INMOBILIARIA HOTELERA DEL CARIBE LTDA., Barranquilla, Colombia; c/o INVERSIONES HOTELERAS DEL LITORAL LTDA., Barranquilla, Colombia; c/o INVERSIONES PRADO TRADE CENTER LTDA., Barranquilla, Colombia; c/o NEGOCIOS Y... VIEJO, Alfredo, c/o INVERSIONES EL PROGRESO S.A., Cartagena, Colombia; DOB 15 Dec 1954; Cedula No...

The contribution of CHEK2 to the TP53-negative Li-Fraumeni phenotype.

PubMed

Ruijs, Marielle W G; Broeks, Annegien; Menko, Fred H; Ausems, Margreet G E M; Wagner, Anja; Oldenburg, Rogier; Meijers-Heijboer, Hanne; van't Veer, Laura J; Verhoef, Senno

2009-02-17

CHEK2 has previously been excluded as a major cause of Li-Fraumeni syndrome (LFS). One particular CHEK2 germline mutation, c.1100delC, has been shown to be associated with elevated breast cancer risk. The prevalence of CHEK2*1100delC differs between populations and has been found to be relatively high in the Netherlands. The question remains nevertheless whether CHEK2 germline mutations contribute to the Li-Fraumeni phenotype. We have screened 65 Dutch TP53-negative LFS/LFL candidate patients for CHEK2 germline mutations to determine their contribution to the LFS/LFL phenotype. We identified six index patients with a CHEK2 sequence variant, four with the c.1100delC variant and two sequence variants of unknown significance, p.Phe328Ser and c.1096-?_1629+?del. Our data show that CHEK2 is not a major LFS susceptibility gene in the Dutch population. However, CHEK2 might be a factor contributing to individual tumour development in TP53-negative cancer-prone families.

Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Figus, A.; Farcia, A.M.G.; Nurchi, A.

1995-12-01

We analyzed mutations and defined the chromosomal haplotype in 127 patients of Mediterranean descent who were affected in Wilson disease (WD): 39 Sardinians, 49 Italians, 33 Turks, and 6 Albanians. Haplotypes were derived by use of the microsatellite markers D13S301, D13S296, D13S297, and D13S298, which are linked to the WD locus. There were five common haplotypes in Sardinians, three in Italians, and two in Turks, which accounted for 85%, 32%, and 30% of the WD chromosomes, respectively. We identified 16 novel mutations: 8 frameshifts, 7 missense mutations, and 1 splicing defect. In addition, we detected the previously described mutations: 2302insC,more » 3404delC, Arg1320ter, Gly944Ser, and His1070Gin. Of the new mutations detected, two, the 1515insT on haplotype I and 2464delC on haplotype XVI, accounted for 6% and 13%, respectively, of the mutations in WD chromsomes in the Sardinian populations. Mutations H1070Q, 2302insC, and 2533delA represented 13%, 8%, and 8%, respectively, of the mutations in WD chromsomes in other Mediterranean populations. The remaining mutations were rare and limited to one or two patients from different populations. Thus, WD results from some frequent mutations and many rare defects. 28 refs., 1 fig., 3 tabs.« less

Clinical and genetic characteristics of 15 families with hereditary hypophosphatemia: Novel Mutations in PHEX and SLC34A3.

PubMed

Acar, Sezer; BinEssa, Huda A; Demir, Korcan; Al-Rijjal, Roua A; Zou, Minjing; Çatli, Gönül; Anık, Ahmet; Al-Enezi, Anwar F; Özışık, Seçil; Al-Faham, Manar S A; Abacı, Ayhan; Dündar, Bumin; Kattan, Walaa E; Alsagob, Maysoon; Kavukçu, Salih; Tamimi, Hamdi E; Meyer, Brian F; Böber, Ece; Shi, Yufei

2018-01-01

Hereditary hypophosphatemia is a group of rare renal phosphate wasting disorders. The diagnosis is based on clinical, radiological, and biochemical features, and may require genetic testing to be confirmed. Clinical features and mutation spectrum were investigated in patients with hereditary hypophosphatemia. Genomic DNA of 23 patients from 15 unrelated families were screened sequentially by PCR-sequencing analysis for mutations in the following genes: PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1. CytoScan HD Array was used to identify large deletions. Genetic evaluation resulted in the identification of an additional asymptomatic but intermittent hypophosphatemic subject. Mutations were detected in 21 patients and an asymptomatic sibling from 13 families (86.6%, 13/15). PHEX mutations were identified in 20 patients from 12 families. Six of them were novel mutations present in 9 patients: c.983_987dupCTACC, c.1586+2T>G, c.1206delA, c.436+1G>T, c.1217G>T, and g.22,215,887-22,395,767del (179880 bp deletion including exon 16-22 and ZNF645). Six previously reported mutations were found in 11 patients. Among 12 different PHEX mutations, 6 were de novo mutations. Patients with de novo PHEX mutations often had delayed diagnosis and significantly shorter in height than those who had inherited PHEX mutations. Novel compound heterozygous mutations in SLC34A3 were found in one patient and his asymptomatic sister: c.1335+2T>A and c.1639_1652del14. No mutation was detected in two families. This is the largest familial study on Turkish patients with hereditary hypophosphatemia. PHEX mutations, including various novel and de novo variants, are the most common genetic defect. More attention should be paid to hypophosphatemia by clinicians since some cases remain undiagnosed both during childhood and adulthood.

Clinical and genetic characteristics of 15 families with hereditary hypophosphatemia: Novel Mutations in PHEX and SLC34A3

PubMed Central

Demir, Korcan; Al-Rijjal, Roua A.; Zou, Minjing; Çatli, Gönül; Anık, Ahmet; Al-Enezi, Anwar F.; Özışık, Seçil; Al-Faham, Manar S. A.; Abacı, Ayhan; Dündar, Bumin; Kattan, Walaa E.; Alsagob, Maysoon; Kavukçu, Salih; Tamimi, Hamdi E.; Meyer, Brian F.; Böber, Ece

2018-01-01

Background Hereditary hypophosphatemia is a group of rare renal phosphate wasting disorders. The diagnosis is based on clinical, radiological, and biochemical features, and may require genetic testing to be confirmed. Methodology Clinical features and mutation spectrum were investigated in patients with hereditary hypophosphatemia. Genomic DNA of 23 patients from 15 unrelated families were screened sequentially by PCR-sequencing analysis for mutations in the following genes: PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1. CytoScan HD Array was used to identify large deletions. Results Genetic evaluation resulted in the identification of an additional asymptomatic but intermittent hypophosphatemic subject. Mutations were detected in 21 patients and an asymptomatic sibling from 13 families (86.6%, 13/15). PHEX mutations were identified in 20 patients from 12 families. Six of them were novel mutations present in 9 patients: c.983_987dupCTACC, c.1586+2T>G, c.1206delA, c.436+1G>T, c.1217G>T, and g.22,215,887–22,395,767del (179880 bp deletion including exon 16–22 and ZNF645). Six previously reported mutations were found in 11 patients. Among 12 different PHEX mutations, 6 were de novo mutations. Patients with de novo PHEX mutations often had delayed diagnosis and significantly shorter in height than those who had inherited PHEX mutations. Novel compound heterozygous mutations in SLC34A3 were found in one patient and his asymptomatic sister: c.1335+2T>A and c.1639_1652del14. No mutation was detected in two families. Conclusions This is the largest familial study on Turkish patients with hereditary hypophosphatemia. PHEX mutations, including various novel and de novo variants, are the most common genetic defect. More attention should be paid to hypophosphatemia by clinicians since some cases remain undiagnosed both during childhood and adulthood. PMID:29505567

[Gene mutation analysis of X-linked hypophosphatemic rickets].

PubMed

Song, Ying; Ma, Hong-Wei; Li, Fang; Hu, Man; Ren, Shuang; Yu, Ya-Fen; Zhao, Gui-Jie

2013-11-01

To investigate the frequency and type of PHEX gene mutations in children with X-linked hypophosphatemic rickets (XLH), the possible presence of mutational hot spots, and the relationship between genotype and clinical phenotype. Clinical data of 10 children with XLH was retrospectively reviewed. The relationship between gene mutation type and severity of XLH was evaluated. PHEX gene mutations were detected in all 10 children with XLH, including 6 cases of missense mutation, 2 cases of splice site mutation, 1 case of frameshift mutation, and 1 case of nonsense mutation. Two new mutations, c.2048T>C and IVS14+1delAG, were found. The type of PHEX gene mutation was not associated with the degree of short stature and leg deformity (P=0.571 and 0.467), and the mutation site was also not associated with the degree of short stature and leg deformity (P=0.400 and 1.000). Missense mutation is the most common type of PHEX gene mutation in children with XLH, and c.2048T>C and IVS14+1delAG are two new PHEX gene mutations. The type and site of PHEX gene mutation are not associated with the severity of XLH.

Tyrosine kinase receptor c-ros-oncogene 1 inhibition alleviates aberrant bone formation of TWIST-1 haploinsufficient calvarial cells from Saethre-Chotzen syndrome patients.

PubMed

Camp, Esther; Anderson, Peter J; Zannettino, Andrew C W; Glackin, Carlotta A; Gronthos, Stan

2018-09-01

Saethre-Chotzen syndrome (SCS), associated with TWIST-1 mutations, is characterized by premature fusion of cranial sutures. TWIST-1 haploinsufficiency, leads to alterations in suture mesenchyme cellular gene expression patterns, resulting in aberrant osteogenesis and craniosynostosis. We analyzed the expression of the TWIST-1 target, Tyrosine kinase receptor c-ros-oncogene 1 (C-ROS-1) in TWIST-1 haploinsufficient calvarial cells derived from SCS patients and calvaria of Twist-1 del/+ mutant mice and found it to be highly expressed when compared to TWIST-1 wild-type controls. Knock-down of C-ROS-1 expression in TWIST-1 haploinsufficient calvarial cells derived from SCS patients was associated with decreased capacity for osteogenic differentiation in vitro. Furthermore, treatment of human SCS calvarial cells with the tyrosine kinase chemical inhibitor, Crizotinib, resulted in reduced C-ROS-1 activity and the osteogenic potential of human SCS calvarial cells with minor effects on cell viability or proliferation. Cultured human SCS calvarial cells treated with Crizotinib exhibited a dose-dependent decrease in alkaline phosphatase activity and mineral deposition, with an associated decrease in expression levels of Runt-related transcription factor 2 and OSTEOPONTIN, with reduced PI3K/Akt signalling in vitro. Furthermore, Crizotinib treatment resulted in reduced BMP-2 mediated bone formation potential of whole Twist-1 del/+ mutant mouse calvaria organotypic cultures. Collectively, these results suggest that C-ROS-1 promotes osteogenic differentiation of TWIST-1 haploinsufficient calvarial osteogenic progenitor cells. Furthermore, the aberrant osteogenic potential of these cells is inhibited by the reduction of C-ROS-1. Therefore, targeting C-ROS-1 with a pharmacological agent, such as Crizotinib, may serve as a novel therapeutic strategy to alleviate craniosynostosis associated with aberrant TWIST-1 function. © 2018 Wiley Periodicals, Inc.

Rare mutations in RINT1 predispose carriers to breast and Lynch Syndrome-spectrum cancers

PubMed Central

Park, Daniel J.; Tao, Kayoko; Le Calvez-Kelm, Florence; Nguyen-Dumont, Tu; Robinot, Nivonirina; Hammet, Fleur; Odefrey, Fabrice; Tsimiklis, Helen; Teo, Zhi L.; Thingholm, Louise B.; Young, Erin L.; Voegele, Catherine; Lonie, Andrew; Pope, Bernard J.; Roane, Terrell C.; Bell, Russell; Hu, Hao; Shankaracharya; Huff, Chad D.; Ellis, Jonathan; Li, Jun; Makunin, Igor V.; John, Esther M.; Andrulis, Irene L.; Terry, Mary B.; Daly, Mary; Buys, Saundra S.; Snyder, Carrie; Lynch, Henry T.; Devilee, Peter; Giles, Graham G.; Hopper, John L.; Feng, Bing J.; Lesueur, Fabienne; Tavtigian, Sean V.; Southey, Melissa C.; Goldgar, David E.

2014-01-01

Approximately half of the familial aggregation of breast cancer remains unexplained. A multiple-case breast cancer family exome sequencing study identified three likely pathogenic mutations in RINT1 (NM_021930.4) not present in public sequencing databases: RINT1 c.343C>T (p.Q115X), c.1132_1134del (p.M378del) and c.1207G>T (p.D403Y). Based on this finding, a population-based case-control mutation-screening study was conducted and identified 29 carriers of rare (MAF < 0.5%), likely pathogenic variants: 23 in 1,313 early-onset breast cancer cases and 6 in 1,123 frequency-matched controls (OR=3.24, 95%CI 1.29-8.17; p=0.013). RINT1 mutation screening of probands from 798 multiple-case breast cancer families identified 4additional carriers of rare genetic variants. Analysis of the incidence of first primary cancers in families of women in RINT1-mutation carrying families estimated that carriers were at increased risks of Lynch syndrome-spectrum cancers (SIR 3.35, 95% CI 1.7-6.0; P=0.005), particularly for relatives diagnosed with cancer under age 60 years (SIR 10.9, 95%CI 4.7-21; P=0.0003). PMID:25050558

Identification of six novel mutations in Iranian patients with maple syrup urine disease and their in silico analysis.

PubMed

Abiri, Maryam; Karamzadeh, Razieh; Karimipoor, Morteza; Ghadami, Shirin; Alaei, Mohammad Reza; Bagheri, Samira Dabagh; Bagherian, Hamideh; Setoodeh, Aria; Noori-Daloii, Mohammad Reza; Sirous Zeinali

2016-04-01

Maple syrup urine disease (MSUD) is a rare inborn error of branched-chain amino acid metabolism. The disease prevalence is higher in populations with elevated rate of consanguineous marriages such as Iran. Different types of disease causing mutations have been previously reported in BCKDHA, BCKDHB, DBT and DLD genes known to be responsible for MSUD phenotype. In this study, two sets of multiplex polymorphic STR (Short Tandem Repeat) markers linked to the above genes were used to aid in homozygosity mapping in order to find probable pathogenic change(s) in the studied families. The families who showed homozygote haplotype for the BCKDHA gene were subsequently sequenced. Our findings showed that exons 2, 4 and 6 contain most of the mutations which are novel. The changes include two single nucleotide deletion (i.e. c. 143delT and c.702delT), one gross deletion covering the whole exon four c.(375+1_376-1)_(8849+1_885-1), two splice site changes (c.1167+1G>T, c. 288+1G>A), and one point mutation (c.731G>A). Computational approaches were used to analyze these two novel mutations in terms of their impact on protein structure. Computational structural modeling indicated that these mutations might affect structural stability and multimeric assembly of branched-chain α-keto acid dehydrogenase complex (BCKDC). Copyright © 2016. Published by Elsevier B.V.

A homozygous MYO7A mutation associated to Usher syndrome and unilateral auditory neuropathy spectrum disorder.

PubMed

Xia, Hong; Hu, Pengzhi; Yuan, Lamei; Xiong, Wei; Xu, Hongbo; Yi, Junhui; Yang, Zhijian; Deng, Xiong; Guo, Yi; Deng, Hao

2017-10-01

Usher syndrome (USH) is an autosomal recessive disorder characterized by sensorineural hearing loss, progressive visual loss and night blindness due to retinitis pigmentosa (RP), with or without vestibular dysfunction. The purpose of this study was to detect the causative gene in a consanguineous Chinese family with USH. A c.3696_3706del (p.R1232Sfs*72) variant in the myosin VIIa gene (MYO7A) was identified in the homozygous state by exome sequencing. The co‑segregation of the MYO7A c.3696_3706del variant with the phenotype of deafness and progressive visual loss in the USH family was confirmed by Sanger sequencing. The variant was absent in 200 healthy controls. Therefore, the c.3696_3706del variant may disrupt the interaction between myosin VIIa and other USH1 proteins, and impair melanosome transport in retinal pigment epithelial cells. Notably, bilateral auditory brainstem responses were absent in two patients of the USH family, while distortion product otoacoustic emissions were elicited in the right ears of the two patients, consistent with clinical diagnosis of unilateral auditory neuropathy spectrum disorder. These data suggested that the homozygous c.3696_3706del variant in the MYO7A gene may be the disease‑causing mutation for the disorder in this family. These findings broaden the phenotype spectrum of the MYO7A gene, and may facilitate understanding of the molecular pathogenesis of the disease, and genetic counseling for the family.

Frequent life-threatening laryngeal attacks in two Croatian families with hereditary angioedema due to C1 inhibitor deficiency harbouring a novel frameshift mutation in SERPING1.

PubMed

Karadža-Lapić, Ljerka; Korošec, Peter; Šilar, Mira; Košnik, Mitja; Cikojević, Draško; Lozić, Bernarda; Rijavec, Matija

2016-11-01

Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease caused by mutations in the SERPING1 gene. It can affect many regions in the body, but potentially life-threatening laryngeal oedemas are of concern. Twenty-three subjects from two families were recruited for clinical data evaluation and molecular analysis at General Hospital Šibenik, Croatia. Decreased levels of C1 inhibitor were detected in 12 adult patients and three young asymptomatic persons. The same novel deletion of two nucleotides on exon 3 (c.74_75delAT) was identified in all of them. A history of laryngeal oedema was present in 10 patients (83%), and all patients reported laryngeal attacks at least once a year. The delay in diagnosis decreased noticeably from the first to the last generation. We identified a novel causative mutation in SERPING1 in several affected members of two apparently unrelated families with a high frequency of laryngeal oedema. Molecular analysis of large C1-INH-HAE families will provide new insights on the genotype-phenotype relationship. Key messages Hereditary angioedema due to C1 inhibitor deficiency is a rare autosomal dominant disease caused by mutations in the SERPING1 gene, and laryngeal oedema is of concern because it can cause death by asphyxiation. A novel causative mutation in SERPING1, a deletion of two nucleotides on exon 3 (c.74_75delAT), was identified in several affected members of two apparently unrelated families with a high frequency of laryngeal oedema. Molecular analysis of large C1-INH-HAE families will provide new insights on the genotype-phenotype relationship because it appears that the mutation type may affect disease severity.

Pleistocene Variations in Delivery and Deposition of Organic Matter Under the Benguela Current Upwelling System - Biomarker Isotopic Evidence From Sediment Light-Dark Color Cycles

NASA Astrophysics Data System (ADS)

Meyers, P. A.; Bouloubassi, I.; Pancost, R. D.; Robinson, R. S.

2007-12-01

The light-dark color cycles that are distinctive features of sediment beneath the Benguela Current Upwelling System imply repetitive alternations in organic matter delivery and deposition. Organic geochemical proxies for paleoproductivity and for depositional conditions were employed to investigate the paleoceanographic processes involved in creating these cycles in two sediment sequences from ODP Site 1084 corresponding to 0.7 and 1.1 Mya. Concentrations of total organic carbon (TOC) vary between 3.5 and 17.1 wt percent, and those of calcium carbonate fluctuate inversely between 68 and 1 percent, suggesting that carbonate dissolution is involved with the light-dark cycles. Bulk organic del 13C and del 15N values that remain constant across the two light-dark sediment intervals indicate that the extent of nutrient utilization did not change in each cycle. Biomarker compositions in both sequences reflect a range of organic matter sources. Abundant n-alkanes and n-alkanols with odd-over-even and even-over-odd distributions, respectively, record land-plant inputs. Other terrestrial biomakers (e.g triterpenoid acids and alcohols) are present but in very low abundances, suggesting that the n- alkyl components derive predominantly from eolian inputs. Carbon isotopic values of n-alkanes range from -25 to -28 permil, suggesting a mixture of C3 and C4 sources. In contrast, n-alkanol isotopic compositions range from -28 to -34 permil, suggesting that they derive solely from C3 plants. Algal biomarkers are abundant and diverse, represented by 1,15-C30 diols (eustigmatophytes), 4-desmethyl and -methylsterols (diatoms, dinoflagellates), and alkenones (haptophytes). These compounds all have del 13C values ranging from ca. -22 to -24 permil, consistent with a marine origin. Systematic differences in isotopic values imply that marine productivity at 1.1 Mya was higher than at 0.7 Mya, but alkenone-based sea-surface temperatures are higher at 1.1 Mya (21 deg) than at 0.7 Mya (15 deg), which indicates that changes in water-mass properties were also involved.

Concentration of mutations causing Schmid metaphyseal chondrodysplasia in the NC1 domain of type X collagen

DOE Office of Scientific and Technical Information (OSTI.GOV)

McIntosh, I.; Abbott, M.H.; Francomano, C.A.

1994-09-01

Schmid metaphyseal chondrodysplasia (SMCD, MIM 156500) is an autosomal dominant disorder of the osseous skeleton resulting in short stature, coxa vara and a waddling gait. Type X collagen is an extracellular matrix protein expressed exclusively by hypertrophic chondrocytes. We have previously identified four mutations in the type X collagen gene (COL10A1) in patients with SMCD. Each of these mutations, as well as another three reported by other investigators, are in the carboxy-terminal non-collagenous domain (NC1). Here, we present data for another three mutations each predicted to cause premature termination of translation within the NC1 domain. Two are nonsense mutations, Y628Xmore » and W651X, while the third is a frameshift resulting from the deletion of two nucleotides, 1856delCC. Each of these mutations occurred de novo, resulting in sporadic cases of SMCD. Four frameshift mutations have now been reported to initiate within 10bp of each other in the NC1 domain, namely 1865delC, 1856delCC, 1856del13 and 1866del10. These findings further support the hypothesis that SMCD is the result of the mutant type X collagen molecule being unable to participate in trimerization, although a dominant-negative model of disease pathogenesis has not been formally excluded.« less

Role of the Polymorphisms of Uncoupling Protein Genes in Childhood Obesity and Their Association with Obesity-Related Disturbances.

PubMed

Gul, Ali; Ateş, Ömer; Özer, Samet; Kasap, Tuba; Ensari, Emel; Demir, Osman; Sönmezgöz, Ergün

2017-09-01

Obesity, one of the most common disorders observed in clinical practice, has been associated with energy metabolism-related protein genes such as uncoupling proteins (UCPs). Herein, we evaluated UCPs as candidate genes for obesity and its morbidities. A total of 268 obese and 185 nonobese children and adolescents were enrolled in this study. To determine dyslipidemia, hypertension, and insulin resistance, laboratory tests were derived from fasting blood samples. UCP1-3826 A/G, UCP2 exon 8 deletion/insertion (del/ins), and UCP3-55C/T variants were also genotyped, and the relationships among the polymorphisms of these UCPs and obesity morbidities were investigated. The mean ages of the obese and control groups were 11.61 ± 2.83 and 10.74 ± 3.36 years, respectively. The respective genotypic frequencies of the AA, AG, and GG genotypes of UCP1 were 46.3%, 33.2%, and 20.5% in obese subjects and 46.5%, 42.2%, and 11.4% in the controls (p = 0.020). G alleles were more frequent in obese subjects with hypertriglyceridemia (42.9%; p = 0.048) than in those without, and the GG genotype presented an odds ratio for obesity of 2.02 (1.17-3.47; p = 0.010). The polymorphisms of UCP2 exon 8 del/ins and UCP3-55C/T did not influence obesity risk (p > 0.05). The I (ins) allele was associated with low HDL cholesterolemia (p = 0.023). The GG genotype of the UCP1-3826 A/G polymorphism appears to contribute to the onset of childhood obesity in Turkish children. The GG genotype of UCP1, together with the del/del genotype of the UCP2 polymorphism, may increase the risk of obesity with synergistic effects. The ins allele of the UCP2 exon 8 del/ins polymorphism may contribute to low HDL cholesterolemia.

Extensión del Formalismo de Orbitales de Defecto Cuántico al tratamiento del efecto Stark (SQDO).

NASA Astrophysics Data System (ADS)

Menéndez, J. M.; Martín, I.; Velasco, A. M.

El estudio experimental de las interacciones de átomos Rydberg altamente excitados con campos eléctricos ha experimentado un creciente interés durante las dos últimas décadas debido, en gran medida, al desarrollo de nuevas técnicas para crear y estudiar átomos Rydberg en el laboratorio. Acompañando a estas nuevas técnicas experimentales, es necesario el desarrollo de modelos teóricos que nos permitan contrastar sus medidas y conocer mejor los fundamentos de los mismos. Desde el punto de vista teórico el conocimiento del desdoblamiento de los niveles energéticos de un átomo en función de la magnitud del campo eléctrico aplicado (lo que se conoce como mapa Stark) es el mejor punto de partida para la descripción del sistema y un prerrequisito fundamental para el cálculo de distintas propiedades atómicas en presencia del campo eléctrico tales como intensidades de transición, umbrales de ionización de campo eléctrico, tiempos de vida, posición y anchura de cruces evitados, etc. En este trabajo presentamos la adaptación del método de orbitales de defecto cuántico [1,2,3] al tratamiento del efecto Stark (SQDO) [4] y su aplicación al cálculo de los desdoblamientos energéticos y fuerzas de oscilador de estados Rydberg en los átomos de Li, Na y K. El propósito de este estudio es, por un lado, desarrollar métodos fiables para la determinación de propiedades atómicas en presencia de campos eléctricos y, por otro, mostrar la fiabilidad de las funciones de onda QDO en la descripción del efecto Stark en sistemas atómicos.

Novel BRCA1 splice-site mutation in ovarian cancer patients of Slavic origin.

PubMed

Krivokuca, Ana; Dragos, Vita Setrajcic; Stamatovic, Ljiljana; Blatnik, Ana; Boljevic, Ivana; Stegel, Vida; Rakobradovic, Jelena; Skerl, Petra; Jovandic, Stevo; Krajc, Mateja; Magic, Mirjana Brankovic; Novakovic, Srdjan

2018-04-01

Mutations in breast cancer susceptibility gene 1 (BRCA1) lead to defects in a number of cellular pathways including DNA damage repair and transcriptional regulation, resulting in the elevated genome instability and predisposing to breast and ovarian cancers. We report a novel mutation LRG_292t1:c.4356delA,p.(Ala1453Glnfs*3) in the 12th exon of BRCA1, in the splice site region near the donor site of intron 12. It is a frameshift mutation with the termination codon generated on the third amino acid position from the site of deletion. Human Splice Finder 3.0 and MutationTaster have assessed this variation as disease causing, based on the alteration of splicing, creation of premature stop codon and other potential alterations initiated by nucleotide deletion. Among the most important alterations are frameshift and splice site changes (score of the newly created donor splice site: 0.82). c.4356delA was associated with two ovarian cancer cases in two families of Slavic origin. It was detected by next generation sequencing, and confirmed with Sanger sequencing in both cases. Because of the fact that it changes the reading frame of the protein, novel mutation c.4356delA p.(Ala1453Glnfs*3) in BRCA1 gene might be of clinical significance for hereditary ovarian cancer. Further functional as well as segregation analyses within the families are necessary for appropriate clinical classification of this variant. Since it has been detected in two ovarian cancer patients of Slavic origin, it is worth investigating founder effect of this mutation in Slavic populations.

Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals.

PubMed

Kuusisto, Kirsi M; Bebel, Aleksandra; Vihinen, Mauno; Schleutker, Johanna; Sallinen, Satu-Leena

2011-02-28

Two major high-penetrance breast cancer genes, BRCA1 and BRCA2, are responsible for approximately 20% of hereditary breast cancer (HBC) cases in Finland. Additionally, rare mutations in several other genes that interact with BRCA1 and BRCA2 increase the risk of HBC. Still, a majority of HBC cases remain unexplained which is challenging for genetic counseling. We aimed to analyze additional mutations in HBC-associated genes and to define the sensitivity of our current BRCA1/2 mutation analysis protocol used in genetic counseling. Eighty-two well-characterized, high-risk hereditary breast and/or ovarian cancer (HBOC) BRCA1/2-founder mutation-negative Finnish individuals, were screened for germline alterations in seven breast cancer susceptibility genes, BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1. BRCA1/2 were analyzed by multiplex ligation-dependent probe amplification (MLPA) and direct sequencing. CHEK2 was analyzed by the high resolution melt (HRM) method and PALB2, RAD50, BRIP1 and CDH1 were analyzed by direct sequencing. Carrier frequencies between 82 (HBOC) BRCA1/2-founder mutation-negative Finnish individuals and 384 healthy Finnish population controls were compared by using Fisher's exact test. In silico prediction for novel missense variants effects was carried out by using Pathogenic-Or-Not -Pipeline (PON-P). Three previously reported breast cancer-associated variants, BRCA1 c.5095C > T, CHEK2 c.470T > C, and CHEK2 c.1100delC, were observed in eleven (13.4%) individuals. Ten of these individuals (12.2%) had CHEK2 variants, c.470T > C and/or c.1100delC. Fourteen novel sequence alterations and nine individuals with more than one non-synonymous variant were identified. One of the novel variants, BRCA2 c.72A > T (Leu24Phe) was predicted to be likely pathogenic in silico. No large genomic rearrangements were detected in BRCA1/2 by multiplex ligation-dependent probe amplification (MLPA). In this study, mutations in previously known breast cancer susceptibility genes can explain 13.4% of the analyzed high-risk BRCA1/2-negative HBOC individuals. CHEK2 mutations, c.470T > C and c.1100delC, make a considerable contribution (12.2%) to these high-risk individuals but further segregation analysis is needed to evaluate the clinical significance of these mutations before applying them in clinical use. Additionally, we identified novel variants that warrant additional studies. Our current genetic testing protocol for 28 Finnish BRCA1/2-founder mutations and protein truncation test (PTT) of the largest exons is sensitive enough for clinical use as a primary screening tool.

Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals

PubMed Central

2011-01-01

Introduction Two major high-penetrance breast cancer genes, BRCA1 and BRCA2, are responsible for approximately 20% of hereditary breast cancer (HBC) cases in Finland. Additionally, rare mutations in several other genes that interact with BRCA1 and BRCA2 increase the risk of HBC. Still, a majority of HBC cases remain unexplained which is challenging for genetic counseling. We aimed to analyze additional mutations in HBC-associated genes and to define the sensitivity of our current BRCA1/2 mutation analysis protocol used in genetic counseling. Methods Eighty-two well-characterized, high-risk hereditary breast and/or ovarian cancer (HBOC) BRCA1/2-founder mutation-negative Finnish individuals, were screened for germline alterations in seven breast cancer susceptibility genes, BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1. BRCA1/2 were analyzed by multiplex ligation-dependent probe amplification (MLPA) and direct sequencing. CHEK2 was analyzed by the high resolution melt (HRM) method and PALB2, RAD50, BRIP1 and CDH1 were analyzed by direct sequencing. Carrier frequencies between 82 (HBOC) BRCA1/2-founder mutation-negative Finnish individuals and 384 healthy Finnish population controls were compared by using Fisher's exact test. In silico prediction for novel missense variants effects was carried out by using Pathogenic-Or-Not -Pipeline (PON-P). Results Three previously reported breast cancer-associated variants, BRCA1 c.5095C > T, CHEK2 c.470T > C, and CHEK2 c.1100delC, were observed in eleven (13.4%) individuals. Ten of these individuals (12.2%) had CHEK2 variants, c.470T > C and/or c.1100delC. Fourteen novel sequence alterations and nine individuals with more than one non-synonymous variant were identified. One of the novel variants, BRCA2 c.72A > T (Leu24Phe) was predicted to be likely pathogenic in silico. No large genomic rearrangements were detected in BRCA1/2 by multiplex ligation-dependent probe amplification (MLPA). Conclusions In this study, mutations in previously known breast cancer susceptibility genes can explain 13.4% of the analyzed high-risk BRCA1/2-negative HBOC individuals. CHEK2 mutations, c.470T > C and c.1100delC, make a considerable contribution (12.2%) to these high-risk individuals but further segregation analysis is needed to evaluate the clinical significance of these mutations before applying them in clinical use. Additionally, we identified novel variants that warrant additional studies. Our current genetic testing protocol for 28 Finnish BRCA1/2-founder mutations and protein truncation test (PTT) of the largest exons is sensitive enough for clinical use as a primary screening tool. PMID:21356067

Genetics of congenital hypogonadotropic hypogonadism in Denmark.

PubMed

Tommiska, Johanna; Känsäkoski, Johanna; Christiansen, Peter; Jørgensen, Niels; Lawaetz, Jacob Gerner; Juul, Anders; Raivio, Taneli

2014-07-01

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder characterized by incomplete/absent puberty caused by deficiency or defective action of gonadotropin-releasing hormone (GnRH). The phenotypic features of patients with CHH vary from genital hypoplasia and absent puberty to reversal of HH later in life. We examined the genetics and clinical features of CHH in Denmark. Forty-one male patients were screened for mutations in KAL1, FGFR1, FGF8, PROK2, PROKR2, GNRHR, TAC3, TACR3, and KISS1R. CHD7 was screened in two patients with hearing loss. In 12 patients, a molecular genetic cause for CHH was found. Four patients had mutations in KAL1 (C105VfsX13, C53X, ex5-8del, R257X), and five in FGFR1 (G97S, R209C, A512V, R646W, and c.1614C>T, (p.I538I), predicted to affect splicing). All 9 had severe HH (cryptorchidism and/or micropenis), and 2 had cleft lip/palate. One patient with a previously reported homozygous R262Q mutation in GNRHR displayed fascinating temporal variation in his phenotype. Two patients with hearing loss had CHD7 mutations (c.7832_7841del (p.K2611MfsX25) and c.2443-2A>C), confirming that CHH patients with CHARGE syndrome-associated features should be screened for mutations in CHD7. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

The effect of the common c.2299delG mutation in USH2A on RNA splicing.

PubMed

Lenassi, Eva; Saihan, Zubin; Bitner-Glindzicz, Maria; Webster, Andrew R

2014-05-01

Recessive variants in the USH2A gene are an important cause of both Usher syndrome and nonsyndromic retinitis pigmentosa. A single base-pair deletion in exon 13 (c.2299delG, p.Glu767Serfs*21) is considered the most frequent mutation of USH2A. It is predicted to generate a premature termination codon and is presumed to lead to nonsense mediated decay. However the effect of this variant on RNA has not been formally investigated. It is not uncommon for exonic sequence alterations to cause aberrant splicing and the aim of the present report is to evaluate the effect of c.2299delG on USH2A transcripts. Nasal cells represent the simplest available tissue to study splicing defects in USH2A. Nasal brushing, RNA extraction from nasal epithelial cells and reverse transcription PCR were performed in five Usher syndrome patients who were homozygous for c.2299delG, two unaffected c.2299delG heterozygotes and seven control individuals. Primers to amplify between exons 12 and 15 and exons 10 and 14 were utilised. Significant variability was observed between different RT-PCR experiments. Importantly, in controls, PCR product of the expected size were amplified on all occasions (13/13 experiments); for patients this was true in only 4/14 experiments (Fisher exact test p = 0.0002). Bioinformatics tools predict the c.2299delG change to disrupt an exonic splicing enhancer and to create an exonic splicing silencer within exon 13. Here, we report an effect of the common c.2299delG mutation on splicing of exons 12 and 13 of USH2A. Future studies are expected to provide important insights into the contribution of this effect on the phenotype. Copyright © 2014 Elsevier Ltd. All rights reserved.

Physical Properties of the SKYLAB North Polar Coronal Hole with an Extended Base and its MHD Self-Consistent Modelling

NASA Astrophysics Data System (ADS)

Bravo, S.; Ocania, G.

1991-04-01

RESUMEN Con base en las observaciones del Skylab del Sol en rayos X que permitieron r la forma de la frontera del hoyo coronal del polo norte y en las observaciones de l 'z que permitieron derivar un perfil de densidad para el flujo de viento solar (IC ese hoyo, Murno yjackson (1977) concluyeron que se requiere una adici6n t l clc energfa al flujo hasta al menos 5 R8. En este trabajo, recalculamos los perfiles de y de temperatura para el mismo hoyo pero considerando una frontera Cs mas ancha en la base, de acuerdo con las observaciones del coron6metro-K del IIAO, los espectroheliogramas en EUV del OSO-7 y las fotografias de la corona solar cerca de los 4 E)()O A. Se tomaron tambien las incertidumbres en el perfil de densidad electr6nica inl & a las observaciones de luz blanca y se consideraron diversos valores posibles dCl fl 'jo (lC masa 1 UA. Encontramos que las diferencias introducidas no son suficientes par clcsc' la necesidad de una energetizaci6n extensa del viento solar, pero una dC las s posibles muestra una concordancia muy buena con el modelado MHD (l( l flujo con el unico t6rmino adicional de la fuerza de Lorentz en la ecuaci6n de # (). ABSTRACT Based on the near to the Sun boundary of the Skylab north polar coroi ' l estimated from the AS & E X-ray photographs and on the density profile fi-C)I white light data, Munro and Jackson (1977) concluded that substantial energy the solar wind flux is required up to at least 5 Rs. In this paper we recalculate `eloci y and temperature profiles for the same hole but considering a different bo ' ry for flux tube which is larger at its base, according to the HAO K- obser"' (i()I0 , the OSO-7 EUV spectroheliograms and pictures of the solar 4500 A. è take into account the uncertainties inherent in the white light observations () electron density profile and consider different possible values of the solar I .' fltix at 1 AU. We that the differences introduced are not sufficient to discard ii y of an extended energetization of the wind, one of the possibilities allowed for fltix the observational uncertailities shows a very good agreement wi4 an NI Ill) seli'consistent modelling with the only additional term of the Lorentz force in the iiii equation. Key words: SUN-CORONA

Molecular and clinical characterization of Waardenburg syndrome type I in an Iranian cohort with two novel PAX3 mutations.

PubMed

Jalilian, Nazanin; Tabatabaiefar, Mohammad Amin; Farhadi, Mohammad; Bahrami, Tayeb; Emamdjomeh, Hesam; Noori-Daloii, Mohammad Reza

2015-12-15

Waardenburg syndrome (WS) is a disease of abnormal neural-crest derived melanocyte development characterized by hearing loss and pigmentary disturbances in hair, eyes and skin. WS is subdivided into four major types, WS1-WS4, where WS1 is recognized by the presence of dystopia canthorum, with PAX3 being the only known gene involved. This study aimed at investigating PAX3 mutations and clinical characteristics of WS1 in a group of Iranian patients. A total of 12 WS1 patients from four unrelated Iranian families were enrolled. Waardenburg consortium guidelines were used for WS1 diagnosis. A detailed family history was traced and a thorough clinical examination was performed for all participants. Furthermore, WS1 patients underwent screening for PAX3 mutations using PCR-sequencing. Dystopia canthorum, broad high nasal root and synophrys were observed in all patients. Early graying, hair discoloration, hypoplastic blue eyes (characteristic brilliant blue iris) and hearing loss were the most common features observed, while heterochromia iridis was the least frequently observed sign among the studied Iranian WS1 patients. Genetic analysis of PAX3 revealed four mutations including c.667C>T, c.784C>T, c.951delT and c.451+3A>C. Two of the four mutations reported here (c.951delT and c.451+3A>C) are being reported for the first time in this study. Our data provide insight into genotypic and phenotypic spectrum of WS1 in an Iranian series of patients. Our results expand the spectrum of PAX3 mutations and may have implications for the genetic counseling of WS in Iran. Copyright © 2015 Elsevier B.V. All rights reserved.

Inherited biallelic CSF3R mutations in severe congenital neutropenia.

PubMed

Triot, Alexa; Järvinen, Päivi M; Arostegui, Juan I; Murugan, Dhaarini; Kohistani, Naschla; Dapena Díaz, José Luis; Racek, Tomas; Puchałka, Jacek; Gertz, E Michael; Schäffer, Alejandro A; Kotlarz, Daniel; Pfeifer, Dietmar; Díaz de Heredia Rubio, Cristina; Ozdemir, Mehmet Akif; Patiroglu, Turkan; Karakukcu, Musa; Sánchez de Toledo Codina, José; Yagüe, Jordi; Touw, Ivo P; Unal, Ekrem; Klein, Christoph

2014-06-12

Severe congenital neutropenia (SCN) is characterized by low numbers of peripheral neutrophil granulocytes and a predisposition to life-threatening bacterial infections. We describe a novel genetic SCN type in 2 unrelated families associated with recessively inherited loss-of-function mutations in CSF3R, encoding the granulocyte colony-stimulating factor (G-CSF) receptor. Family A, with 3 affected children, carried a homozygous missense mutation (NM_000760.3:c.922C>T, NP_000751.1:p.Arg308Cys), which resulted in perturbed N-glycosylation and aberrant localization to the cell surface. Family B, with 1 affected infant, carried compound heterozygous deletions provoking frameshifts and premature stop codons (NM_000760.3:c.948_963del, NP_000751.1:p.Gly316fsTer322 and NM_000760.3:c.1245del, NP_000751.1:p.Gly415fsTer432). Despite peripheral SCN, all patients had morphologic evidence of full myeloid cell maturation in bone marrow. None of the patients responded to treatment with recombinant human G-CSF. Our study highlights the genetic and morphologic SCN variability and provides evidence both for functional importance and redundancy of G-CSF receptor-mediated signaling in human granulopoiesis. © 2014 by The American Society of Hematology.

Inherited biallelic CSF3R mutations in severe congenital neutropenia

PubMed Central

Triot, Alexa; Järvinen, Päivi M.; Arostegui, Juan I.; Murugan, Dhaarini; Kohistani, Naschla; Dapena Díaz, José Luis; Racek, Tomas; Puchałka, Jacek; Gertz, E. Michael; Schäffer, Alejandro A.; Kotlarz, Daniel; Pfeifer, Dietmar; Díaz de Heredia Rubio, Cristina; Ozdemir, Mehmet Akif; Patiroglu, Turkan; Karakukcu, Musa; Sánchez de Toledo Codina, José; Yagüe, Jordi; Touw, Ivo P.; Unal, Ekrem

2014-01-01

Severe congenital neutropenia (SCN) is characterized by low numbers of peripheral neutrophil granulocytes and a predisposition to life-threatening bacterial infections. We describe a novel genetic SCN type in 2 unrelated families associated with recessively inherited loss-of-function mutations in CSF3R, encoding the granulocyte colony-stimulating factor (G-CSF) receptor. Family A, with 3 affected children, carried a homozygous missense mutation (NM_000760.3:c.922C>T, NP_000751.1:p.Arg308Cys), which resulted in perturbed N-glycosylation and aberrant localization to the cell surface. Family B, with 1 affected infant, carried compound heterozygous deletions provoking frameshifts and premature stop codons (NM_000760.3:c.948_963del, NP_000751.1:p.Gly316fsTer322 and NM_000760.3:c.1245del, NP_000751.1:p.Gly415fsTer432). Despite peripheral SCN, all patients had morphologic evidence of full myeloid cell maturation in bone marrow. None of the patients responded to treatment with recombinant human G-CSF. Our study highlights the genetic and morphologic SCN variability and provides evidence both for functional importance and redundancy of G-CSF receptor-mediated signaling in human granulopoiesis. PMID:24753537

Pesticide Avoidance Behavior in Anopheles albimanus, a Malaria Vectorin Central and South America

DTIC Science & Technology

1995-07-11

Clements, A.N. 1992. The Bjoloey of MOSQuitoes. Volume 1. Development, nutrition , and reproduction. Chapman & Hall, 509 pp. EL-Khatib. Z.l...WHO 29(suppl): 121-126. Hoffman, C.C. 1934. Contribucion al conocimiento del paludismo en Ja peninsula de Yucatan . Boletia dellnstituto de

Functional polymorphisms in NFκB1/IκBα predict risks of chronic obstructive pulmonary disease and lung cancer in Chinese.

PubMed

Huang, Dongsheng; Yang, Lei; Liu, Yehua; Zhou, Yumin; Guo, Yuan; Pan, Mingan; Wang, Yunnan; Tan, Yigang; Zhong, Haibo; Hu, Min; Lu, Wenju; Ji, Weidong; Wang, Jian; Ran, Pixin; Zhong, Nanshan; Zhou, Yifeng; Lu, Jiachun

2013-04-01

Lung inflammation is the major pathogenetic feature for both chronic obstructive pulmonary disease (COPD) and lung cancer. The nuclear factor-kappa B (NFκB) and its inhibitor (IκB) play crucial roles in inflammatory. Here, we tested the hypothesis that single nucleotide polymorphisms (SNPs) in NFκB/IκB confer consistent risks for COPD and lung cancer. Four putative functional SNPs (NFκB1: -94del>insATTG; NFκB2: -2966G>A; IκBα: -826C>T, 2758G>A) were analyzed in southern and validated in eastern Chineses to test their associations with COPD risk in 1,511 COPD patients and 1,677 normal lung function controls, as well as lung cancer risk in 1,559 lung cancer cases and 1,679 cancer-free controls. We found that the -94ins ATTG variants (ins/del + ins/ins) in NFκB1 conferred an increased risk of COPD (OR 1.27, 95% CI 1.06-1.52) and promoted COPD progression by accelerating annual FEV1 decline (P = 0.015). The 2758AA variant in IκBα had an increased risk of lung cancer (OR 1.53, 95% CI 1.30-1.80) by decreasing IκBα expression due to the modulation of microRNA hsa-miR-449a but not hsa-miR-34b. Furthermore, both adverse genotypes exerted effect on increasing lung cancer risk in individuals with pre-existing COPD, while the -94del>insATTG did not in those without pre-existing COPD. However, no significant association with COPD or lung cancer was observed for -2966G>A and -826C>T. Our data suggested a common susceptible mechanism of inflammation in lung induced by genetic variants in NFκB1 (-94del>ins ATTG) or IκBα (2758G>A) to predict risk of COPD or lung cancer.

H3+: superficies de energía potencial, estados y transiciones rovibracionales

NASA Astrophysics Data System (ADS)

Aguado, M. Paniagua Y. A.

Hemos calculado varias superficies globales de energía potencial para el estado fundamental y excitados del sistema H3+ en más de ocho mil geometrías diferentes usando una base (9s 3p 1d)/[4s 3p 1d] en cada átomo de Hidrógeno y mediante un método de cálculo de interacción de configuraciones completa (FCI). Hemos ajustado las superficies a formas analíticas del tipo Aguado y Paniagua con un error promedio menor de 50 cm-1 y menor en el pozo de potencial del estado fundamental. Finalmente hemos calculado y analizado los niveles vibracionales para los dos estados electrónicos más bajos, siendo la desviación respecto de los mejores valores publicados, tanto experimentales como teóricos, de unos pocos números de onda.

Exome Sequencing Identifies a REEP1 Mutation Involved in Distal Hereditary Motor Neuropathy Type V

PubMed Central

Beetz, Christian; Pieber, Thomas R.; Hertel, Nicole; Schabhüttl, Maria; Fischer, Carina; Trajanoski, Slave; Graf, Elisabeth; Keiner, Silke; Kurth, Ingo; Wieland, Thomas; Varga, Rita-Eva; Timmerman, Vincent; Reilly, Mary M.; Strom, Tim M.; Auer-Grumbach, Michaela

2012-01-01

The distal hereditary motor neuropathies (dHMNs) are a heterogeneous group of neurodegenerative disorders affecting the lower motoneuron. In a family with both autosomal-dominant dHMN and dHMN type V (dHMN/dHMN-V) present in three generations, we excluded mutations in all genes known to be associated with a dHMN phenotype through Sanger sequencing and defined three potential loci through linkage analysis. Whole-exome sequencing of two affected individuals revealed a single candidate variant within the linking regions, i.e., a splice-site alteration in REEP1 (c.304-2A>G). A minigene assay confirmed complete loss of splice-acceptor functionality and skipping of the in-frame exon 5. The resulting mRNA is predicted to be expressed at normal levels and to encode an internally shortened protein (p.102_139del). Loss-of-function REEP1 mutations have previously been identified in dominant hereditary spastic paraplegia (HSP), a disease associated with upper-motoneuron pathology. Consistent with our clinical-genetic data, we show that REEP1 is strongly expressed in the lower motoneurons as well. Upon exogeneous overexpression in cell lines we observe a subcellular localization defect for p.102_139del that differs from that observed for the known HSP-associated missense mutation c.59C>A (p.Ala20Glu). Moreover, we show that p.102_139del, but not p.Ala20Glu, recruits atlastin-1, i.e., one of the REEP1 binding partners, to the altered sites of localization. These data corroborate the loss-of-function nature of REEP1 mutations in HSP and suggest that a different mechanism applies in REEP1-associated dHMN. PMID:22703882

GJB2 and GJB6 mutations are an infrequent cause of autosomal-recessive nonsyndromic hearing loss in residents of Mexico.

PubMed

Hernández-Juárez, Aideé Alejandra; Lugo-Trampe, José de Jesús; Campos-Acevedo, Luis Daniel; Lugo-Trampe, Angel; Treviño-González, José Luis; de-la-Cruz-Ávila, Israel; Martínez-de-Villarreal, Laura Elia

2014-12-01

Mutations in the DFNB1 locus are the most common cause of autosomal-recessive nonsyndromic hearing loss (ARNSHL) worldwide. The aim of this study was to identify the most frequent mutations in patients with ARNSHL who reside in Northeastern Mexico. We determined the nucleotide sequence the coding region of GJB2 of 78 patients with ARNSHL. Polymerase chain reaction assays were used to detect the GJB2 IVS1+1G>A mutation and deletions within GJB6. GJB2 mutations were detected in 9.6% of the alleles, and c.35delG was the most frequent. Six other less-frequent mutations were detected, including an extremely rare variant (c.645_648delTAGA), a novel mutation (c.35G>A), and one of possible Mexican origin (c.34G>T). GJB6 deletions and GJB2 IVS1+1G>A were not detected. These data suggest that mutations in the DFNB1 locus are a rare cause of ARNSHL among the population of Northeastern Mexico. This confirms the genetic heterogeneity of this condition and indicates that further research is required to determine the other mechanisms of pathogenesis of ARNSHL in Mexicans. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Biallelic mutations in GPD1 gene in a Chinese boy mainly presented with obesity, insulin resistance, fatty liver, and short stature.

PubMed

Li, Niu; Chang, Guoying; Xu, Yufei; Ding, Yu; Li, Guoqiang; Yu, Tingting; Yao, Ruen; Li, Juan; Shen, Yiping; Wang, Xiumin; Wang, Jian

2017-12-01

Biallelic mutations in the GPD1 gene cause a rare autosomal recessive inherited disease known as transient infantile hypertriglyceridemia (OMIM #614480). To date, only five pathogenic variants have been reported in 15 patients from three studies. The clinical symptoms of the affected individuals present a certain degree of heterogeneity. Here, we describe a chinese adolescent patient who mainly presented with obesity, insulin resistance, fatty liver, and short stature. Targeted next-generation sequencing revealed a novel compound heterozygous variant in GPD1 gene (c.220-2A>G and c.820G>A; p.Ala274Thr). In vitro studies demonstrated that the Ala274Thr variant induced a decrease in GPD1 protein expression. Further in vitro investigation of the splicing pattern in a minigene construct in HEK293 cells showed that the c.220-2A>G variant generated an altered transcript with one cryptic splice site in exon 3, resulting in the loss of 69 bases in exon 3 (c.220_288del, p.74_96del). This is the first report involving an Asian who harbored GPD1 mutations. Our work not only expands the mutant spectrum of the GPD1 gene but also provides new insights on its resulting phenotype. © 2017 Wiley Periodicals, Inc.

A novel deletion mutation is recurrent in von Willebrand disease types 1 and 3.

PubMed

Sutherland, Megan S; Cumming, Anthony M; Bowman, Mackenzie; Bolton-Maggs, Paula H B; Bowen, Derrick J; Collins, Peter W; Hay, Charles R M; Will, Andrew M; Keeney, Stephen

2009-07-30

Direct sequencing of VWF genomic DNA in 21 patients with type 3 von Willebrand disease (VWD) failed to reveal a causative homozygous or compound heterozygous VWF genotype in 5 cases. Subsequent analysis of VWF mRNA led to the discovery of a deletion (c.221-977_532 + 7059del [p.Asp75_Gly178del]) of VWF in 7 of 12 white type 3 VWD patients from 6 unrelated families. This deletion of VWF exons 4 and 5 was absent in 9 patients of Asian origin. We developed a genomic DNA-based assay for the deletion, which also revealed its presence in 2 of 34 type 1 VWD families, segregating with VWD in an autosomal dominant fashion. The deletion was associated with a specific VWF haplotype, indicating a possible founder origin. Expression studies indicated markedly decreased secretion and defective multimerization of the mutant VWF protein. Further studies have found the mutation in additional type 1 VWD patients and in a family expressing both type 3 and type 1 VWD. The c.221-977_532 + 7059del mutation represents a previously unreported cause of both types 1 and 3 VWD. Screening for this mutation in other type 1 and type 3 VWD patient populations is required to elucidate further its overall contribution to VWD arising from quantitative deficiencies of VWF.

The role of alternative GJB2 transcription in screening for neonatal sensorineural deafness in Austria.

PubMed

Parzefall, Thomas; Lucas, Trevor; Koenighofer, Martin; Ramsebner, Reinhard; Frohne, Alexandra; Czeiger, Shelly; Baumgartner, Wolf-Dieter; Schoefer, Christian; Gstoettner, Wolfgang; Frei, Klemens

2017-04-01

Alterations within a novel putative Exon 1a within the gap junction beta 2 (GJB2) gene may play a role in the development of genetic hearing impairment in Austria. Mutations in the GJB2 gene are the most common cause of hereditary sensorineural deafness. Genome-wide screening for alternative transcriptional start sites in the human genome has revealed the presence of an additional GJB2 exon (E1a). This study tested the hypothesis of whether alternative GJB2 transcription involving E1a may play a role in the development of congenital sensorineural deafness in Austria. GJB2 E1a and flanking regions were sequenced in randomized normal hearing control subjects and three different patient groups with non-syndromic hearing impairment (NSHI), and bioinformatic analysis was performed. Statistical analysis of disease association was carried out using the Cochran-Armitage test for trend. A single change 2410 bp proximal to the translational start site (c.-2410T > C, rs7994748, NM_004004.5:c.-23 + 792T > C) was found to be significantly associated with the common c.35delG GJB2 mutation (p = .009). c.35delG in combination with c.-2410CC occurred at a 6.9-fold increased frequency compared to the control group. Additionally, one patient with idiopathic congenital hearing loss was found to be homozygous c.-2410CC.

DRD2/ANKK1 gene polymorphisms in forensic autopsies of methamphetamine intoxication fatalities.

PubMed

Matsusue, Aya; Ishikawa, Takaki; Ikeda, Tomoya; Tani, Naoto; Arima, Hisatomi; Waters, Brian; Hara, Kenji; Kashiwagi, Masayuki; Takayama, Mio; Ikematsu, Natsuki; Kubo, Shin-Ichi

2018-04-22

Dopamine D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) gene polymorphisms have been associated with responses to psychotropic drugs and addiction. We analyzed two DRD2/ANKK1 polymorphisms, Taq1A and -141C Ins/Del, in 37 fatal methamphetamine (MA) intoxication cases and 235 control cases in which MA and psychotropic drugs were not detected. The association among polymorphism, cause of death, and cerebrospinal fluid (CSF) dopamine concentration was evaluated. The Taq1A polymorphism distribution in the fatal MA intoxication cases differed from in the controls (P = 0.030) with a significantly high A1/A1 + A1/A2 genotype frequency. No significant associations were observed between -141C Ins/Del polymorphisms and MA intoxication cases or between DRD2/ANKK1 polymorphisms and CSF dopamine concentrations. Our findings suggest that the DRD2/ANKK1 Taq1A polymorphism is associated with susceptibility to fatal MA intoxication. Copyright © 2018 Elsevier B.V. All rights reserved.

Hereditary Angioedema Nationwide Study in Slovenia Reveals Four Novel Mutations in SERPING1 Gene

PubMed Central

Rijavec, Matija; Korošec, Peter; Šilar, Mira; Zidarn, Mihaela; Miljković, Jovan; Košnik, Mitja

2013-01-01

Hereditary angioedema (HAE) is a rare autosomal dominant disease characterized by swelling of the face, lips, tongue, larynx, genitalia, or extremities, with abdominal pain caused by intra-abdominal edema. HAE is caused by mutations affecting the C1 inhibitor gene, SERPING1, resulting in low levels of C1 inhibitor (Type I HAE) or normal levels of ineffective C1 inhibitor (Type II HAE). A nationwide survey identified nine unrelated families with HAE in Slovenia, among whom 17 individuals from eight families were recruited for genetic analyses. A diagnosis of HAE was established in the presence of clinical and laboratory criteria (low C1 inhibitor antigenic levels and/or function), followed up by a positive family history. Genetic studies were carried out using PCR and sequencing to detect SERPING1 mutations in promoter, noncoding exon 1, the 7 coding exons, and exon-intron boundaries. Multiplex ligation-dependent probe amplification was performed in order to search for large deletions/duplications in SERPING1 gene. A mutation responsible for HAE was identified in patients from seven families with the disease. In HAE type I families, one previously reported substitution (Gln67Stop, c.265C>T) and four novel mutations were identified. The new mutations included two missense substitutions, Ser128Phe (c.449C>T), and Glu429Lys (c.1351G>A), together with two frameshift mutations, indel (c.49delGinsTT) and deletion (c.593_594delCT). Both families with HAE type II harbored the two well-known substitutions affecting the arginyl residue at the reactive center in exon 8, Arg444Cys (c.1396C>T) and Arg444His (c.1397G>A), respectively. In one patient only the homozygous variant g.566T>C (c.-21T>C) was identified. Our study identified four novel mutations in the Slovenian HAE population, highlighting the heterogeneity of mutations in the SERPING1 gene causing C1 inhibitor deficiency and HAE. In a single patient with HAE a homozygous variant g.566T>C (c.-21T>C) might be responsible for the disease. PMID:23437219

Hereditary angioedema nationwide study in Slovenia reveals four novel mutations in SERPING1 gene.

PubMed

Rijavec, Matija; Korošec, Peter; Šilar, Mira; Zidarn, Mihaela; Miljković, Jovan; Košnik, Mitja

2013-01-01

Hereditary angioedema (HAE) is a rare autosomal dominant disease characterized by swelling of the face, lips, tongue, larynx, genitalia, or extremities, with abdominal pain caused by intra-abdominal edema. HAE is caused by mutations affecting the C1 inhibitor gene, SERPING1, resulting in low levels of C1 inhibitor (Type I HAE) or normal levels of ineffective C1 inhibitor (Type II HAE). A nationwide survey identified nine unrelated families with HAE in Slovenia, among whom 17 individuals from eight families were recruited for genetic analyses. A diagnosis of HAE was established in the presence of clinical and laboratory criteria (low C1 inhibitor antigenic levels and/or function), followed up by a positive family history. Genetic studies were carried out using PCR and sequencing to detect SERPING1 mutations in promoter, noncoding exon 1, the 7 coding exons, and exon-intron boundaries. Multiplex ligation-dependent probe amplification was performed in order to search for large deletions/duplications in SERPING1 gene. A mutation responsible for HAE was identified in patients from seven families with the disease. In HAE type I families, one previously reported substitution (Gln67Stop, c.265C>T) and four novel mutations were identified. The new mutations included two missense substitutions, Ser128Phe (c.449C>T), and Glu429Lys (c.1351G>A), together with two frameshift mutations, indel (c.49delGinsTT) and deletion (c.593_594delCT). Both families with HAE type II harbored the two well-known substitutions affecting the arginyl residue at the reactive center in exon 8, Arg444Cys (c.1396C>T) and Arg444His (c.1397G>A), respectively. In one patient only the homozygous variant g.566T>C (c.-21T>C) was identified. Our study identified four novel mutations in the Slovenian HAE population, highlighting the heterogeneity of mutations in the SERPING1 gene causing C1 inhibitor deficiency and HAE. In a single patient with HAE a homozygous variant g.566T>C (c.-21T>C) might be responsible for the disease.

Inversor Resonante de Tres Elementos L-LC con Caracteristica Cortocircuitable para Aplicaciones de Calentamiento por Induccion

NASA Astrophysics Data System (ADS)

Espi Huerta, Jose Miguel

Los generadores de calentamiento por induccion son puentes inversores con carga resonante, cuya mision es basicamente crear una corriente sinusoidal de gran amplitud sobre la "bobina de caldeo", que forma parte del tanque resonante. En el interior de esta bobina se introduce la pieza que se desea calentar. EI campo magnetico creado induce corrientes superficiales (corrientes de Foucault) sobre la pieza, que producen su calentamiento. Los tanques resonantes (tambien llamados osciladores) utilizados en la actualidad son el resonante serie y el resonante paralelo. Aunque ya desde hace algun tiempo se vienen construyendo generadores de alta potencia basados en estos dos osciladores, el exito nunca ha. sido completo en ninguno de los dos casos. Tal y como se explica en la introduccion de esta memoria, los puentes inversores utilizados deben operar sobre una carga inductiva (corriente retrasada) para evitar el fenomeno de la recuperacion inversa de sus diodos y la consiguiente ruptura de los transistores. De la restriccion topologica anterior se deduce que el generador paralelo debe conmutar a frecuencias inferiores a la resonancia, y el serie a frecuencias superiores. A esta restriccion topologica hay que unir otra que es exclusiva del calentamiento por induccion: La corriente por la bobina de caldeo debe ser sinusoidal. De no ser asi, resultaria imposible disponer toda la potencia de calentamiento sobre la pieza en el espesor requerido por la aplicacion. Como consecuencia, los inversores no pueden operar por debajo de la frecuencia de resonancia del oscilador, pues en ese caso se amplifican los armonicos de orden superior de la tension/corriente de entrada situados sobre la resonancia, con la consiguiente distorsion de la corriente de salida. La conjuncion de las dos restricciones anteriores obligan al inversor paralelo a funcionar a la frecuencia de resonancia del oscilador. Esto imposibilita un control por variacion de frecuencia, regulandose la potencia desde la seccion de entrada mediante un mayor o menor aporte de corriente al puente. Como consecuencia, la seccion de entrada del paralelo, ya de por si mas voluminosa que lao del serie por el uso de grandes componentes magneticos (bobinas de filtro o de "alisamiento"), result a tambien mas complicada y costosa debido a la necesidad de ser implementada mediante rectificador controlado. Ademas, la regulacion que ofrece el rectificador es pobre, dada su baja frecuencia de conmutacion. En cambio, el circuito serie puede funcionar por encima de la resonancia manteniendo una secuencia de conmutacion sin riesgos de recuperacion inversa y con una corriente de salida practicamente sinusoidal, lo que permite un control de la potencia por variacion de frecuencia. Puesto que la tarea de regulacion se realiza desde el puente inversor, la regulacion resulta mucho mas eficaz y la seccion de entrada se puede implementar mediante un simple rectificador no controlado y un condensador de filtro. (Abstract shortened by UMI.).

Molecular analysis of brazilian patients with combined pituitary hormone deficiency and orthotopic posterior pituitary lobe reveals eight different PROP1 alterations with three novel mutations.

PubMed

Madeira, Joao Lo; Nishi, Mirian Y; Nakaguma, Marilena; Benedetti, Anna F; Biscotto, Isabela Peixoto; Fernandes, Thamiris; Pequeno, Thiago; Figueiredo, Thalita; Franca, Marcela M; Correa, Fernanda A; Otto, Aline P; Abrão, Milena; Miras, Mirta B; Santos, Silvana; Jorge, Alexander Al; Costalonga, Everlayny F; Mendonca, Berenice B; Arnhold, Ivo Jp; Carvalho, Luciani R

2017-12-01

Mutations in PROP1, HESX1 and LHX3 are associated with combined pituitary hormone deficiency (CPHD) and orthotopic posterior pituitary lobe (OPP). To identify mutations in PROP1, HESX1 and LHX3 in a large cohort of patients with CPHD and OPP (35 Brazilian, two Argentinian). We studied 23 index patients with CPHD and OPP (six familial and 17 sporadic) as well as 14 relatives. PROP1 was sequenced by the Sanger method in all except one sporadic case studied using a candidate gene panel. Multiplex ligation-dependent probe amplification (MLPA) was applied to one familial case in whom PROP1 failed to amplify by PCR. In the 13 patients without PROP1 mutations, HESX1 and LHX3 were sequenced by the Sanger method. We identified PROP1 mutations in 10 index cases. Three mutations were novel: one affecting the initiation codon (c.1A>G) and two affecting splicing sites, c.109+1G>A and c.342+1G>C. The known mutations, c.150delA (p.Arg53Aspfs*112), c.218G>A (p.Arg73His), c.263T>C (p.Phe88Ser) and c.301_302delAG (p.Leu102Cysfs*8), were also detected. MLPA confirmed complete PROP1 deletion in one family. We did not identify HESX1 and LHX3 mutations by Sanger. PROP1 mutations are a prevalent cause of congenital CPHD with OPP, and therefore, PROP1 sequencing must be the first step of molecular investigation in patients with CPHD and OPP, especially in populations with a high frequency of PROP1 mutations. In the absence of mutations, massively parallel sequencing is a promising approach. The high prevalence and diversity of PROP1 mutations is associated with the ethnic background of this cohort. © 2017 John Wiley & Sons Ltd.

Novel mutations in the STK11 gene in Thai patients with Peutz-Jeghers syndrome

PubMed Central

Ausavarat, Surasawadee; Leoyklang, Petcharat; Vejchapipat, Paisarn; Chongsrisawat, Voranush; Suphapeetiporn, Kanya; Shotelersuk, Vorasuk

2009-01-01

Peutz-Jeghers syndrome (PJS), a rare autosomal dominant inherited disorder, is characterized by hamartomatous gastrointestinal polyps and mucocutaneous pigmentation. Patients with this syndrome have a predisposition to a variety of cancers in multiple organs. Mutations in the serine/threonine kinase 11 (STK11) gene have been identified as a major cause of PJS. Here we present the clinical and molecular findings of two unrelated Thai individuals with PJS. Mutation analysis by Polymerase Chain Reaction-sequencing of the entire coding region of STK11 revealed two potentially pathogenic mutations. One harbored a single nucleotide deletion (c.182delG) in exon 1 resulting in a frameshift leading to premature termination at codon 63 (p.Gly61AlafsX63). The other carried an in-frame 9-base-pair (bp) deletion in exon 7, c.907_915del9 (p.Ile303_Gln305del). Both deletions were de novo and have never been previously described. This study has expanded the genotypic spectrum of the STK11 gene. PMID:19908348

Operation Plan I-45 ICEBERG

DTIC Science & Technology

1945-02-01

8217COmIIAND OF MAJOR- GENERAL del VALLE: R. O, BARE, Col, USMC, ·C of S. ANNEXES: ABLE - Distribution B1iKER - Intelligence CHARLIE - Naval Gunfire Support Plan...3. ABLE Annex BAKER to Opn Plan 1-45, 1st MarDiv-(Rein) INTELLIGENCE 00015 1st Mar Div (Rein). 1990-5-80 In The Field 475/355 . 1100, 1OFeb, 1945. AP...distributed. (c) JANIS No. 86, August, 1944; JANIS No. 86 (Change 1), October 1944. (d) Engineer Intelligence Information of OKINAWA SHIMA prepared by Eng

Worldwide Report, Nuclear Development and Proliferation No. 186

DTIC Science & Technology

1983-05-03

normality that at first took a great deal of effort to achieve. 33 C___ ACIRC//TO AGUA VAPOR SECUNt/ CMMWMI CU’CTO AG3UA RMFI(3PACION 1. Nucleo del reactor 6...is used to cool various components of the powerplant, but in any case it is separated from possibly contaminated ele- ments by at least two...Central do Asc6 10. Aqua do ref rigeracibn hay 3 generadorea do vapor) (Procedente en este caso del rio Ebro) 4. Presurizador 11. Transformador (Sirve

Molecular screening of deafness in Algeria: high genetic heterogeneity involving DFNB1 and the Usher loci, DFNB2/USH1B, DFNB12/USH1D and DFNB23/USH1F.

PubMed

Ammar-Khodja, Fatima; Faugère, Valérie; Baux, David; Giannesini, Claire; Léonard, Susana; Makrelouf, Mohamed; Malek, Rahia; Djennaoui, Djamel; Zenati, Akila; Claustres, Mireille; Roux, Anne-Françoise

2009-01-01

A systematic approach, involving haplotyping and genotyping, to the molecular diagnosis of non-syndromic deafness within 50 families and 9 sporadic cases from Algeria is described. Mutations at the DFNB1 locus (encompassing the GJB2 and GJB6 genes) are responsible for more than half of autosomal recessive prelingual non-syndromic deafness in various populations. A c.35delG mutation can account for up to 85% of GJB2 mutations and two large deletions del(GJB6-D13S1830) and del(GJB6-D13S1854) have also been reported in several population groups. In view of the genetic heterogeneity a strategy was developed which involved direct analysis of DFNB1. In negative familial cases, haplotype analysis was carried out, where possible, to exclude DFNB1 mutations. Following this, haplotype analysis of five Usher syndrome loci, sometimes involved in autosomal non-syndromic hearing loss, was carried out to identify cases in which Usher gene sequencing was indicated. When homozygosity was observed at a locus in a consanguineous family, the corresponding gene was exhaustively sequenced. Pathogenic DFNB1 genotypes were identified in 40% of the cases. Of the 21 cases identified with 2 pathogenic mutations, c.35delG represented 76% of the mutated alleles. The additional mutations were one nonsense, two missense and one splicing mutation. Four additional patients were identified with a single DFNB1 mutation. None carried the large deletions. Three families with non-syndromic deafness carried novel unclassified variants (UVs) in MYO7A (1 family) and CDH23 (2 families) of unknown pathogenic effect. Additionally, molecular diagnosis was carried out on two Usher type I families and pathogenic mutations in MYO7A and PCDH15 were found.

Survival and contralateral breast cancer in CHEK2 1100delC breast cancer patients: impact of adjuvant chemotherapy.

PubMed

Kriege, M; Hollestelle, A; Jager, A; Huijts, P E A; Berns, E M; Sieuwerts, A M; Meijer-van Gelder, M E; Collée, J M; Devilee, P; Hooning, M J; Martens, J W M; Seynaeve, C

2014-08-26

We assessed the sensitivity to adjuvant chemotherapy in cell cycle checkpoint kinase 2 (CHEK2) vs non-CHEK2 breast cancer patients by comparing the contralateral breast cancer incidence and distant disease-free and breast cancer-specific survival between both groups, stratified for adjuvant chemotherapy. One Dutch hereditary non-BRCA1/2 breast cancer patient cohort (n=1220) and two Dutch cohorts unselected for family history (n=1014 and n=2488, respectively) were genotyped for CHEK2 1100delC. Hazard ratios for contralateral breast cancer, distant disease-free and breast cancer-specific death for mutation carriers vs noncarriers were calculated using the Cox proportional hazard method, stratified for adjuvant chemotherapy. The CHEK2 mutation carriers (n=193) had an increased incidence of contralateral breast cancer (multivariate hazard ratio 3.97, 95% confidence interval 2.59-6.07). Distant disease-free and breast cancer-specific survival were similar in the first 6 years in mutation carriers compared with noncarriers, but diverted as of 6 years after breast cancer diagnosis (multivariate hazard ratios and 95% confidence intervals 2.65 (1.79-3.93) and 2.05 (1.41-2.99), respectively). No significant interaction between CHEK2 and adjuvant chemotherapy was observed. The CHEK2 1100delC-associated breast cancer is associated with a higher contralateral breast cancer rate as well as worse survival measures beyond 6 years after diagnosis. No differential sensitivity to adjuvant chemotherapy was observed in CHEK2 patients.

Associations between uncoupling protein 2, body composition, and resting energy expenditure in lean and obese African American, white, and Asian children.

PubMed

Yanovski, J A; Diament, A L; Sovik, K N; Nguyen, T T; Li, H; Sebring, N G; Warden, C H

2000-06-01

Little is known about genes that affect childhood body weight. The objective of this study was to examine the association between alleles of the mitochondrial uncoupling protein 2 (UCP2) gene and obesity because UCP2 may influence energy expenditure. We related UCP2 genotype to body composition and resting energy expenditure in 105 children aged 6-10 y. Overweight children and nonoverweight children of overweight parents were genotyped for a 45-base pair deletion/insertion (del/ins) in 3'-untranslated region of exon 8 and for an exon 4 C to T transition. Eighty-nine children were genotyped for the exon 8 allele: 50 children had del/del, 33 had del/ins, and 6 had ins/ins. Mean (+/-SD) body mass index (BMI; in kg/m(2)) was greater for children with del/ins (24.1 +/- 5.9) than for children with del/del (20.4 +/- 4.8; P < 0.001). BMI of ins/ins children (23.7 +/- 7.8) was not significantly different from that of del/ins children. A greater BMI in del/ins children was independent of race and sex. Body composition was also different according to UCP2 genotype. All body circumferences and skinfold thicknesses examined were significantly greater in del/ins than in del/del children. Body fat mass as determined by dual-energy X-ray absorptiometry was also greater in del/ins than in del/del children (P < 0.005). For 104 children genotyped at exon 4, no significant differences in BMI or body composition were found among the 3 exon 4 genotypes. Neither resting energy expenditure nor respiratory quotient were different according to UCP2 exon 4 or exon 8 genotype. The exon 8 ins/del polymorphism of UCP2 appears to be associated with childhood-onset obesity. The UCP2/UCP3 genetic locus may play a role in childhood body weight.

Comparative use of InDel and SSR markers in deciphering the interspecific structure of cultivated citrus genetic diversity: a perspective for genetic association studies.

PubMed

García-Lor, Andrés; Luro, François; Navarro, Luis; Ollitrault, Patrick

2012-01-01

Genetic stratification associated with domestication history is a key parameter for estimating the pertinence of genetic association study within a gene pool. Previous molecular and phenotypic studies have shown that most of the diversity of cultivated citrus results from recombination between three main species: C. medica (citron), C. reticulata (mandarin) and C. maxima (pummelo). However, the precise contribution of each of these basic species to the genomes of secondary cultivated species, such as C. sinensis (sweet orange), C. limon (lemon), C. aurantium (sour orange), C. paradisi (grapefruit) and recent hybrids is unknown. Our study focused on: (1) the development of insertion-deletion (InDel) markers and their comparison with SSR markers for use in genetic diversity and phylogenetic studies; (2) the analysis of the contributions of basic taxa to the genomes of secondary species and modern cultivars and (3) the description of the organisation of the Citrus gene pool, to evaluate how genetic association studies should be done at the cultivated Citrus gene pool level. InDel markers appear to be better phylogenetic markers for tracing the contributions of the three ancestral species, whereas SSR markers are more useful for intraspecific diversity analysis. Most of the genetic organisation of the Citrus gene pool is related to the differentiation between C. reticulata, C. maxima and C. medica. High and generalised LD was observed, probably due to the initial differentiation between the basic species and a limited number of interspecific recombinations. This structure precludes association genetic studies at the genus level without developing additional recombinant populations from interspecific hybrids. Association genetic studies should also be affordable at intraspecific level in a less structured pool such as C. reticulata.

Detecting novel genetic mutations in Chinese Usher syndrome families using next-generation sequencing technology.

PubMed

Qu, Ling-Hui; Jin, Xin; Xu, Hai-Wei; Li, Shi-Ying; Yin, Zheng-Qin

2015-02-01

Usher syndrome (USH) is the most common cause of combined blindness and deafness inherited in an autosomal recessive mode. Molecular diagnosis is of great significance in revealing the molecular pathogenesis and aiding the clinical diagnosis of this disease. However, molecular diagnosis remains a challenge due to high phenotypic and genetic heterogeneity in USH. This study explored an approach for detecting disease-causing genetic mutations in candidate genes in five index cases from unrelated USH families based on targeted next-generation sequencing (NGS) technology. Through systematic data analysis using an established bioinformatics pipeline and segregation analysis, 10 pathogenic mutations in the USH disease genes were identified in the five USH families. Six of these mutations were novel: c.4398G > A and EX38-49del in MYO7A, c.988_989delAT in USH1C, c.15104_15105delCA and c.6875_6876insG in USH2A. All novel variations segregated with the disease phenotypes in their respective families and were absent from ethnically matched control individuals. This study expanded the mutation spectrum of USH and revealed the genotype-phenotype relationships of the novel USH mutations in Chinese patients. Moreover, this study proved that targeted NGS is an accurate and effective method for detecting genetic mutations related to USH. The identification of pathogenic mutations is of great significance for elucidating the underlying pathophysiology of USH.

A case report of Fanconi anemia diagnosed by genetic testing followed by prenatal diagnosis.

PubMed

Lee, Hwa Jeen; Park, Seungman; Kang, Hyoung Jin; Jun, Jong Kwan; Lee, Jung Ae; Lee, Dong Soon; Park, Sung Sup; Seong, Moon-Woo

2012-09-01

Fanconi anemia (FA) is a rare genetic disorder affecting multiple body systems. Genetic testing, including prenatal testing, is a prerequisite for the diagnosis of many clinical conditions. However, genetic testing is complicated for FA because there are often many genes that are associated with its development, and large deletions, duplications, or sequence variations are frequently found in some of these genes. This study describes successful genetic testing for molecular diagnosis, and subsequent prenatal diagnosis, of FA in a patient and his family in Korea. We analyzed all exons and flanking regions of the FANCA, FANCC, and FANCG genes for mutation identification and subsequent prenatal diagnosis. Multiplex ligation-dependent probe amplification analysis was performed to detect large deletions or duplications in the FANCA gene. Molecular analysis revealed two mutations in the FANCA gene: a frameshift mutation c.2546delC and a novel splice-site mutation c.3627-1G>A. The FANCA mutations were separately inherited from each parent, c.2546delC was derived from the father, whereas c.3627-1G>A originated from the mother. The amniotic fluid cells were c.3627-1G>A heterozygotes, suggesting that the fetus was unaffected. This is the first report of genetic testing that was successfully applied to molecular diagnosis of a patient and subsequent prenatal diagnosis of FA in a family in Korea.

North-South Gradients in Carbon Isotopic Compositions of Atlantic Ocean Black Shales: Evidence for Paleohydrologic Influences on Mid-Cretaceous Black Shale Deposition

NASA Astrophysics Data System (ADS)

Meyers, P. A.

2013-12-01

Organic del13C values of organic-carbon-rich Albian-Cenomanian-Turonian black shales from a north-south transect of the Atlantic Ocean have been compiled to explore for possible existence of latitudinal patterns. Black shales at equatorial sites have mean del13C values of -28 per mil, whereas black shales at mid-latitude sites have mean del13C values around -25 per mil. The mid-Cretaceous del13C values are routinely lower than those of modern marine sediments. The more negative Cretaceous del13C values generally reflect concentrations of atmospheric CO2 that were four to six times higher than today, but the geographic differences imply a regional overprint on this global feature. Latitudinal differences in oceanic temperature might be a factor, but a low thermal gradient from the poles to the equator during the mid-Cretaceous makes this factor not likely to be significant. Instead, a correspondence between the geographic differences in the organic del13C values of black shales with the modern latitudinal precipitation pattern suggests that differences in precipitation are a more likely factor. Establishment of a strongly salinity-stratified near-surface ocean and magnified delivery of land-derived phosphorus by continental runoff during this time of a magnified hydrologic cycle were evidently significant to deposition of marine black shales. A likely scenario is that the stratification resulted in blooms of nitrogen-fixing bacteria that become the dominant photoautotrophs and thereby stimulated primary production of organic matter. Regional differences in precipitation resulted in different amounts of runoff, consequent stratification, enhancement of primary production, and therefore the different carbon isotopic compositions of the black shales.

An effective diagnostic strategy for accurate detection of RhD variants including Asian DEL type in apparently RhD-negative blood donors in Korea.

PubMed

Seo, M H; Won, E J; Hong, Y J; Chun, S; Kwon, J R; Choi, Y S; Kim, J N; Lee, S A; Lim, A H; Kim, S H; Park, K U; Cho, D

2016-11-01

The purpose of this study was to provide an effective RHD genotyping strategy for the East Asian blood donors. RhD phenotyping, weak D testing and RhCE phenotyping were performed on 110 samples from members of the RhD-negative club, private organization composed of RhD-negative blood donors, in the GwangJu-Chonnam region of Korea. The RHD promoter, intron 4, and exons 7 and 10 were analysed by real-time PCR. Two nucleotide changes (c.1227 G>A, and c.1222 T>C) in exon 9 were analysed by sequencing. Of 110 RhD-negative club members, 79 (71·8%) showed complete deletion of the RHD gene, 10 (9·1%) showed results consistent with RHD-CE-D hybrid, and 21 (19·1%) showed amplification of RHD promoter, intron 4, and exons 7 and 10. Of the latter group, 16 (14·5%) were in the DEL blood group including c.1227 G>A (N = 14) and c.1222 T>C (N = 2), 2 (1·8%) were weak D, 1(0·9%) was partial D, and 2 (1·8%) were undetermined. The RhD-negative phenotype samples consisted of 58 C-E-c+e+, 19 C-E+c+e+, 3 C-E+c+e-, 21 C+E-c+e-, 6 C+E-c+e+ and 3 C+E-c-e + . Notably, all 58 samples with the C-E-c+e+ phenotype were revealed to have complete deletion of the RHD gene. The C-E-c+e+ phenotype showed 100% positive predictive value for detecting D-negative cases. RHD genotyping is not required in half of D-negative cases. We suggest here an effective RHD genotyping strategy for accurate detection of RhD variants in apparently RhD-negative blood donors in East Asia. © 2016 International Society of Blood Transfusion.

?`Es necesario calcular detalladamente funciones de partición atómicas?

NASA Astrophysics Data System (ADS)

Milone, L. A.; Merlo, D. C.

Basándonos en extensos y precisos cómputos de funciones de partición realizados por nosotros para distintos átomos, se muestra que en el cálculo u obtención de ciertas magnitudes (notablemente la presión electrónica, la abundancia de un elemento deducida a partir de un estado fuertemente ionizado, etc.) el error porcentual que se comete es pequeño (inferior a 1 %) si se adopta, como valor de la función de partición, el peso estadístico del término correspondiente al estado fundamental del átomo. Esta notable simplificación acelera el cálculo, por ejemplo, de un modelo de atmósfera estelar, sin disminuir la precisión de los resultados.

High frequency of the recurrent c.1310_1313delAAGA BRCA2 mutation in the North-East of Morocco and implication for hereditary breast-ovarian cancer prevention and control.

PubMed

Laarabi, Fatima-Zahra; Ratbi, Ilham; Elalaoui, Siham Chafai; Mezzouar, Loubna; Doubaj, Yassamine; Bouguenouch, Laila; Ouldim, Karim; Benjaafar, Noureddine; Sefiani, Abdelaziz

2017-06-02

To date, a limited number of BRCA1/2 germline mutations have been reported in hereditary breast and/or ovarian cancer in the Moroccan population. Less than 20 different mutations of these two genes have been identified in Moroccan patients, and recently we reported a further BRCA2 mutation (c.1310_1313delAAGA; p.Lys437IlefsX22) in three unrelated patients, all from the North-East of the country. We aimed in this study to evaluate the frequency and geographic distribution of this BRCA2 frameshift mutation, in order to access its use as the first-line BRCA genetic testing strategy for Moroccan patients. We enrolled in this study 122 patients from different regions of Morocco, with suggestive inherited predisposition to breast and ovarian cancers. All subjects gave written informed consent to BRCA1/2 genetic testing. According to available resources of our lab and enrolled families, 51 patients were analyzed by the conventional individual exon-by-exon Sanger sequencing, 23 patients were able to benefit from a BRCA next generation sequencing and a target screening for exon 10 of BRCA2 gene was performed in 48 patients. Overall, and among the 122 patients analyzed for at least the exon 10 of the BRCA2 gene, the c.1310_1313delAAGA frameshift mutation was found in 14 patients. Genealogic investigation revealed that all carriers of this mutation shared the same geographic origin and were descendants of the North-East of Morocco. In this study, we highlighted that c.1310_1313delAAGA mutation of BRCA2 gene is recurrent with high frequency in patients from the North-East region of Morocco. Therefore, we propose to use, in public health strategies, the detection of this mutation as the first-line screening tests in patients with breast and ovarian cancer originated from this region.

Construction of an interspecific genetic map based on InDel and SSR for mapping the QTLs affecting the initiation of flower primordia in pepper (Capsicum spp.).

PubMed

Tan, Shu; Cheng, Jiao-Wen; Zhang, Li; Qin, Cheng; Nong, Ding-Guo; Li, Wei-Peng; Tang, Xin; Wu, Zhi-Ming; Hu, Kai-Lin

2015-01-01

Re-sequencing permits the mining of genome-wide variations on a large scale and provides excellent resources for the research community. To accelerate the development and application of molecular markers and identify the QTLs affecting the flowering time-related trait in pepper, a total of 1,038 pairs of InDel and 674 SSR primers from different sources were used for genetic mapping using the F2 population (n = 154) derived from a cross between BA3 (C. annuum) and YNXML (C. frutescens). Of these, a total of 224 simple PCR-based markers, including 129 InDels and 95 SSRs, were validated and integrated into a map, which was designated as the BY map. The BY map consisted of 13 linkage groups (LGs) and spanned a total genetic distance of 1,249.77 cM with an average marker distance of 5.60 cM. Comparative analysis of the genetic and physical map based on the anchored markers showed that the BY map covered nearly the whole pepper genome. Based on the BY map, one major and five minor QTLs affecting the number of leaves on the primary axis (Nle) were detected on chromosomes P2, P7, P10 and P11 in 2012. The major QTL on P2 was confirmed based on another subset of the same F2 population (n = 147) in 2014 with selective genotyping of markers from the BY map. With the accomplishment of pepper whole genome sequencing and annotations (release 2.0), 153 candidate genes were predicted to embed in the Nle2.2 region, of which 12 important flowering related genes were obtained. The InDel/SSR-based interspecific genetic map, QTLs and candidate genes obtained by the present study will be useful for the downstream isolation of flowering time-related gene and other genetic applications for pepper.

El diseño final del espectrógrafo de banco (EBASIM) para CASLEO

NASA Astrophysics Data System (ADS)

Simmons, J.; Levato, H.

Utilizando el código de óptica ACCOS V se ha finalizado el diseño del espectrógrafo de banco para CASLEO. En una comunicación anterior habíamos indicado que utilizaríamos un colimador de 150 mm de diámetro con un radio de curvatura de 1540 mm. Para el espejo cámara, que tiene un diámetro de 200 mm, el radio de curvatura es de 1200 mm, ambos radios con una tolerancia no mayor a los 3 mm. En la presente, se informa sobre los detalles finales del cálculo del espectrógrafo que incluye el cómputo para 5 longitudes de onda diferentes y alrededor de 100 rayos. En todos los casos el 75 % de energía está dentro de un diámetro de 13 micrones. El diseño ha sido probado entre 3500 Å hasta 9000 Å con resultados satisfactorios.

Nitrogen and 15N in the Mer Bleue peatland

NASA Astrophysics Data System (ADS)

Moore, Tim

2017-04-01

Although much of our attention in peatlands has focussed on carbon, as CO2, CH4 and DOC processing and fluxes, N plays an important role in the functioning of these ecosystems. Here, I present information on the distribution of N and 15N in plant and peat tissues and relate them to the cycling of N. N concentration in foliar tissues, ranged from 0.67 to 1.3% in evergreen shrubs and trees and mosses with little seasonal variation, and with a strong seasonal variation from 0.5 to 3.5% in the deciduous forbs, shrubs and trees, with a strong overall relationship to [chlorophyll]. Although the proportion of shrubs and mosses varied with microtopography the spatial foliar mass of N varied little with water table position, resulting in minor spatial variations in photosynthetic potential. Decomposition of plant tissues through litter to peat resulted in a decrease in the C:N ratio from about 50:1 to about 30:1 at the base of the profile, representing peat about 8000 yr old. This marginally larger loss of N through decomposition (mainly as TDN, 0.4 g N m-2 yr-1) compared to C produced a long-term N accumulation rate of 0.9 g N m-2 yr-1, being smaller in the bog phase, 0.6 N m-2 yr-1, and over past 150 yr, 0.8 g N m-2 yr-1. Although N is 'hard won' through N2 fixation, northern peatlands are significant global sinks of N and have limited N availability. del15N in foliar tissues ranged from -4 to -9 ‰ in evergreen and deciduous shrubs and trees, from -4 to -5 ‰ in mosses and from -1 to +1 ‰ in sedges and forbs. This appears to be a function of the mycorhizzal infection of the shrubs and trees, compared to sedges and forbs and the values for mosses may partially reflect the signature of atmospheric N deposition. There was no strong correlation between foliar [N] and del15N. In peat profiles from bog and fen sections of Mer Bleue, del15N values in peat fell from -5 to -2 ‰ in the top 10 cm to values of -1 to +1 ‰ at a depth of 40 cm and remained close to 0 ‰ below this. In 30-cm thick beaver pond sediments, the del15N values remained between 0 and +2 ‰. A number of processes may account for the increase in the del15N with depth in the peat profile: more rapid decomposition of tissues with larger del15N values than the slowly decomposing mosses; fractionation of N during decomposition, leaving the heavier 15N enriched in the peat; fractionation during denitrification (though denitrification potentials and emissions are small). An intriguing possibility is that methane oxidation at and just above the water table would lead to an increase in del15N, assuming the fixed N2 has a del15N close to 0.

Estimation and Mapping of Clouds and Rainfall Areas with an Interactive Computer.

DTIC Science & Technology

1982-12-01

test. C . TEST PROCEDURES The following lis1t is the set of procedures for this test of the SPADS Cloud Model. The steps taken were to: 1. Capture...12, 1640-1648. 121 0 APPENDIX4 SPADS CLOUD MlDEL COMPUTER PROGrRArt C CLOY) -IS DRIVER/IMAIN PROGRAIM C T41S PROC.RAM ANALYZES VIS AND IR. TOGETHEI TO...NITH AN INTERACTIVE COMPUTER(U) NAYAL POSTGRADUATE SCHOOL MONTEREY CA C A NELSON DEC 92 UNLSSIFIED F/G 9/2 NUC MENOMONE NONI smhhhhhhhhohh

A founder mutation in COL4A3 causes autosomal recessive Alport syndrome in the Ashkenazi Jewish population.

PubMed

Webb, B D; Brandt, T; Liu, L; Jalas, C; Liao, J; Fedick, A; Linderman, M D; Diaz, G A; Kornreich, R; Trachtman, H; Mehta, L; Edelmann, L

2014-08-01

Alport syndrome is an inherited progressive nephropathy arising from mutations in the type IV collagen genes, COL4A3, COL4A4, and COL4A5. Symptoms also include sensorineural hearing loss and ocular lesions. We determined the molecular basis of Alport syndrome in a non-consanguineous Ashkenazi Jewish family with multiple affected females using linkage analysis and next generation sequencing. We identified a homozygous COL4A3 mutation, c.40_63del, in affected individuals with mutant alleles inherited from each parent on partially conserved haplotypes. Large-scale population screening of 2017 unrelated Ashkenazi Jewish samples revealed a carrier frequency of 1 in 183 indicating that COL4A3 c.40_63del is a founder mutation which may be a common cause of Alport syndrome in this population. Additionally, we determined that heterozygous mutation carriers in this family do not meet criteria for a diagnosis of Thin Basement Membrane Nephropathy and concluded that carriers of c.40_63del are not likely to develop benign familial hematuria. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

ASSOCIATIONS BETWEEN UNCOUPLING PROTEIN 2, BODY COMPOSITION, AND RESTING ENERGY EXPENDITURE IN LEAN AND OBESE AFRICAN AMERICAN, CAUCASIAN, AND ASIAN CHILDREN

PubMed Central

Yanovski, J.A.; Diament, A.L.; Sovik, K.N.; Nguyen, T.T.; Li, H.; Sebring, N.G.; Warden, C.H.

2015-01-01

Background Little is known about genes affecting childhood body weight. Objective To examine alleles of the mitochondrial uncoupling protein-2 (UCP2) gene for association with obesity, since UCP2 may influence energy expenditure. Design We related UCP2 genotype to body composition, and to resting energy expenditure, in 105 children aged 6–10y. Overweight children and non-overweight children of overweight parents were genotyped for a 45 bp deletion/insertion (del/ins) in 3’ UTR of exon 8 and for an exon 4 C to T transition. Results 89 children were genotyped for the exon 8 allele: 50 children had del/del, 33 del/ins, and 6 ins/ins. Body mass index (BMI) was greater for del/ins (24.1 ± 5.9 kg/m2) than for del/del (20.4 ± 4.8 kg/m2, p<0.001). BMI of ins/ins (23.7 ± 7.8 kg/m2) was not different from del/ins. This effect was independent of race and gender (ANOVAs, p< 0.05). Body composition was also different according to UCP2 genotype. All body circumferences and skin fold thicknesses examined were significantly greater in del/ins than in del/del. DXA body fat mass (p<0.005) was also greater in del/ins than del/del. For 104 children genotyped at exon 4, no significant differences in BMI or body composition were found among the three exon 4 genotypes. Neither resting energy expenditure nor respiratory quotient were different according to UCP2 exon 4 or exon 8 genotype. Conclusion The exon 8 ins/del polymorphism of UCP2 appears to be associated with childhood-onset obesity. The UCP2/UCP3 genetic locus may play a role in childhood body weight. PMID:10837279

The novel complex allele [A238V;F508del] of the CFTR gene: clinical phenotype and possible implications for cystic fibrosis etiological therapies.

PubMed

Diana, Anna; Polizzi, Angela Maria; Santostasi, Teresa; Ratclif, Luigi; Pantaleo, Maria Giuseppina; Leonetti, Giuseppina; Iusco, Danila Rosa; Gallo, Crescenzio; Conese, Massimo; Manca, Antonio

2016-06-01

Few mutations in cis have been annotated for F508del homozygous patients. Southern Italy patients who at a first analysis appeared homozygous for the F508del mutation (n=63) or compound heterozygous for the F508del and another mutation in the cystic fibrosis transmembrane conductance regulator gene (n=155) were searched for the A238V mutation in exon 6. The allelic frequency of the complex allele [A238V;F508del] was 0.04. When the whole data set was used (comprised also of 56 F508del/F508del and 34 F508del/other mutation controls), no differences reached the statistical significance in the clinical parameters, except chloride concentrations which were lower in [A238V;F508del]/other mutation compared with F508del/other mutation (P=0.03). The two study groups presented less complications than the control groups. Within the minimal data set (34 F508del/F508del, 27 F508del/other mutation, 4 [A238V;F508del]/F508del cases and 5 [A238V;F508del]/other mutation cases); that is, presenting all the variables in each patient, forced expiratory volume in 1 s and forced vital capacity presented a trend to lower levels in the study groups in comparison with the F508del/F508del group, and C-reactive protein approximated statistically significant higher levels in the [A238V;F508del]/other mutation as compared with F508del/F508del patients (P=0.09). The analysis of statistical dependence among the variables showed a significant anticorrelation between chloride and body mass index in the [A238V;F508del]/other mutation group. In conclusion, the complex allele [A238V;F508del] seems to be associated with less general complications than in the control groups, on the other hand possibly giving a worse pulmonary phenotype and higher systemic/local inflammatory response. These findings have implications for the correct recruitment and clinical response of F508del patients in the clinical trials testing the new etiological drugs for cystic fibrosis.

Estudio fotométrico de estrellas tardías de alta luminosidad en 23 cúmulos abiertos

NASA Astrophysics Data System (ADS)

Clariá, J. J.; Piatti, A. E.; Osborn, W.

Se presentan resultados obtenidos en los Observatorios de Cerro Tololo, Kitt Peak, Lowell y Las Campanas, a partir de fotometría UBV y DDO de 54 estrellas tardías de alta luminosidad en 23 cúmulos abiertos. La aplicación de dos criterios fotométricos independientes permite asignar a cada estrella probabilidades de pertenencia a cada agregado. Se encuentra que 32 estrellas son muy probablemente miembros de los cúmulos, mientras que las restantes son objetos del campo. En todos los casos se determinan excesos de color E(B-V) a través de procedimientos fotométricos y espectroscópicos tradicionales. Recientes calibraciones del sistema DDO permiten, además, derivar tipos espectrales MK, temperaturas efectivas, y abundancias superficiales de la muestra examinada. Las metalicidades DDO derivadas se distribuyen entre valores típicos de cúmulos moderadamente pobres en metales ([Fe/H]~=-0.3) y moderadamente ricos ([Fe/H]~=0.2), en tanto que las masas calculadas para las gigantes rojas oscilan entre 1 y 4 masas solares, con una dispersión dentro de cada cúmulo menor que 1 Msolar.

ARSENICALS INHIBIT THIOREDOXIN REDUCTASE ACTIVITY IN CULTURED RAT HEPATOCYTES

EPA Science Inventory

ARSENICALS INHIBIT THIOREDOXIN REDUCTASE ACTIVITY IN CULTURED RAT HEPATOCYTES.

S. Lin1, L. M. Del Razo1, M. Styblo1, C. Wang2, W. R. Cullen2, and D.J. Thomas3. 1Univ. North Carolina, Chapel Hill, NC; 2Univ. British Columbia, Vancouver, BC, Canada; 3National Health and En...

Estimating KC-137 Aircraft Ownership Costs in the Brazilian Air Force

DTIC Science & Technology

1997-06-01

Cycle Costing A-1 M manpower m meter Maint. Maintenance Mainten. Maintenance O&S Operation and Support OPAC Online Public Access Catalog PAMAGL Parque ...1.2 e 1.3. ))as informag6es quanto a pagarnento dar~o urn pouco de trabaiho, mas creio que podern ser conseguidas na tesouraria do Parque . N~o basta...pela Base na manutengo das aeronaves (e que n~o sejam fornecidos pelo Parque ), tais como gaxetas, componentes eletr6nicos, brocas, produtos qufmicos, etc

Constitutional del(19)(q12q13.1) in a three-year-old girl with severe phenotypic abnormalities affecting multiple organ systems.

PubMed

Kulharya, A S; Michaelis, R C; Norris, K S; Taylor, H A; Garcia-Heras, J

1998-06-05

We present the clinical, cytogenetic, and molecular studies on a constitutional deletion of 19q ascertained prenatally due to decreased fetal activity and IUGR. Chromosome analysis by GTG banding on amniocytes suggested a del(19)(q13.1q13.3), but the analysis of microsatellites by PCR demonstrated that the deletion involved the distal segment of q12 and the proximal segment of q13.1 (15 cM). The severely affected female infant born at 38 weeks has clinical findings that may be related to haploinsufficiency of specific genes within 19q12.1-->q13.1 that control important processes of normal development and cell function.

Precessão do jato de 3C120: simulações hidrodinâmicas 3D

NASA Astrophysics Data System (ADS)

Caproni, A.; de Gouveia dal Pino, E. M.; Abraham, Z.; Raga, A. C.

2003-08-01

Observações com técnicas de interferometria com longa linha de base têm mostrado a existência de um jato relativístico com componentes superluminais na região central de 3C 120. Estas componentes são ejetadas em distintas direções no plano do céu e com diferentes velocidades aparentes. Estas características foram interpretadas em trabalhos anteriores como efeitos da precessão do jato relativístico. Neste trabalho, realizamos simulações tri-dimensionais do jato de 3C 120 utilizando os parâmetros de precessão determinados em trabalhos anteriores e variando as características iniciais do jato e meio ambiente, tais como densidade numérica e temperatura. Todas as simulações foram feitas com o código hidrodinâmico YGUAZÚ-A, assumindo-se um jato adiabático descrito por uma equação de estado relativística. Pelo fato de estarmos utilizando um código hidrodinâmico, nós assumimos que a intensidade do campo magnético e a distribuição de partículas, necessários para se calcular a emissão sincrotron, são proporcionais à pressão hidrodinâmica. Comparação entre dois cenários distintos, nos quais o material do jato é ejetado com velocidade constante (jato contínuo) e com velocidade modulada por um padrão sinusoidal no tempo (jato intermitente), é apresentada e discutida. Para jatos que apresentam fenômenos de precessão e intermitência, com amplitude de variação na velocidade de injeção maior que dez por cento da velocidade média de injeção, a hipótese balística, controlada pela intermitencia, é mais provável. Por outro lado, para jatos com precessão mas sem intermitência (ou com amplitude de variabilidade em velocidade mais baixa que no caso anterior), o efeito da precessão na morfologia do jato não é desprezível. Portanto, de um modo geral, ambos efeitos (precessão e movimentos balísticos) devem estar concorrendo para afetar a morfologia dos jatos superluminais.

CH-47C Vulnerability Reduction Modification Program - Fly-by-Wire Backup Demonstration

DTIC Science & Technology

1976-08-01

Actuator Position for Combined Axis Input ............................. 91 4 Systems Assessment Summary................... 95 C-1 Instrumentation Parameters ...SERVO CARD jEETO FROM MIXERS SUfEV __________ HYLIC AMPL AMPLVLE SHUT-O- DOWN DC PWR LOGIC REA MIONITOR SUMMER *O:EO SWITCH- BUFFER OVER 1 NETWORK...and ranels (Figures 12 and 13). The existing DELS preflight test set, which provides access to the system parameters , was installed along with the

Novel mutations in CRB1 gene identified in a chinese pedigree with retinitis pigmentosa by targeted capture and next generation sequencing

PubMed Central

Lo, David; Weng, Jingning; Liu, xiaohong; Yang, Juhua; He, Fen; Wang, Yun; Liu, Xuyang

2016-01-01

PURPOSE To detect the disease-causing gene in a Chinese pedigree with autosomal-recessive retinitis pigmentosa (ARRP). METHODS All subjects in this family underwent a complete ophthalmic examination. Targeted-capture next generation sequencing (NGS) was performed on the proband to detect variants. All variants were verified in the remaining family members by PCR amplification and Sanger sequencing. RESULTS All the affected subjects in this pedigree were diagnosed with retinitis pigmentosa (RP). The compound heterozygous c.138delA (p.Asp47IlefsX24) and c.1841G>T (p.Gly614Val) mutations in the Crumbs homolog 1 (CRB1) gene were identified in all the affected patients but not in the unaffected individuals in this family. These mutations were inherited from their parents, respectively. CONCLUSION The novel compound heterozygous mutations in CRB1 were identified in a Chinese pedigree with ARRP using targeted-capture next generation sequencing. After evaluating the significant heredity and impaired protein function, the compound heterozygous c.138delA (p.Asp47IlefsX24) and c.1841G>T (p.Gly614Val) mutations are the causal genes of early onset ARRP in this pedigree. To the best of our knowledge, there is no previous report regarding the compound mutations. PMID:27806333

PubMed

Torrado, Julio; Piazuelo, María Blanca; Ruiz, Irune; Izarzugaza, María Isabel; Camargo, María Constanza; Delgado, Alberto; Abdirad, Afshin; Correa, Pelayo

2010-01-01

ANTECEDENTES: El esófago de Barrett es una reconocida lesión precursora de adenocarcinoma esofágico. Aunque generalmente asociada al reflujo gastroesofágico, los mecanismos patogénicos de la enfermedad no son bien conocidos. El objetivo del presente estudio es explorar la historia natural e identificar marcadores de progreso del proceso precanceroso. MATERIAL Y M#ENTITYSTARTX000E9;TODOS: Se utilizaron cortes histológicos de 67 especímenes de esófago correspondientes a 14 pacientes con esófago de Barrett, a los que se siguió entre 1 - 9 años. Se clasificaron las lesiones en: esófago de Barrett sin displasia, indefinido para displasia o con displasia. Se evaluó la expresión de diferentes mucinas en las células caliciformes y en las columnares usando técnicas de histoquímica e inmunohistoquímica. RESULTADOS: En todos los casos se comprobó la presencia de metaplasia intestinal incompleta. Las células columnares dentro del epitelio metaplásico contenían mucinas neutras. A mayor severidad de la lesión se encontró significativamente menor expresión de sialomucinas en las células columnares (p de tendencia igual a 0,03). En sujetos con lesiones indefinidas para displasia se observó un mayor contenido de sulfomucinas en las células caliciformes (p=0,034) y de MUC2 en las células columnares (p=0,029) que en sujetos con esófago de Barrett sin displasia. Se observó expresión de la mucina intestinal MUC2 y de la mucina gástrica MUC5AC en todas las muestras. MUC6, una mucina de las glándulas profundas gástricas, se presentó ocasionalmente. CONCLUSI#ENTITYSTARTX000F3;N: La evaluación de los perfiles de mucinas en el esófago de Barrett sugiere una transición gradual del fenotipo del epitelio metaplásico a medida que la lesión avanza en el tiempo.

El fenotipo de las mucinas en el esófago de Barrett

PubMed Central

Torrado, Julio; Piazuelo, María Blanca; Ruiz, Irune; Izarzugaza, María Isabel; Camargo, María Constanza; Delgado, Alberto; Abdirad, Afshin; Correa, Pelayo

2011-01-01

Antecedentes El esófago de Barrett es una reconocida lesión precursora de adenocarcinoma esofágico. Aunque generalmente asociada al reflujo gastroesofágico, los mecanismos patogénicos de la enfermedad no son bien conocidos. El objetivo del presente estudio es explorar la historia natural e identificar marcadores de progreso del proceso precanceroso. Material y métodos Se utilizaron cortes histológicos de 67 especímenes de esófago correspondientes a 14 pacientes con esófago de Barrett, a los que se siguió entre 1 – 9 años. Se clasificaron las lesiones en: esófago de Barrett sin displasia, indefinido para displasia o con displasia. Se evaluó la expresión de diferentes mucinas en las células caliciformes y en las columnares usando técnicas de histoquímica e inmunohistoquímica. Resultados En todos los casos se comprobó la presencia de metaplasia intestinal incompleta. Las células columnares dentro del epitelio metaplásico contenían mucinas neutras. A mayor severidad de la lesión se encontró significativamente menor expresión de sialomucinas en las células columnares (p de tendencia igual a 0,03). En sujetos con lesiones indefinidas para displasia se observó un mayor contenido de sulfomucinas en las células caliciformes (p=0,034) y de MUC2 en las células columnares (p=0,029) que en sujetos con esófago de Barrett sin displasia. Se observó expresión de la mucina intestinal MUC2 y de la mucina gástrica MUC5AC en todas las muestras. MUC6, una mucina de las glándulas profundas gástricas, se presentó ocasionalmente. Conclusión La evaluación de los perfiles de mucinas en el esófago de Barrett sugiere una transición gradual del fenotipo del epitelio metaplásico a medida que la lesión avanza en el tiempo. PMID:21804831

Association between a promoter dopamine D2 receptor gene variant and the personality trait detachment.

PubMed

Jönsson, Erik G; Cichon, Sven; Gustavsson, J Petter; Grünhage, Frank; Forslund, Kaj; Mattila-Evenden, Marja; Rylander, Gunnar; Asberg, Marie; Farde, Lars; Propping, Peter; Nöthen, Markus M

2003-04-01

Personality traits have shown considerable heritable components. Striatal dopamine D(2) receptor density, as determined by positron-emission tomography, has been associated with detached personality, as assessed by the Karolinska Scales of Personality. A putative functional promoter polymorphism in the dopamine D(2) receptor gene (DRD2), -141C ins/del, has been associated with dopamine D(2) receptor density. In this study healthy subjects (n = 235) who filled in at least one of several personality questionnaires (Karolinska Scales of Personality, Swedish Universities Scales of Personality, Health-relevant Five-factor Personality Inventory, and Temperament and Character Inventory) were analyzed with regard to the DRD2 -141C ins/del variant. There was an association (p =.001) between the DRD2 -141C ins/del variant and Karolinska Scales of Personality Detachment scale, indicating higher scores in subjects with the -141C del variant. There were also associations between the DRD2 -141C ins/del variant and a number of Karolinska Scales of Personality and Swedish Universities Scales of Personality Neuroticism-related scales, but of these only Swedish Universities Scales of Personality Lack of Assertiveness scale (p =.001) survived correction for multiple testing. These results add further support for the involvement of dopamine D(2) receptor in certain personality traits. The results should be treated with caution until replicated.

NYX mutations in four families with high myopia with or without CSNB1

PubMed Central

Zhou, Lin; Song, Xiusheng; Li, Yin; Li, Hongyan; Dan, Handong

2015-01-01

Purpose Mutations in the NYX gene are known to cause complete congenital stationary night blindness (CSNB1), which is always accompanied by high myopia. In this study, we aimed to investigate the association between NYX mutations and high myopia with or without CSNB1. Methods Four Chinese families having high myopia with or without CSNB1 and 96 normal controls were recruited. We searched for mutations in the NYX gene using Sanger sequencing. Further analyses of the detected variations in the available family members were performed, and the frequencies of the detected variations in 96 normal controls were determined to verify our deduction. The effect of each variation on the nyctalopin protein was predicted using online tools. Results Four potential pathogenic variations in the NYX gene were found in four families with high myopia with or without CSNB1. Three of the four variants were novel (c.626G>C; c.121delG; c.335T>C). The previously identified variant, c.529_530delGCinsAT, was found in an isolated highly myopic patient and an affected brother, but the other affected brother did not carry the same variation. Further linkage analyses of this family showed a coinheritance of markers at MYP1. These four mutations were not identified in the 96 normal controls. Conclusions Our study expands the mutation spectrum of NYX for cases of high myopia with CSNB1; however, more evidence is needed to elucidate the pathogenic effects of NYX on isolated high myopia. PMID:25802485

A case report: a heterozygous deletion (2791_2805 del) in exon 18 of the filamin C gene causing filamin C-related myofibrillar myopathies in a Chinese family.

PubMed

Miao, Jing; Su, Fei-Fei; Liu, Xue-Mei; Wei, Xiao-Jing; Yuan, Yun; Yu, Xue-Fan

2018-06-04

Filamin C-related myofibrillar myopathies (MFM) are progressive skeletal myopathies with an autosomal dominant inheritance pattern. The conditions are caused by mutations of the filamin C gene (FLNC) located in the chromosome 7q32-q35 region. Genetic variations in the FLNC gene result in various clinical phenotypes. We describe a 43-year-old woman who suffered filamin C-related MFM, with symptoms first presenting in the proximal muscles of the lower limbs and eventually spreading to the upper limbs and distal muscles. The patient's serum level of creatine kinase was mildly increased. Mildy myopathic changes in the electromyographic exam and moderate lipomatous alterations in lower limb MRI were found. Histopathological examination revealed increased muscle fiber size variability, disturbances in oxidative enzyme activity, and the presence of abnormal protein aggregates and vacuoles in some muscle fibers. Ultrastructural analysis showed inclusions composed of thin filaments and interspersed granular densities. DNA sequencing analysis detected a novel 15-nucleotide deletion (c.2791_2805del, p.931_935del) in the FLNC gene. The patient's father, sister, brother, three paternal aunts, one paternal uncle, and the uncle's son also had slowly progressive muscle weakness, and thus, we detected an autosomal dominant inheritance pattern of the disorder. A novel heterogeneous 15-nucleotide deletion (c.2791_2805del, p.931_935del) in the Ig-like domain 7 of the FLNC gene was found to cause filamin C-related MFM. This deletion in the FLNC gene causes protein aggregation, abnormalities in muscle structure, and impairment in muscle fiber function, which leads to muscle weakness.

2. Historic American Buildings Survey, Frederik C. Gjessing, Photographer January, ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

2. Historic American Buildings Survey, Frederik C. Gjessing, Photographer January, 1956 ELEVATION OF CHAPEL AND SALLY PORT TOWARDS THE COURTYARD PLAZA DE ARMAS, SAN FELIPE DEL MORRO. - Castillo de San Felipe del Morro Sally Port & Chapel, Northwest end of San Juan Island, San Juan, San Juan Municipio, PR

The 14 bp Del/Ins HLA-G polymorphism is related with high blood pressure in acute coronary syndrome and type 2 diabetes mellitus.

PubMed

García-González, Ilian Janet; Valle, Yeminia; Rivas, Fernando; Figuera-Villanueva, Luis Eduardo; Muñoz-Valle, José Francisco; Flores-Salinas, Hector Enrique; Gutiérrez-Amavizca, Bianca Ethel; Dávalos-Rodríguez, Nory Omayra; Padilla-Gutiérrez, Jorge Ramón

2014-01-01

Immunologic and inflammatory processes are involved in the pathogenesis of acute coronary syndrome (ACS) and type 2 diabetes mellitus (DM2). Human leukocyte antigen-G (HLA-G) is a negative regulator of the immune response. This study evaluates the 14 bp Del/Ins HLA-G polymorphism in ACS and DM2. Three hundred and seventy individuals from Western Mexico were recruited and categorized into three groups: ACS (86), DM2 without coronary complications (70), and healthy subjects (214). Genotyping of the 14 bp Del/Ins HLA-G polymorphism was performed by PCR and Native-PAGE. The most common risk factors were hypertension and overweight in ACS and DM2, respectively. The genetic distribution of the 14 bp Del/Ins HLA-G polymorphism showed no significant differences between groups (P ≥ 0.23). Nonetheless, the Ins/Ins genotype was associated with high blood pressure (HBP) in the DM2 group (OR(c) = 1.65, P = 0.02). The genetic recessive model showed similar findings (OR(c) = 3.03, P = 0.04). No association was found in ACS, with a P of 0.05; nevertheless, the prevalence of Ins/Ins carriers was quite similar to that found in the DM2-HBP group. The 14 bp Del/Ins HLA-G polymorphism was not a susceptibility factor for ACS or DM2; however, the Ins/Ins genotype might have contributed to the development of HBP in the studied groups.

BEST1 sequence variants in Italian patients with vitelliform macular dystrophy

PubMed Central

Sodi, Andrea; Passerini, Ilaria; Caputo, Roberto; Bacci, Giacomo Maria; Bodoj, Mirela; Torricelli, Francesca; Menchini, Ugo

2012-01-01

Purpose To analyze the spectrum of sequence variants in the BEST1 gene in a group of Italian patients affected by Best vitelliform macular dystrophy (VMD). Methods Thirty Italian patients with a diagnosis of VMD and 20 clinically healthy relatives were recruited. They belonged to 19 Italian families predominantly originating from central Italy. They received a standard ophthalmologic examination, OCT scan, and electrophysiological tests (ERG and EOG). Fluorescein and ICG angiographies and fundus autofluorescence imaging were performed in selected cases. DNA samples were analyzed for sequence variants of the BEST1 gene by direct sequencing techniques. Results Nine missense variants and one deletion were found in the affected patients; each patient carried one mutation. Five variants [c.73C>T (p.Arg25Trp), c.652C>T (p.Arg218Cys), c.652C>G (p.Arg218Gly), c.728C>T (p.Ala243Val), c.893T>C (p.Phe298Ser)] have already been described in literature while another five variants [c.217A>C (p.Ile73Leu), c.239T>G (p.Phe80Cys), c.883_885del (p.Ile295del), c.907G>A (p.Asp303Asn), c.911A>G (p.Asp304Gly)] had not previously been reported. Affected patients, sometimes even from the same family, occasionally showed variable phenotypes. One heterozygous variant was also found in five clinically healthy relatives with normal fundus, visual acuity and ERG but with abnormal EOG. Conclusions Ten variants in the BEST1 gene were detected in a group of individuals with clinically apparent VMD, and in some clinically normal individuals with an abnormal EOG. The high prevalence of novel variants and the frequent report of a specific variant (p.Arg25Trp) that has rarely been described in other ethnic groups suggests a distribution of BEST1 variants peculiar to Italian VMD patients. PMID:23213274

Rare Compound Heterozygous Frameshift Mutations in ALMS1 Gene Identified Through Exome Sequencing in a Taiwanese Patient With Alström Syndrome.

PubMed

Tsai, Meng-Che; Yu, Hui-Wen; Liu, Tsunglin; Chou, Yen-Yin; Chiou, Yuan-Yow; Chen, Peng-Chieh

2018-01-01

Alström syndrome (AS) is a rare autosomal recessive disorder that shares clinical features with other ciliopathy-related diseases. Genetic mutation analysis is often required in making differential diagnosis but usually costly in time and effort using conventional Sanger sequencing. Herein we describe a Taiwanese patient presenting cone-rod dystrophy and early-onset obesity that progressed to diabetes mellitus with marked insulin resistance during adolescence. Whole exome sequencing of the patient's genomic DNA identified a novel frameshift mutation in exons 15 (c.10290_10291delTA, p.Lys3431Serfs * 10) and a rare mutation in 16 (c.10823_10824delAG, p.Arg3609Alafs * 6) of ALMS1 gene. The compound heterozygous mutations were predicted to render truncated proteins. This report highlighted the clinical utility of exome sequencing and extended the knowledge of mutation spectrum in AS patients.

A novel missense mutation p.L76P in the GJB2 gene causing nonsyndromic recessive deafness in a Brazilian family.

PubMed

Batissoco, A C; Auricchio, M T B M; Kimura, L; Tabith-Junior, A; Mingroni-Netto, R C

2009-02-01

Mutations in the GJB2 gene, encoding connexin 26 (Cx26), are a major cause of nonsyndromic recessive hearing loss in many countries. We report here on a novel point mutation in GJB2, p.L76P (c.227C>T), in compound heterozygosity with a c.35delG mutation, in two Brazilian sibs, one presenting mild and the other profound nonsyndromic neurosensorial hearing impairment. Their father, who carried a wild-type allele and a p.L76P mutation, had normal hearing. The mutation leads to the substitution of leucine (L) by proline (P) at residue 76, an evolutionarily conserved position in Cx26 as well as in other connexins. This mutation is predicted to affect the first extracellular domain (EC1) or the second transmembrane domain (TM2). EC1 is important for connexon-connexon interaction and for the control of channel voltage gating. The segregation of the c.227C>T (p.L76P) mutation together with c.35delG in this family indicates a recessive mode of inheritance. The association between the p.L76P mutation and hearing impairment is further supported by its absence in a normal hearing control group of 100 individuals, 50 European-Brazilians and 50 African-Brazilians.

Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome.

PubMed

Ekvall, Sara; Sjörs, Kerstin; Jonzon, Anders; Vihinen, Mauno; Annerén, Göran; Bondeson, Marie-Louise

2014-03-01

Neurofibromatosis-Noonan syndrome (NFNS) is a rare condition with clinical features of both neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). All three syndromes belong to the RASopathies, which are caused by dysregulation of the RAS-MAPK pathway. The major gene involved in NFNS is NF1, but co-occurring NF1 and PTPN11 mutations in NFNS have been reported. Knowledge about possible involvement of additional RASopathy-associated genes in NFNS is, however, very limited. We present a comprehensive clinical and molecular analysis of eight affected individuals from three unrelated families displaying features of NF1 and NFNS. The genetic etiology of the clinical phenotypes was investigated by mutation analysis, including NF1, PTPN11, SOS1, KRAS, NRAS, BRAF, RAF1, SHOC2, SPRED1, MAP2K1, MAP2K2, and CBL. All three families harbored a heterozygous NF1 variant, where the first family had a missense variant, c.5425C>T;p.R1809C, the second family a recurrent 4bp-deletion, c.6789_6792delTTAC;p.Y2264Tfs*6, and the third family a splice-site variant, c.2991-1G>A, resulting in skipping of exon 18 and an in-frame deletion of 41 amino acids. These NF1 variants have all previously been reported in NF1 patients. Surprisingly, both c.6789_6792delTTAC and c.2991-1G>A are frequently associated with NF1, but association to NFNS has, to our knowledge, not previously been reported. Our results support the notion that NFNS represents a variant of NF1, genetically distinct from NS, and is caused by mutations in NF1, some of which also cause classical NF1. Due to phenotypic overlap between NFNS and NS, we propose screening for NF1 mutations in NS patients, preferentially when café-au-lait spots are present. © 2013 Wiley Periodicals, Inc.

Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome.

PubMed

Blackburn, Patrick R; Xu, Zhi; Tumelty, Kathleen E; Zhao, Rose W; Monis, William J; Harris, Kimberly G; Gass, Jennifer M; Cousin, Margot A; Boczek, Nicole J; Mitkov, Mario V; Cappel, Mark A; Francomano, Clair A; Parisi, Joseph E; Klee, Eric W; Faqeih, Eissa; Alkuraya, Fowzan S; Layne, Matthew D; McDonnell, Nazli B; Atwal, Paldeep S

2018-04-05

AEBP1 encodes the aortic carboxypeptidase-like protein (ACLP) that associates with collagens in the extracellular matrix (ECM) and has several roles in development, tissue repair, and fibrosis. ACLP is expressed in bone, the vasculature, and dermal tissues and is involved in fibroblast proliferation and mesenchymal stem cell differentiation into collagen-producing cells. Aebp1 -/- mice have abnormal, delayed wound repair correlating with defects in fibroblast proliferation. In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers-Danlos syndrome (EDS). Analysis of skin biopsies revealed decreased dermal collagen with abnormal collagen fibrils that were ragged in appearance. Exome sequencing revealed compound heterozygous variants in AEBP1 (c.1470delC [p.Asn490_Met495delins(40)] and c.1743C>A [p.Cys581 ∗ ]) in the first individual, a homozygous variant (c.1320_1326del [p.Arg440Serfs ∗ 3]) in the second individual, and a homozygous splice site variant (c.1630+1G>A) in two siblings from the third family. We show that ACLP enhances collagen polymerization and binds to several fibrillar collagens via its discoidin domain. These studies support the conclusion that bi-allelic pathogenic variants in AEBP1 are the cause of this autosomal-recessive EDS subtype. Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Nitrogen cycling in ombrotrophic peat bogs in the Czech Republic: Is microbial N-fixation occurring at atmospheric depositions of reactive N higher than 10 kg/ha/yr?

NASA Astrophysics Data System (ADS)

Novak, Martin; Jackova, Ivana; Cejkova, Bohuslava; Buzek, Frantisek; Curik, Jan; Stepanova, Marketa; Prechova, Eva; Veselovsky, Frantisek; Komarek, Arnost

2017-04-01

Biogeochemical cycling of carbon (C) and nitrogen (N) in peat bogs are coupled. Whereas at low pollution levels, reactive nitrogen (Nr, mainly nitrate- and ammonium-N) inputs may positively affect C storage, high Nr deposition may have a detrimental effect on C storage. We have previously reported N isotope systematics at two ombrotrophic peat bogs in the Czech Republic, receiving medium levels of Nr of about 10 kg/ha/yr via atmospheric deposition. Nitrogen of living Sphagnum was systematically heavier than N of the atmospheric input (p < 0.001), and close to the N isotope signature of atmospheric N2 (del15N-N2 of 0.0 per mil). We argued that even at medium Nr pollution, such as that in the Czech Republic, the amount of Nr in rainfall becomes minute toward the end of major precipitation events, possible triggering off microbial N-fixation. This process may be responsible for the del15N shift in Sphagnum from negative values of atmospheric deposition to the zero value of N2. In 2016, we conducted a laboratory study in which living Sphagnum from sites receiving annually slightly over 10 kg Nr/ha/yr via atmospheric deposition was incubated in an atmosphere enriched in 15N-N2. At the end of the incubation, we detected a 1 to 3 per mil increase in del15N of Sphagnum. Rinsing Sphagnum capitula in deionized water prior to the 15N-N2 incubation has led to a slight further increase in del15N of Sphagnum. Also in 2016, we monitored del15N of atmospheric deposition at three medium Nr-polluted peat bogs. Open-area precipitation had the following mean del 15N values: Uhlirska -6.1 per mil (NH4) and -6.2 per mil (NO3); Brumiste -1.7 per mil (NH4) and -3.4 per mil (NO3); Male Mechove Jezirko -3.3 per mil (NH4) and -3.9 per mil (NO3). At all sites, atmospheric Nr deposition was made up by NO3-N and NH4-N in a roughly 1.1 ratio. We found that N of winter-time deposition became isotopically extremely light (less than -10.0 per mil). During the growing season, del15N of total atmospheric input was higher, closer to 0.0 per mil, but still slightly lower than del15N of living Sphagnum. These data thus confirm a N isotope discrepancy between the N isotope signature of deposition and Sphagnum. In the paper, we will also discuss a mass balance discrepancy in long-term atmospheric N input and N storage at the Czech sites, determined for replicated, lead-210 dated peat cores. We took into consideration a 30 % contribution of horizontal deposition (mainly fog interception), which we had directly measured, to total Nr deposition. Still, the dated peat cores appeared to accumulate 30 to 60 % more N than the maximum estimated atmospheric Nr input (both estimates for the period 1900-2015). Preliminarily, we conclude that three independent lines of evidence indicate intermittent N-fixation even at medium Nr-polluted peat bogs in Central Europe.

Theoretical Study of Topside Ionospheric Clutter

DTIC Science & Technology

1992-07-15

investigated. 4. References: Foster. J.C.. C. del Pozo. K. Groves, and J.-P. St. Maurice , Radar observations of the onlst of current drivenr instabilities... Clemmons , and F. S. Mozer, High-resolution sounding rocket observations of large-amplitude Alfvin waves, J. Geophys. Res., 95, 12157-12171, 1990. [51 Breit...equilibrium. Can. J. Phys., 38, 1114-1133, 1960. i16] Foster, J. C., C. del Pozo, K. Groves, and J.-P. St. Maurice , Radar observations of the onset of

Nature and Recurrence of AVPR2 Mutations in X-linked Nephrogenic Diabetes Insipidus

PubMed Central

Bichet, Daniel G.; Birnbaumer, Mariel; Lonergan, Michèle; Arthus, Marie-Françoise; Rosenthal, Walter; Goodyer, Paul; Nivet, Hubert; Benoit, Stéphane; Giampietro, Philip; Simonetti, Simonetta; Fish, Alfred; Whitley, Chester B.; Jaeger, Philippe; Gertner, Joseph; New, Maria; DiBona, Francis J.; Kaplan, Bernard S.; Robertson, Gary L.; Hendy, Geoffrey N.; Fujiwara, T. Mary; Morgan, Kenneth

1994-01-01

X-linked nephrogenic diabetes insipidus (NDI) is a rare disease with defective renal and extrarenal arginine-vasopressin V2 receptor responses due to mutations in the AVPR2 gene in Xq28. We analyzed 31 independent NDI families to determine the nature and recurrence of AVPR2 mutations. Twenty-one new putative disease-causing mutations were identified: 113delCT, 253del35, 255del9, 274insG, V88M, R106C, 402delCT, C112R, Y124X, S126F, W164S, S167L, 684delTA, 804insG, W284X, A285P, W293X, R337X, and three large deletions or gene rearrangements. Five other mutations—R113W, Y128S, R137H, R181C, and R202C—that previously had been reported in other families were detected. There was evidence for recurrent mutation for four mutations (R113W, R137H, S167L, and R337X). Eight de novo mutation events were detected (274insG, R106C, Y128S, 167L [twice], R202C, 684delTA, and R337X). The origins were maternal (one), grandmaternal (one), and grandpaternal (six). In the 31 NDI families and 6 families previously reported by us, there is evidence both for mutation hot spots for nucleotide substitutions and for small deletions and insertions. More than half (58%) of the nucleotide substitutions in 26 families could be a consequence of 5-methylcytosine deamination at a CpG dinucleotide. Most of the small deletions and insertions could be attributed to slipped mispairing during DNA replication. PMID:8037205

Estudio de la formación de galaxias espirales en un modelo de agregación jerárquica

NASA Astrophysics Data System (ADS)

Tissera, P.; Saiz, A.; Dominguez-Tenreiro, R.

El estudio de formación de galaxias espirales ha llevado al desarrollo de numerosos modelos teóricos (e.g. White & Rees 1978). En la actualidad, el modelo más aceptado predice la formación de una galaxia espiral a partir del colapso disipativo del gas en el pozo de potencial de un halo oscuro, conservando su momento angular específco (Fall & Efstathiou 1980). En los últimos años, ha sido posible realizar simulaciones numéricas hidrodinámicas, las cuales describen la evolución conjunta de la materia oscura y los bariones. Estos experimentos han señalado la dificultad de formar estructuras discoidales con propiedades consistentes con las observaciones, en modelos de agregación jerárquica. El problema principal se origina en la pérdida catastrófica de momento angular de la componente disipativa, durante el proceso de ensamblaje de los objetos, a través de la fusión de subestructura (Navarro & Steinmetz 1997). Estos experimentos no incluían procesos de formación estelar. En este trabajo, se expondrán resultados de simulaciones hidrodinámicas cosmológicas, incluyendo formación estelar (Tissera et al 1997), donde ha sido posible reproducir objetos discoidales con contrapartida observacional. El elemento fundamental ha sido la formación de bulbos estelares, los cuales han evitado la pérdida catastrófica de momento angular de los bariones. Se encontró que los discos exponenciales puramente gaseosos son altamente inestables y suceptibles de generar barras, responsables de la pérdida de momento angular y la caída violenta del gas hacia la región central. Estas inestabilidades son fácilmente inducidas durante interacciones y fusiones con objetos vecinos (Barnes & Hernquist 1996). Un bulbo estelar (o un objeto masivo y compacto) estabiliza el disco ante perturbaciones externas, asegurándole un potencial simétrico (Sellwood & Moore 1998, Van der Bosch 1998). En este caso, el gas en el disco no pierde completamente su momento angular intrínseco durante las fusiones, sino que, las sobrevive aportando una contribución distinta de cero, a partir de la cual el disco se regenera acretando en una segunda etapa, gas del halo de acuerdo al modelo tradicional de Fall & Efstathiou.

Binarias en cúmulos abiertos: ?`Qué hay de nuevo?

NASA Astrophysics Data System (ADS)

Levato, H.

Las herramientas modernas para detectar duplicidad han jugado un papel fundamental en el resurgimiento del estudio de la binaridad en cúmulos abiertos. El fracaso de las teorías de bifurcación para explicar la formación de estrellas dobles ha puesto en consideración los encuentros de estrellas en cúmulos para formar binarias. Existen muchas pruebas empíricas que pueden realizarse para verificar las creencias actuales. En esta revisión del tema se hace un breve resumen de la historia del problema y se analiza el conocimiento actual. Se proponen las investigaciones y programas que darían lugar a la comprobación de las predicciones que surgen de considerar que las binarias en cúmulos se forman por encuentros.

Sistemas Correctores de Campo Para EL Telescopio Cassegrain IAC80

NASA Astrophysics Data System (ADS)

Galan, M. J.; Cobos, F. J.

1987-05-01

El proyecto de instrumentación de mayor importancia que ha tenido el Instituto de Astrofisica de Canarias en los últimos afios ha sido el diseflo y construcción del te1escopio IAC8O. Este requería del esfuerzo con junto en mec´nica, óptica y electrónica, lo que facilitó la estructuración y el crecimiento de los respectivos grupos de trabajo, que posteriormente se integraron en departamentos En su origen (1977), el telescopio IAC80 fue concebido como un sistema clásico tipo Cassegrain, con una razón focal F/i 1.3 para el sistema Casse grain y una razón focal F/20 para el sistema Coudé. Posteriormente, aunque se mantuvo la filosofia de que el sistema básico fuera el F/11.3, se consideró conveniente el diseño de secundarios para razones focales F/16 y F/32, y se eliminó el de F/20. Sin embargo, dada la importancia relativa que un foco estrictamente fotográfico tiene en un telescopio moderno, diseñado básicamente para fotometría fotoeléctrica y con un campo util mínimamente de 40 minutos de arco, se decídió Ilevar a cabo el diseño de un secundario F/8 con un sistema corrector de campo, pero que estuviera formado únicamente por lentes con superficies esféricas para que asl su construcción fuera posible en España ó en México. La creciente utilización de detectores bidimensionales para fines de investigación astron6mica y la viabilidad de que en un futuro cercano éstos tengan un área sensible cada vez mayor, hicieron atractiva la idea de tener diseñado un sistema corrector de campo para el foco primario (F/3), con un campo útil mínimo de un grado, y también con la limitante de que sus componentes tuvieron sólamente supérficies esféricas. Ambos diseños de los sis-temas correctores de campo se llevaron a cabo, en gran medida, como parte de un proyecto de colaboración e intercambio en el área de diseño y evaluación de sistemas ópticos.

A novel mutation in NDUFS4 causes Leigh syndrome in an Ashkenazi Jewish family.

PubMed

Anderson, S L; Chung, W K; Frezzo, J; Papp, J C; Ekstein, J; DiMauro, S; Rubin, B Y

2008-12-01

Leigh syndrome is a neurodegenerative disorder of infancy or childhood generally due to mutations in nuclear or mitochondrial genes involved in mitochondrial energy metabolism. We performed linkage analysis in an Ashkenazi Jewish (AJ) family without consanguinity with three affected children. Linkage to microsatellite markers D5S1969 and D5S407 led to evaluation of the complex I gene NDUFS4, in which we identified a novel homozygous c.462delA mutation that disrupts the reading frame. The resulting protein lacks a cAMP-dependent protein kinase phosphorylation site required for activation of mitochondrial respiratory chain complex I. In a random sample of 5000 healthy AJ individuals, the carrier frequency of the NDUFS4 mutation c.462delA was 1 in 1000, suggesting that it should be considered in all AJ patients with Leigh syndrome.

Differentiating Alström from Bardet-Biedl syndrome (BBS) using systematic ciliopathy genes sequencing.

PubMed

Aliferis, K; Hellé, S; Gyapay, G; Duchatelet, S; Stoetzel, C; Mandel, J L; Dollfus, H

2012-03-01

Early onset retinal degeneration associated with obesity can present a diagnostic challenge in paediatric ophthalmology practice. Clinical overlap between Bardet-Biedl syndrome (BBS) and Alström syndrome has been described, although the two entities are genetically distinct. To date, 16 genes are known to be associated with BBS (BBS1-16) and only one gene has been identified for Alström syndrome (ALMS1). In collaboration with the French National Center for Sequencing (CNS, Evry), all coding exons and flanking introns were sequenced for 27 ciliopathy genes (BBS1-12, MGC1203, TTC21b, AHI1, NPHP2-8 (NPHP6=BBS14), MKS1(BBS13), MKS3, C2ORF86, SDCCAG8, ALMS1) in 96 patients referred with a clinical diagnosis of BBS. ALMS1 gene analysis included sequencing of all coding exons. BBS known gene mutations were found in 44 patients (36 with two mutations and 8 heterozygous). ALMS1 mutations were found in four cases. The rate of ALMS1 mutations among patients suspected of having BBS was 4.2%. Clinically, all four patients presented early-onset severe retinal degeneration with congenital nystagmus associated with obesity. The difficult early differential diagnosis between the two syndromes is outlined. One mutation had already been reported (c.11310delAGAG/p.R3770fsX) and three were novel (c.2293C > T/p.Q765X, c.6823insA/p.R2275fsX, c.9046delA/p.N3016fsX). Ciliopathy genes sequencing can be very helpful in providing a timely diagnosis in this group of patients, hence appropriate genetic counselling for families and adequate medical follow-up for affected children.

The first case of NSHL by direct impression on EYA1 gene and identification of one novel mutation in MYO7A in the Iranian families.

PubMed

Razmara, Ehsan; Bitarafan, Fatemeh; Esmaeilzadeh-Gharehdaghi, Elika; Almadani, Navid; Garshasbi, Masoud

2018-03-01

Targeted next-generation sequencing (NGS) provides a consequential opportunity to elucidate genetic factors in known diseases, particularly in profoundly heterogeneous disorders such as non-syndromic hearing loss (NSHL). Hearing impairments could be classified into syndromic and non-syndromic types. This study intended to assess the significance of mutations in these genes to the autosomal recessive/dominant non-syndromic genetic load among Iranian families. Two families were involved in this research and two patients were examined by targeted next-generation sequencing. Here we report two novel mutations in the MYO7A and EYA1 genes in two patients detected by targeted NGS. They were confirmed by Sanger sequencing and quantitative real-time PCR techniques. In this investigation, we identified a novel mutation in MYO7A , c.3751G>C, p.A1251P, along with another previously identified mutation (c.1708C>T) in one of the cases. This mutation is located in the MYTH4 protein domain which is a pivotal domain for the myosin function. Another finding in this research was a novel de-novo deletion which deletes the entire EYA1 coding region (EX1-18 DEL). Mutations in EYA1 gene have been found in branchiootorenal (BOR) syndrome. Interestingly the patient with EYA1 deletion did not show any other additional clinical implications apart from HL. This finding might argue for the sole involvement of EYA1 function in the mechanism of hearing. This investigation exhibited that the novel mutations in MYO7A , c.3751G>C, p.A1251P, and EYA1 , EX1-18 DEL, were associated with NSHL. Our research increased the mutation spectrum of hearing loss in the Iranian population.

Mutations in SURF1 are important genetic causes of Leigh syndrome in Slovak patients.

PubMed

Danis, Daniel; Brennerova, Katarina; Skopkova, Martina; Kurdiova, Timea; Ukropec, Jozef; Stanik, Juraj; Kolnikova, Miriam; Gasperikova, Daniela

2018-04-01

Leigh syndrome is a progressive early onset neurodegenerative disease typically presenting with psychomotor regression, signs of brainstem and/or basal ganglia disease, lactic acidosis, and characteristic magnetic resonance imaging findings. At molecular level, deficiency of respiratory complexes and/or pyruvate dehydrogenase complex is usually observed. Nuclear gene SURF1 encodes an assembly factor for cytochrome c-oxidase complex of the respiratory chain and autosomal recessive mutations in SURF1 are one of the most frequent causes of cytochrome c-oxidase-related Leigh syndrome cases. Here, we aimed to elucidate the genetic basis of Leigh syndrome in three Slovak families. Three probands presenting with Leigh syndrome were selected for DNA analysis. The first proband, presenting with atypical LS onset without abnormal basal ganglia magnetic resonance imaging findings, was analyzed with whole exome sequencing. In the two remaining probands, SURF1 was screened by Sanger sequencing. Four different heterozygous mutations were identified in SURF1: c.312_321delinsAT:p.(Pro104Profs*1), c.588+1G>A, c.823_833+7del:p. (?) and c.845_846del:p.(Ser282Cysfs*9). All the mutations are predicted to have a loss-of-function effect. We identified disease-causing mutations in all three probands, which points to the important role of SURF1 gene in etiology of Leigh syndrome in Slovakia. Our data showed that patients with atypical Leigh syndrome phenotype without lesions in basal ganglia may benefit from the whole exome sequencing method. In the case of probands presenting the typical phenotype, Sanger sequencing of the SURF1 gene seems to be an effective method of DNA analysis.

Guia del Proceso del IFSP de Colorado: Conexiones para la Ninez Temprana, Iniciativa Infantil de Colorado Parte C del Acta de Educacion para Individuos con Desabilidades (Colorado Guidelines for the IFSP Process: Early Childhood Connections, Colorado's Infant/Toddler Initiative for Part C of the Individuals with Disabilities Education Act).

ERIC Educational Resources Information Center

Miller, Jerri; Petersen, Sandy

This booklet for Spanish-speaking parents of young children with disabilities describes Colorado's Individualized Family Service Plan (IFSP) process. It explains guidelines, shares family stories and reflections for families and care providers, and the describes the values that drive the IFSP process in Colorado. Information is provided on…

BRCA1 mutations in South African breast and/or ovarian cancer families: evidence of a novel founder mutation in Afrikaner families.

PubMed

Reeves, Michelle D; Yawitch, Tali M; van der Merwe, Nerina C; van den Berg, Hester J; Dreyer, Greta; van Rensburg, Elizabeth J

2004-07-10

Germ-line mutations within BRCA1 are responsible for different proportions of inherited susceptibility to breast/ovarian cancer, and the spectrum of mutations within this gene is often unique to certain populations. At this time, there have been no reports regarding the role of BRCA1 in South African breast and/or ovarian cancer families. We therefore screened 90 South African breast/ovarian cancer families for BRCA1 mutations by means of PCR-based mutation detection assays. Eighteen families (20%) were identified with BRCA1 disease-causing mutations. Four Ashkenazi Jewish families were identified with the 185delAG mutation, whereas 2 Afrikaner and 1 Ashkenazi Jewish family were found to harbor the 5382insC mutation. Five of the families (5.56%), all of whom are Afrikaners, were found to carry the novel E881X mutation. Genotype analyses show that these patients share a common ancestor. Genealogic studies have identified 3 possible founding couples for this mutation, all of whom arrived in the Cape from France in the late 1600s. Of the remaining mutations detected, 3 have not been reported previously and include the S451X, 1493delC (detected twice) and 4957insC mutations. Copyright 2004 Wiley-Liss, Inc.

A novel Norrie disease pseudoglioma gene mutation, c.-1_2delAAT, responsible for Norrie disease in a Chinese family.

PubMed

Zhang, Xin-Yu; Jiang, Wei-Ying; Chen, Lu-Ming; Chen, Su-Qin

2013-01-01

To investigate the genetic findings and phenotypic characteristics of a Chinese family with Norrie disease (ND). Molecular genetic analysis and clinical examinations were performed on a Chinese family with ND. Mutations in the Norrie disease pseudoglioma (NDP) gene were detected by direct sequencing. Haplotypes were constructed and compared with the phenotypes in the family. Evolutionary comparisons and mutant open reading frame (ORF) prediction were also undertaken. Two family members with ocular manifestations were diagnosed with ND. No signs of sensorineural hearing loss were observed in either patient, while one of them showed signs of mild mental retardation. A novel heterozygous mutation in the NDP gene, c.-1_2delAAT, was detected in both patients. The mutation and the mutation bearing haplotype co-segregated with the ND phenotype in males and was transmitted from their mothers and/or grandmothers (II:2). The male without ND did not harbor the mutation. The mutation occurred at the highly conserved nucleotides. ORF finder predicted that the mutation would lead to the production of a truncated protein that lacks the first 11 N-terminal amino acids. A novel mutation, c.-1_2delAAT in the NDP gene, was identified in a Chinese family with ND. This mutation caused ND without obvious sensorineural hearing loss. Mental disorder was found in one but not the other patients. The clinical heterogeneity in the family indicated that other genetic variants and epigenetic factors may also play a role in the disease presentation.

A novel Norrie disease pseudoglioma gene mutation, c.-1_2delAAT, responsible for Norrie disease in a Chinese family

PubMed Central

Zhang, Xin-Yu; Jiang, Wei-Ying; Chen, Lu-Ming; Chen, Su-Qin

2013-01-01

AIM To investigate the genetic findings and phenotypic characteristics of a Chinese family with Norrie disease (ND). METHODS Molecular genetic analysis and clinical examinations were performed on a Chinese family with ND. Mutations in the Norrie disease pseudoglioma (NDP) gene were detected by direct sequencing. Haplotypes were constructed and compared with the phenotypes in the family. Evolutionary comparisons and mutant open reading frame (ORF) prediction were also undertaken. RESULTS Two family members with ocular manifestations were diagnosed with ND. No signs of sensorineural hearing loss were observed in either patient, while one of them showed signs of mild mental retardation. A novel heterozygous mutation in the NDP gene, c.-1_2delAAT, was detected in both patients. The mutation and the mutation bearing haplotype co-segregated with the ND phenotype in males and was transmitted from their mothers and/or grandmothers (II:2). The male without ND did not harbor the mutation. The mutation occurred at the highly conserved nucleotides. ORF finder predicted that the mutation would lead to the production of a truncated protein that lacks the first 11 N-terminal amino acids. CONCLUSION A novel mutation, c.-1_2delAAT in the NDP gene, was identified in a Chinese family with ND. This mutation caused ND without obvious sensorineural hearing loss. Mental disorder was found in one but not the other patients. The clinical heterogeneity in the family indicated that other genetic variants and epigenetic factors may also play a role in the disease presentation. PMID:24392318

Survival and contralateral breast cancer in CHEK2 1100delC breast cancer patients: impact of adjuvant chemotherapy

PubMed Central

Kriege, M; Hollestelle, A; Jager, A; Huijts, P E A; Berns, E M; Sieuwerts, A M; Meijer-van Gelder, M E; Collée, J M; Devilee, P; Hooning, M J; Martens, J W M; Seynaeve, C

2014-01-01

Background: We assessed the sensitivity to adjuvant chemotherapy in cell cycle checkpoint kinase 2 (CHEK2) vs non-CHEK2 breast cancer patients by comparing the contralateral breast cancer incidence and distant disease-free and breast cancer-specific survival between both groups, stratified for adjuvant chemotherapy. Methods: One Dutch hereditary non-BRCA1/2 breast cancer patient cohort (n=1220) and two Dutch cohorts unselected for family history (n=1014 and n=2488, respectively) were genotyped for CHEK2 1100delC. Hazard ratios for contralateral breast cancer, distant disease-free and breast cancer-specific death for mutation carriers vs noncarriers were calculated using the Cox proportional hazard method, stratified for adjuvant chemotherapy. Results: The CHEK2 mutation carriers (n=193) had an increased incidence of contralateral breast cancer (multivariate hazard ratio 3.97, 95% confidence interval 2.59–6.07). Distant disease-free and breast cancer-specific survival were similar in the first 6 years in mutation carriers compared with noncarriers, but diverted as of 6 years after breast cancer diagnosis (multivariate hazard ratios and 95% confidence intervals 2.65 (1.79–3.93) and 2.05 (1.41–2.99), respectively). No significant interaction between CHEK2 and adjuvant chemotherapy was observed. Conclusions: The CHEK2 1100delC-associated breast cancer is associated with a higher contralateral breast cancer rate as well as worse survival measures beyond 6 years after diagnosis. No differential sensitivity to adjuvant chemotherapy was observed in CHEK2 patients. PMID:24918820

Plasma lipidomics reveals potential prognostic signatures within a cohort of cystic fibrosis patients

PubMed Central

Ollero, Mario; Astarita, Giuseppe; Guerrera, Ida Chiara; Sermet-Gaudelus, Isabelle; Trudel, Stéphanie; Piomelli, Daniele; Edelman, Aleksander

2011-01-01

Cystic fibrosis (CF) is associated with abnormal lipid metabolism. We have recently shown variations in plasma levels of several phosphatidylcholine (PC) and lysophopshatidylcholine (LPC) species related to disease severity in CF patients. Here our goal was to search for blood plasma lipid signatures characteristic of CF patients bearing the same mutation (F508del) and different phenotypes, and to study their correlation with forced expiratory volume in 1 s (FEV1) and Pseudomonas aeruginosa chronic infection, evaluated at the time of testing (t = 0) and three years later (t = 3). Samples from 44 F508del homozygotes were subjected to a lipidomic approach based on LC-ESI-MS. Twelve free fatty acids were positively correlated with FEV1 at t = 0 (n = 29). Four of them (C20:3n-9, C20:5n-3, C22:5n-3, and C22:6n-3) were also positively correlated with FEV1 three years later, along with PC(32:2) and PC(36:4) (n = 31). Oleoylethanolamide (OEA) was negatively correlated with FEV1 progression (n = 17). Chronically infected patients at t = 0 showed lower PC(32:2), PC(38:5), and C18:3n-3 and higher cholesterol, cholesterol esters, and triacylglycerols (TAG). Chronically infected patients at t = 3 showed significantly lower levels of LPC(18:0). These results suggest a potential prognostic value for some lipid signatures in, to our knowledge, the first longitudinal study aimed at identifying lipid biomarkers for CF. PMID:21335323

Modelizacion, control e implementacion de un procesador energetico paralelo para aplicacion en sistemas multisalida

NASA Astrophysics Data System (ADS)

Ferreres Sabater, Agustin

Cualquier sistema electronico que incluya un procesado o tratamiento de la senal, y ademas, algun tipo de actuador mecanico generalmente necesita, como minimo, dos tensiones diferentes de alimentacion. Excluyendo los sistemas de alimentacion distribuida, la solucion tecnica mas utilizada para proporcionar dos o mas tensiones consiste en las fuentes de alimentacion multisalida. En una fuente de alimentacion multisalida los diferentes circuitos que conforman cada salida comparten un mismo transformador de potencia optimizando coste, masa, y volumen. Las ventajas obtenidas con este procedimiento tienen en su contra el efecto que sobre cada salida individual provocan las demas en su conjunto debido, principalmente, a los efectos de los elementos parasitos de los componentes. Un cambio de carga en una de las salidas produce un transitorio que es visto por todas las demas como un efecto de impedancia cruzada, y al final del transitorio, la tension de cada salida es diferente respecto a la que tenian antes del transitorio. Este ultimo resultado se conoce como regulacion cruzada. La disminucion de los efectos de la regulacion cruzada ha sido objeto de estudio durante los ultimos anos. El objetivo ha sido el desarrollo de distintas estrategias que permiten, desde disminuir los efectos de la regulacion cruzada hasta los niveles deseables, a eliminarla completamente. El resultado final suele suponer una penalizacion sobre el diseno del sistema directamente proporcional al grado de regulacion a conseguir en las distintas salidas. Entre las soluciones propuestas para eliminar la regulacion cruzada las tecnicas de post-regulacion se han consolidado como la opcion mas aceptada ya que, pueden aplicarse a cualquier convertidor y no suponen ninguna complejidad adicional a la hora de plantear el diseno. En esta Tesis Doctoral se abordara el estudio de la tecnica conocida como postregulacion mediante transformador controlado, que si bien se ha empleado en convertidores resonantes, su modelizacion, y aplicacion en convertidores PWM, esta aun por estudiar y valorar. El primer Capitulo consiste en una breve introduccion al problema de la regulacion cruzada y la impedancia cruzada para posteriormente describir las tecnicas de post-regulacion actualmente mas empleadas, con especial atencion al post-regulador con transformador controlado. El Capitulo segundo trata del estudio de las caracteristicas estaticas del postregulador con transformador controlado. Partiendo de los estudios disponibles sobre el postregulador se plantean mejoras en su modo de actuacion y se discuten tres alternativas diferentes para controlar el transformador. Las dos primeras consisten en emplear un convertidor auxiliar Boost en sus dos modos de funcionamiento, continuo y discontinuo. La tercera consiste en controlar el transformador con una tension PWM directamente, sin filtrado. Finalmente se comprueba experimentalmente, para el estado estacionario, el funcionamiento del post-regulador para cada uno de los tres metodos de control. El Capitulo tercero trata de la dinamica de la salida controlada con el post-regulador cuando este emplea un convertidor auxiliar tipo Boost. Mediante la tecnica de promediado de variables de estado se propone el modelo de pequena senal, tanto para el modo continuo como para el modo discontinuo de funcionamiento del convertidor auxiliar. Los resultados mas significativos de esta seccion son las expresiones analiticas de las impedancias cruzadas y de la impedancia de la salida post-regulada. Como complemento al modelo de pequena senal se plantea un modelo de gran senal implementado sobre el simulador Pspice. Con este nuevo modelo se reproducen los resultados obtenidos con el modelo de pequena senal y ademas es posible simular los transitorios en las tensiones de salida ante cambios de carga. La modelizacion del convertidor cuando el transformador se controla con una tension PWM sin filtrar es el objetivo del Capitulo 4. En las secciones siguientes del Capitulo se plantea el correspondiente modelo de gran senal aplicado a un nuevo prototipo experimental, de mayor tension de entrada y mayores corrientes de salida. El final del Capitulo contrasta los resultados experimentales con los teoricos confirmando la utilidad del modelo de gran senal como una herramienta basica de diseno. Finalmente, en el Capitulo 5, se presentan las conclusiones y la valoracion de los diferentes estudios plateados a lo largo de la Tesis Doctoral.

COMPARATIVE METABOLISM OF ARSENIC IN MICE AFTER A SINGLE OR REPEATED ORAL ADMINISTRATION OF ARSENATE

EPA Science Inventory

COMPARATIVE METABOLISM OF ARSENIC IN MICE AFTER A SINGLE OR REPEATED ORAL ADMINISTRATION OF ARSENATE
Michael F. Hughes*1, Elaina M. Kenyon1, Brenda C. Edwards1, Carol T. Mitchell1, Luz Maria Del Razo2 and David J. Thomas1
1US EPA, ORD, NHEERL, ETD, PKB, Research Triangle Pa...

Los Protectores del Planeta: actividades para niños y recursos educativos sobre reciclaje

EPA Pesticide Factsheets

Información sobre el Club Protectores del Planeta que enseña cómo reducir la basura desde el punto de origen, cómo reciclar y conservar los recursos naturales. La información incluye recursos educativos para el salón de clases.

Número de ganglios linfáticos metastásicos como determinante de los resultados después de prostatectomía radical de rescate para el cáncer de próstata de radiación recurrente

PubMed Central

Gugliemetti, G; Sukhu, R; Conca Baenas, M A.; Meeks, J; Sjoberg, D D.; Eastham, J A.; Scardino, P T.; Touijer, K

2017-01-01

Resumen Antecedentes La presencia de metástasis en los ganglios linfáticos (MGL) en la prostatectomía radical de rescate (PRs) se asocia con un mal pronóstico. Los factores predictivos de resultados en este contexto siguen siendo indeterminados. El objetivo fue evaluar el papel de número de ganglios linfáticos positivos sobre el resultado de los pacientes con MGL después de PRs y para el cáncer de próstata de radio-recurrente. Material y métodos Se analizaron los datos de una cohorte consecutiva de 215 hombres tratados con PRr en una sola institución. Se utilizaron los modelos de regresión de riesgos proporcionales de Cox univariante para la recurrencia bioquímica (RBQ) y los resultados metastásicos, con el antígeno prostático específico, la puntuación de Gleason, la extensión extraprostática, la invasión de vesículas seminales, el tiempo entre la terapia de radiación y PRr y el número de ganglios positivos como factores predictivos. Resultados De los 47 pacientes con MGL, 37 desarrollaron RBQ, 11 desarrollaron metástasis a distancia y 4 fallecieron con una mediana de seguimiento de 2,3 años para los supervivientes. El riesgo de metástasis aumentó con mayores niveles preoperatorios de PSA (HR 1,19 por 1 ng/ml; IC del 95%: 1,06, 1,34; p = 0,003). Los factores predictivos restantes no alcanzaron niveles convencionales de significación. Sin embargo, la eliminación de 3 o más ganglios linfáticos positivos demostró una asociación positiva, como se esperaba, con enfermedad metastásica (HR 3,44, IC: 0,91, 13,05; p = 0,069) en comparación con uno o dos ganglios positivos. Del mismo modo, la presencia de extensión extraprostática, invasión de vesículas seminales y grado de Gleason superior a 7 también demostraron una asociación positiva con un mayor riesgo de metástasis, con índices de riesgo de 3,97 (IC del 95% 0,50; 31,4; p = 0,2), 3,72 (IC 95% 0,80, 17,26; p = 0,1) y 1,45 (IC del 95% 0,44, 4,76; p = 0,5), respectivamente. Conclusiones En los pacientes con MGL después de PRr para el cáncer de próstata radiorecurrente, es probable que el riesgo de metástasis a distancia esté influenciado por el número de ganglios positivos (3 o más), alto PSA preoperatorio, grado de Gleason y estadio patológico avanzado. Estos resultados son consistentes con los hallazgos del número de ganglios (de 1 a 2 frente a 3 o más ganglios positivos) como un indicador pronóstico después de la prostatectomía radical primaria y fortalecen la petición de una revisión de la estadificación ganglionar del cáncer de próstata. PMID:27184342

CHEK2 mutations and the risk of papillary thyroid cancer.

PubMed

Siołek, Monika; Cybulski, Cezary; Gąsior-Perczak, Danuta; Kowalik, Artur; Kozak-Klonowska, Beata; Kowalska, Aldona; Chłopek, Małgorzata; Kluźniak, Wojciech; Wokołorczyk, Dominika; Pałyga, Iwona; Walczyk, Agnieszka; Lizis-Kolus, Katarzyna; Sun, Ping; Lubiński, Jan; Narod, Steven A; Góźdż, Stanisław

2015-08-01

Mutations in the cell cycle checkpoint kinase 2 (CHEK2) tumor suppressor gene are associated with multi-organ cancer susceptibility including cancers of the breast and prostate. A genetic association between thyroid and breast cancer has been suggested, however little is known about the determinants of this association. To characterize the association of CHEK2 mutations with thyroid cancer, we genotyped 468 unselected patients with papillary thyroid cancer and 468 (matched) cancer-free controls for four founder mutations of CHEK2 (1100delC, IVS2 + 1G>A, del5395 and I157T). We compared the family histories reported by patients with a CHEK2 mutation to those of non-carriers. A CHEK2 mutation was seen in 73 of 468 (15.6%) unselected patients with papillary thyroid cancer, compared to 28 of 460 (6.0%) age- and sex-matched controls (OR 3.3; p < 0.0001). A truncating mutation (IVS2 + 1G>A, 1100delC or del5395) was associated with a higher risk of thyroid cancer (OR = 5.7; p = 0.006), than was the missense mutation I157T (OR = 2.8; p = 0.0001). CHEK2 mutation carriers reported a family history of breast cancer 2.2 times more commonly than non-carriers (16.4% vs.8.1%; p = 0.05). A CHEK2 mutation was found in seven of 11 women (63%) with multiple primary cancers of the breast and thyroid (OR = 10; p = 0.0004). These results suggest that CHEK2 mutations predispose to thyroid cancer, familial aggregations of breast and thyroid cancer and to double primary cancers of the breast and thyroid. © 2015 UICC.

Rescue of murine F508del CFTR activity in native intestine by low temperature and proteasome inhibitors.

PubMed

Wilke, Martina; Bot, Alice; Jorna, Huub; Scholte, Bob J; de Jonge, Hugo R

2012-01-01

Most patients with Cystic Fibrosis (CF) carry at least one allele with the F508del mutation, resulting in a CFTR chloride channel protein with a processing, gating and stability defect, but with substantial residual activity when correctly sorted to the apical membranes of epithelial cells. New therapies are therefore aimed at improving the folding and trafficking of F508del CFTR, (CFTR correctors) or at enhancing the open probability of the CFTR chloride channel (CFTR potentiators). Preventing premature breakdown of F508del CFTR is an alternative or additional strategy, which is investigated in this study. We established an ex vivo assay for murine F508del CFTR rescue in native intestinal epithelium that can be used as a pre-clinical test for candidate therapeutics. Overnight incubation of muscle stripped ileum in modified William's E medium at low temperature (26°C), and 4 h or 6 h incubation at 37°C with different proteasome inhibitors (PI: ALLN, MG-132, epoxomicin, PS341/bortezomib) resulted in fifty to hundred percent respectively of the wild type CFTR mediated chloride secretion (forskolin induced short-circuit current). The functional rescue was accompanied by enhanced expression of the murine F508del CFTR protein at the apical surface of intestinal crypts and a gain in the amount of complex-glycosylated CFTR (band C) up to 20% of WT levels. Sustained rescue in the presence of brefeldin A shows the involvement of a post-Golgi compartment in murine F508del CFTR degradation, as was shown earlier for its human counterpart. Our data show that proteasome inhibitors are promising candidate compounds for improving rescue of human F508del CFTR function, in combination with available correctors and potentiators.

Novel Mutations Causing C5 Deficiency in Three North-African Families.

PubMed

Colobran, Roger; Franco-Jarava, Clara; Martín-Nalda, Andrea; Baena, Neus; Gabau, Elisabeth; Padilla, Natàlia; de la Cruz, Xavier; Pujol-Borrell, Ricardo; Comas, David; Soler-Palacín, Pere; Hernández-González, Manuel

2016-05-01

The complement system plays a central role in defense to encapsulated bacteria through opsonization and membrane attack complex (MAC) dependent lysis. The three activation pathways (classical, lectin, and alternative) converge in the cleavage of C5, which initiates MAC formation and target lysis. C5 deficiency is associated to recurrent infections by Neisseria spp. In the present study, complement deficiency was suspected in three families of North-African origin after one episode of invasive meningitis due to a non-groupable and two uncommon Meningococcal serotypes (E29, Y). Activity of alternative and classical pathways of complement were markedly reduced and the measurement of terminal complement components revealed total C5 absence. C5 gene analysis revealed two novel mutations as causative of the deficiency: Family A propositus carried a homozygous deletion of two adenines in the exon 21 of C5 gene, resulting in a frameshift and a truncated protein (c.2607_2608del/p.Ser870ProfsX3 mutation). Families B and C probands carried the same homozygous deletion of three consecutive nucleotides (CAA) in exon 9 of the C5 gene, leading to the deletion of asparagine 320 (c.960_962del/p.Asn320del mutation). Family studies confirmed an autosomal recessive inheritance pattern. Although sharing the same geographical origin, families B and C were unrelated. This prompted us to investigate this mutation prevalence in a cohort of 768 North-African healthy individuals. We identified one heterozygous carrier of the p.Asn320del mutation (allelic frequency = 0.065 %), indicating that this mutation is present at low frequency in North-African population.

Distribution of the most common polymorphisms in TYMS gene in Slavic population of central Europe.

PubMed

Pastorakova, A; Chandogova, D; Chandoga, J; Luha, J; Bohmer, D; Malova, J; Braxatorisova, T; Juhosova, M; Reznakova, S; Petrovic, R

2017-01-01

Thymidylate synthetase (TS) plays a critical role in the de novo synthesis of dTMP inside the cell. Therefore, TS is a suitable target for cytotoxic drugs such as fluoropyrimidines. Drug efficacy and toxicity depend on the intracellular level of TS, which is significantly influenced by the polymorphisms in the 5'UTR (TSER - rs45445694, TSER*3G>C - rs2853542) and 3'UTR (1494del TTAAAG - rs151264360) of TYMS gene. Polymorphic variants of TYMS gene affect TS activity via gene expression and transcript stability. Patients who undergo fluoropyrimidine therapy may benefit from genetic testing prior to the administration of chemotherapy. At the 5' terminus of TYMS, there is a polymorphic region represented by a variable number of 28bp long tandem repeats (2-9 tandems) with the G or C nucleotide variant (SNP G>C). The 3'end of TYMS gene may decrease the stability of mRNA in the case of 6 base deletion (1494del6, D). In our study, we have focused on testing of TYMS gene polymorphisms, determination of TYMS variant frequencies in Western Slavic population and comparison of Slovak population with other populations.We performed identification of 5'UTR (rs45445694 - TSER*2 or TSER*3; rs2853542 - TSER*3G>C; TSER*3+ins6) and 3'UTR (rs151264360/1494del6/D) polymorphic regions of TYMS gene among 96 volunteers by PCR-RFLP and fragment analysis. Slovak frequencies of selected polymorphisms were established as follows: the frequency of TSER*2, TSER*3, TSER*3G>C, 1494del6/D and I to be 41%, 59%, 34%, 37.5% and 62.5% respectively. The high resolution of the capillary electrophoresis technique allowed among TSER*3 group identification of a subgroup of four individuals with rare 6bp insertion in 3R allele, id est 2.1% TSER*3+ins6 allele frequency. In our study, we have revealed individuals with rare G>C substitution in the first 28bp tandem repeat of TSER*2 promoter enhancer region (rs183205964) as well, the overall frequency of this polymorphic allele in Slovak population was 2.1%. Our results proved that Slovak population is in Hardy-Weinberg equilibrium and proportion of TYMS polymorphisms is in accordance with other published data.

Recurrent truncating mutations in alanine-glyoxylate aminotransferase gene in two South Indian families with primary hyperoxaluria type 1 causing later onset end-stage kidney disease

PubMed Central

Dutta, A. K.; Paulose, B. K.; Danda, S.; Alexander, S.; Tamilarasi, V.; Omprakash, S.

2016-01-01

Primary hyperoxaluria type 1 is an autosomal recessive inborn error of metabolism due to liver-specific peroxisomal enzyme alanine-glyoxylate transaminase deficiency. Here, we describe two unrelated patients who were diagnosed to have primary hyperoxaluria. Homozygous c.445_452delGTGCTGCT (p.L151Nfs*14) (Transcript ID: ENST00000307503; human genome assembly GRCh38.p2) (HGMD ID CD073567) mutation was detected in both the patients and the parents were found to be heterozygous carriers. Our patients developed end-stage renal disease at 23 years and 35 years of age. However, in the largest series published from OxalEurope cohort, the median age of end-stage renal disease for null mutations carriers was 9.9 years, which is much earlier than our cases. Our patients had slower progressions as compared to three unrelated patients from North India and Pakistan, who had homozygous c.302T>C (p.L101P) (HGMD ID CM093792) mutation in exon 2. Further, patients need to be studied to find out if c.445_452delGTGCTGCT mutation represents a founder mutation in Southern India. PMID:27512303

Biallelic UNC80 mutations caused infantile hypotonia with psychomotor retardation and characteristic facies 2 in two Chinese patients with variable phenotypes.

PubMed

He, Yunjuan; Ji, Xing; Yan, Hui; Ye, Xiantao; Liu, Yu; Wei, Wei; Xiao, Bing; Sun, Yu

2018-06-20

Biallelic UNC80 mutations cause infantile hypotonia with psychomotor retardation and characteristic facies 2 (IHPRF2), which is characterized by hypotonia, developmental delay (DD)/intellectual disability (ID), intrauterine growth retardation, postnatal growth retardation and characteristic facial features. We report two unrelated Chinese patients with compound heterozygous UNC80 mutations inherited from their parents, as identified by whole-exome sequencing (WES). Mutations c.3719G>A (p.W1240*)/c.4926_4937del (p.N1643_L1646del) and c.4963C>T (p.R1655C)/c.8385C>G (p.Y2795*) were identified in patient 1 and patient 2, respectively. Although both patients presented with DD/ID and hypotonia, different manifestations also occurred. Patient 1 presented with infantile hypotonia, epilepsy and hyperactivity without growth retardation, whereas patient 2 presented with persistent hypotonia, growth retardation and self-injury without epilepsy. Furthermore, we herein summarize the genotypes and phenotypes of patients with UNC80 mutations reported in the literature, revealing that IHPRF2 is a phenotypically heterogeneous disease. Common facial dysmorphisms include a thin upper lip, a tented upper lip, a triangular face, strabismus and microcephaly. To some extent, the manifestations of IHPRF2 mimic those of Angelman syndrome (AS)-like syndromes. Copyright © 2018 Elsevier B.V. All rights reserved.

The Spectrum of Niemann-Pick Type C Disease in Greece.

PubMed

Mavridou, Irene; Dimitriou, Evangelia; Vanier, Marie T; Vilageliu, Lluisa; Grinberg, Daniel; Latour, Philippe; Xaidara, Athina; Lycopoulou, Lilia; Bostantjopoulou, Sevasti; Zafeiriou, Dimitrios; Michelakakis, Helen

2017-01-01

Niemann-Pick type C disease (NPC) is a neurovisceral lysosomal storage disease caused by mutations in either the NPC1 or the NPC2 gene. It is a cellular lipid trafficking disorder characterized by the accumulation of unesterified cholesterol and various sphingolipids in the lysosomes and late endosomes, and it exhibits a broad clinical spectrum. Today, over 420 disease-causing mutations have been identified in the NPC1 and the NPC2 genes. We present the clinical, biochemical, and molecular findings in 14 cases diagnosed in Greece during the last 28 years. Age at diagnosis ranged from 2.5 months to 48 years. Systemic manifestations were present in 7/14 patients. All developed neurological manifestations (age of onset 5 months to 42 years). Six patients are still alive (age: 5-50 years). Classical filipin staining pattern was observed in all but four patients (3 NPC1, 1 NPC2). The rate of LDL-induced cholesteryl ester formation was severely reduced in 4/7 and significantly reduced in 3/7 patients studied. Increased chitotriosidase activity was observed in 9/12 patients. Mutation analysis in 11 unrelated patients identified 12 different mutations in the NPC1 gene: eight previously described p.E1089K (c.3265G>A), p.F284Lfs*26 (c.852delT), p.A1132P(c.3394G>C), del promoter region and exons 1-10, p.R1186H (c.3557G>A), p.P1007A (c.3019C>G), p.Q92R(c.275A>G),p.S940L (c.2819C>T), and four novel ones: (p.N701K fs*13 (c.2102-2103insA), p.K1057R (c.3170A>G), IVS23+3insT(c.3591+3insT), p.C1119*(c.3357T>C); and the previously described IVS2+5G>A(c.190+5G>A) mutation in the NPC2 gene. All patients were of Greek origin. Assuming a birth rate of 100,000/year, a rough incidence estimate for NPC disease in Greece would be 0.5/100,000 births.

Long-range PCR facilitates the identification of PMS2-specific mutations.

PubMed

Clendenning, Mark; Hampel, Heather; LaJeunesse, Jennifer; Lindblom, Annika; Lockman, Jan; Nilbert, Mef; Senter, Leigha; Sotamaa, Kaisa; de la Chapelle, Albert

2006-05-01

Mutations within the DNA mismatch repair gene, "postmeiotic segregation increased 2" (PMS2), have been associated with a predisposition to hereditary nonpolyposis colorectal cancer (HNPCC; Lynch syndrome). The presence of a large family of highly homologous PMS2 pseudogenes has made previous attempts to sequence PMS2 very difficult. Here, we describe a novel method that utilizes long-range PCR as a way to preferentially amplify PMS2 and not the pseudogenes. A second, exon-specific, amplification from diluted long-range products enables us to obtain a clean sequence that shows no evidence of pseudogene contamination. This method has been used to screen a cohort of patients whose tumors were negative for the PMS2 protein by immunohistochemistry and had not shown any mutations within the MLH1 gene. Sequencing of the PMS2 gene from 30 colorectal and 11 endometrial cancer patients identified 10 novel sequence changes as well as 17 sequence changes that had previously been identified. In total, putative pathologic mutations were detected in 11 of the 41 families. Among these were five novel mutations, c.705+1G>T, c.736_741del6ins11, c.862_863del, c.1688G>T, and c.2007-1G>A. We conclude that PMS2 mutation detection in selected Lynch syndrome and Lynch syndrome-like patients is both feasible and desirable. Published 2006 Wiley-Liss, Inc.

A masked NES in INI1/hSNF5 mediates hCRM1-dependent nuclear export: implications for tumorigenesis

PubMed Central

Craig, Errol; Zhang, Zhi-Kai; Davies, Kelvin P.; Kalpana, Ganjam V.

2002-01-01

INI1 (integrase interactor 1)/hSNF5 is a component of the mammalian SWI/SNF complex and a tumor suppressor mutated in malignant rhabdoid tumors (MRT). We have identified a nuclear export signal (NES) in the highly conserved repeat 2 domain of INI1 that is unmasked upon deletion of a downstream sequence. Mutation of conserved hydrophobic residues within the NES, as well as leptomycin B treatment abrogated the nuclear export. Full-length INI1 specifically associated with hCRM1/exportin1 in vivo and in vitro. A mutant INI1 [INI1(1–319) delG950] found in MRT lacking the 66 C-terminal amino acids mislocalized to the cytoplasm. Full-length INI1 but not the INI1(1–319 delG950) mutant caused flat cell formation and cell cycle arrest in cell lines derived from MRT. Disruption of the NES in the delG950 mutant caused nuclear localization of the protein and restored its ability to cause cell cycle arrest. These observations demonstrate that INI1 has a masked NES that mediates regulated hCRM1/exportin1-dependent nuclear export and we propose that mutations that cause deregulated nuclear export of the protein could lead to tumorigenesis. PMID:11782423

A de novo deletion mutation in SOX10 in a Chinese family with Waardenburg syndrome type 4.

PubMed

Wang, Xiong; Zhu, Yaowu; Shen, Na; Peng, Jing; Wang, Chunyu; Liu, Haiyi; Lu, Yanjun

2017-01-27

Waardenburg syndrome type 4 (WS4) or Waardenburg-Shah syndrome is a rare genetic disorder with a prevalence of <1/1,000,000 and characterized by the association of congenital sensorineural hearing loss, pigmentary abnormalities, and intestinal aganglionosis. There are three types of WS4 (WS4A-C) caused by mutations in endothelin receptor type B, endothelin 3, and SRY-box 10 (SOX10), respectively. This study investigated a genetic mutation in a Chinese family with one WS4 patient in order to improve genetic counselling. Genomic DNA was extracted, and mutation analysis of the three WS4 related genes was performed using Sanger sequencing. We detected a de novo heterozygous deletion mutation [c.1333delT (p.Ser445Glnfs*57)] in SOX10 in the patient; however, this mutation was absent in the unaffected parents and 40 ethnicity matched healthy controls. Subsequent phylogenetic analysis and three-dimensional modelling of the SOX10 protein confirmed that the c.1333delT heterozygous mutation was pathogenic, indicating that this mutation might constitute a candidate disease-causing mutation.

A de novo deletion mutation in SOX10 in a Chinese family with Waardenburg syndrome type 4

PubMed Central

Wang, Xiong; Zhu, Yaowu; Shen, Na; Peng, Jing; Wang, Chunyu; Liu, Haiyi; Lu, Yanjun

2017-01-01

Waardenburg syndrome type 4 (WS4) or Waardenburg-Shah syndrome is a rare genetic disorder with a prevalence of <1/1,000,000 and characterized by the association of congenital sensorineural hearing loss, pigmentary abnormalities, and intestinal aganglionosis. There are three types of WS4 (WS4A–C) caused by mutations in endothelin receptor type B, endothelin 3, and SRY-box 10 (SOX10), respectively. This study investigated a genetic mutation in a Chinese family with one WS4 patient in order to improve genetic counselling. Genomic DNA was extracted, and mutation analysis of the three WS4 related genes was performed using Sanger sequencing. We detected a de novo heterozygous deletion mutation [c.1333delT (p.Ser445Glnfs*57)] in SOX10 in the patient; however, this mutation was absent in the unaffected parents and 40 ethnicity matched healthy controls. Subsequent phylogenetic analysis and three-dimensional modelling of the SOX10 protein confirmed that the c.1333delT heterozygous mutation was pathogenic, indicating that this mutation might constitute a candidate disease-causing mutation. PMID:28128317

A novel DNMT1 mutation associated with early onset hereditary sensory and autonomic neuropathy, cataplexy, cerebellar atrophy, scleroderma, endocrinopathy, and common variable immune deficiency.

PubMed

Fox, Robin; Ealing, John; Murphy, Helen; Gow, David P; Gosal, David

2016-09-01

DNA methyltransferase 1 (DNMT1) is an enzyme which has a role in methylation of DNA, gene regulation, and chromatin stability. Missense mutations in the DNMT1 gene have been previously associated with two neurological syndromes: hereditary sensory and autonomic neuropathy type 1 with dementia and deafness (HSAN1E) and autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN). We report a case showing overlap of both of these syndromes plus associated clinical features of common variable immune deficiency, scleroderma, and endocrinopathy that could also be mutation associated. Our patient was found to be heterozygous for a previously unreported frameshift mutation, c.1635_1637delCAA p.(Asn545del) in the DNMT1 gene exon 20. This case displays both the first frameshift mutation described in the literature which is associated with a phenotype with a high degree of overlap between HSAN1E and ADCA-DN and early age of onset (c. 8 years). Our case is also of interest as the patient displays a number of new non-neurological features, which could also be DNMT1 mutation related. © 2016 Peripheral Nerve Society.

CHEK2 mutations and HNPCC-related colorectal cancer.

PubMed

Suchy, Janina; Cybulski, Cezary; Wokołorczyk, Dominika; Oszurek, Oleg; Górski, Bohdan; Debniak, Tadeusz; Jakubowska, Anna; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Dziuba, Ireneusz; Gogacz, Marek; Wiśniowski, Rafał; Wandzel, Piotr; Banaszkiewicz, Zbigniew; Kurzawski, Grzegorz; Kładny, Józef; Narod, Steven A; Lubiński, Jan

2010-06-15

Recently, the 1100delC variant of cell cycle checkpoint kinase 2 (CHEK2) has been reported to confer a colorectal cancer risk in hereditary non-polyposis-colorectal cancer (HNPCC) and HNPCC-related families in the Netherlands. To investigate whether CHEK2 mutations confer increased cancer risk in HNPCC and HNPCC-related families in Poland, we genotyped 463 probands from HNPCC and HNPCC-related families, and 5,496 controls for 4 CHEK2 alleles (1100delC, IVS2+1G>A, del5395, I157T). All 463 probands were screened for mutations in the HNPCC-related genes MSH2, MLH1 and MSH6. A positive association was observed for HNPCC-related cancer and the I157T missense CHEK2 mutation (OR = 1.7; p = 0.007), but not for the truncating alleles (OR = 1.0; p = 1.0). The association with the I157T was seen both for the 117 cases who fulfill Amsterdam criteria (OR = 1.9; p = 0.1) and for the 346 cases who do not fulfill the criteria (OR = 1.6; p = 0.03). One hundred forty-five of the 463 families had a mutation in MSH2, MLH1 or MSH6 (MMR-positive families). A positive association between the CHEK2 I157T mutation and HNPCC-related cancer was observed only for MMR-negative cases (OR = 2.1; p = 0.0004), but not for MMR-positive cases (OR = 0.8; p = 0.9). The association with I157T was particularly strong for MMR-negative cases with familial colorectal cancer (2 or more first-degree relatives affected) (OR = 2.5; p < 0.0001). We conclude that the I157T variant of CHEK2 increases the risk of colorectal cancer among MMR-negative, HNPCC/HNPCC-related families in Poland.

Genetic counseling in Usher syndrome: linkage and mutational analysis of 10 Colombian families.

PubMed

Tamayo, M L; Lopez, G; Gelvez, N; Medina, D; Kimberling, W J; Rodríguez, V; Tamayo, G E; Bernal, J E

2008-01-01

Usher Syndrome (US), an autosomal recessive disease, is characterized by retinitis pigmentosa (RP), vestibular dysfunction, and congenital sensorineural deafness. There are three recognized clinical types of the disorder. In order to improve genetic counseling for affected families, we conducted linkage analysis and DNA sequencing in 10 Colombian families with confirmed diagnosis of US (4 type I and 6 type II). Seventy-five percent of the US1 families showed linkage to locus USH1B, while the remaining 25% showed linkage to loci USH1B and USH1C. Among families showing linkage to USH1B we found two different mutations in the MYO7A gene: IVS42-26insTTGAG in exon 43 (heterozygous state) and R634X (CGA-TGA) in exon 16 (homozygous state). All six US2 families showed linkage to locus USH2A. Of them, 4 had c.2299delG mutation (1 homozygote state and 3 heterozygous); in the remaining 2 we did not identify any pathologic DNA variant. USH2A individuals with a 2299delG mutation presented a typical and homogeneous retinal phenotype with bilateral severe hearing loss, except for one individual with a heterozygous 2299delG mutation, whose hearing loss was asymmetric, but more profound than in the other cases. The study of these families adds to the genotype-phenotype characterization of the different types and subtypes of US and facilitates genetic counseling in these families. We would like to emphasize the need to perform DNA studies as a prerequisite for genetic counseling in affected families.

The SLCO1A2 -189_-188InsA polymorphism reduces clearance of rocuronium in patients submitted to elective surgeries.

PubMed

Costa, A C C; Coelho, E B; Lanchote, V L; Correia, B V; Abumansur, J T; Lauretti, G R; de Moraes, N V

2017-08-01

Rocuronium (ROC) is a neuromuscular blocker mainly eliminated by biliary excretion dependent on organic anion transporting polypeptide 1A2 (OATP1A2) hepatocellular uptake. However, the influence of SLCO1A2 (gene encoding OATP1A2) genetic polymorphism on ROC pharmacokinetics was never described before. The objective of this work was to evaluate the influence of genetic polymorphisms of SLCO1A2 on the pharmacokinetics of rocuronium (ROC). Patients undergoing elective surgeries under general anesthesia using rocuronium as a neuromuscular blocker were genotyped for SLCO1A2 polymorphisms in the coding region (41A>G, 382A>T, 404A>T, 502C>T, 516A>C, 559G>A, 830C>A, and 833delA) and in the promoter region (-1105G>A, -1032G>A, -715T>C, -361G>A, and -189_-188insA). Rocuronium pharmacokinetic parameters were estimated by non-compartmental analysis. None of the patients had heterozygous or homozygous variant of 404A>T, 382A>T, 502C>T, 833delA, 830C>A, 41A>G, and -715T>C. A linkage disequilibrium was found between -1105G>A and -1032G>A genotypes. Patients genotyped as -A or AA (n = 17) for SLCO1A2 -189_-188InsA showed reduced total clearance of ROC compared to patients genotyped as -/- (n = 13) (151.6 vs 207.1 mL/min, p ≤ 0.05). The pharmacokinetics parameters of ROC were not significantly different between other SLCO1A2 genotypes. SLCO1A2 -189_-188InsA polymorphism is related to the reduced clearance of rocuronium in patients submitted to elective surgeries under general anesthesia. NCT 02399397 ( ClinicalTrials.gov ).

Identificación de los miembros del cúmulo NGC 2516

NASA Astrophysics Data System (ADS)

de Elía, G. C.; Orellana, R. B.

El cúmulo abierto NGC 2516 (α = 7h 58m y δ = -60o 45') tiene una edad de, aproximadamente, 150 Myr. El análisis de este sistema es particularmente importante en el Hemisferio Sur debido a su abundancia de estrellas peculiares y muy estudiado aplicando técnicas fotométricas, pero muy poco analizado desde el punto de vista astrométrico. A partir de una placa obtenida en el Observatorio Astronómico de La Plata y observaciones más actuales, nos hemos abocado al estudio de los movimientos propios de este cúmulo con el fin de determinar la pertenencia al mismo de las estrellas del campo de dicho cúmulo. Luego de llevar a cabo la determinación de los movimientos propios de todas las estrellas a partir de las posiciones obtenidas de la placa existente en el Observatorio de La Plata de 1914 y leídas con la MAMA en París, las observaciones realizadas con el círculo meridiano de San Fernando que se encuentra en el Observatorio Félix Aguilar de San Juan y las posiciones existentes en los catálogos AC 2000, Tycho, USNO y UCAC, programamos el método de Vasilevsky y Sanders para determinar la pertenencia de las estrellas de la región al cúmulo en cuestión. En un paso posterior, se realizó una modificación al método anterior para la determinación de los miembros. En esta modificación se consideró la densidad de las estrellas del cúmulo y la densidad de estrellas de campo. Esto permitió evaluar la pertenencia, no sólo a partir del movimiento propio de las estrellas, sino también a partir de la posición de las mismas con respecto al centro del cúmulo. También se consideró la dependencia de los parámetros con la magnitud. Los resultados así obtenidos fueron comparados con otras investigaciones de movimientos propios de la región del cúmulo. El movimiento propio absoluto del cúmulo fue comparado con el obtenido a partir de los catálogos estelares. Se encontró que los resultados coincidían para estrellas brillantes (magnitud más brillante que 12.0 aproximadamente) y que no coincidían para estrellas más débiles. La tarea que llevamos a cabo en estos momentos está referida a encontrar la causa de tales discrepancias con el fin de obtener los mejores resultados.

Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients

PubMed Central

2014-01-01

Background Mutations in the cyclin-dependent kinase-like 5 (CDKL5) (NM_003159.2) gene have been associated with early-onset epileptic encephalopathies or Hanefeld variants of RTT(Rett syndrome). In order to clarify the CDKL5 genotype-phenotype correlations in Chinese patients, CDKL5 mutational screening in cases with early-onset epileptic encephalopathies and RTT without MECP2 mutation were performed. Methods The detailed clinical information including clinical manifestation, electroencephalogram (EEG), magnetic resonance imaging (MRI), blood, urine amino acid and organic acid screening of 102 Chinese patients with early-onset epileptic encephalopathies and RTT were collected. CDKL5 gene mutations were analyzed by PCR, direct sequencing and multiplex ligation-dependent probe amplification (MLPA). The patterns of X-chromosome inactivation (XCI) were studied in the female patients with CDKL5 gene mutation. Results De novo CDKL5 gene mutations were found in ten patients including one missense mutation (c.533G > A, p.R178Q) which had been reported, two splicing mutations (ISV6 + 1A > G, ISV13 + 1A > G), three micro-deletions (c.1111delC, c.2360delA, c.234delA), two insertions (c.1791 ins G, c.891_892 ins TT in a pair of twins) and one nonsense mutation (c.1375C > T, p.Q459X). Out of ten patients, 7 of 9 females with Hanefeld variants of RTT and the remaining 2 females with early onset epileptic encephalopathy, were detected while only one male with infantile spasms was detected. The common features of all female patients with CDKL5 gene mutations included refractory seizures starting before 4 months of age, severe psychomotor retardation, Rett-like features such as hand stereotypies, deceleration of head growth after birth and poor prognosis. In contrast, the only one male patient with CDKL5 mutation showed no obvious Rett-like features as females in our cohort. The X-chromosome inactivation patterns of all the female patients were random. Conclusions Mutations in CDKL5 gene are responsible for 7 with Hanefeld variants of RTT and 2 with early-onset epileptic encephalopathy in 71 girls as well as for 1 infantile spasms in 31 males. There are some differences in the phenotypes among genders with CDKL5 gene mutations and CDKL5 gene mutation analysis should be considered in both genders. PMID:24564546

Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients.

PubMed

Zhao, Ying; Zhang, Xiaoying; Bao, Xinhua; Zhang, Qingping; Zhang, Jingjing; Cao, Guangna; Zhang, Jie; Li, Jiarui; Wei, Liping; Pan, Hong; Wu, Xiru

2014-02-25

Mutations in the cyclin-dependent kinase-like 5 (CDKL5) (NM_003159.2) gene have been associated with early-onset epileptic encephalopathies or Hanefeld variants of RTT(Rett syndrome). In order to clarify the CDKL5 genotype-phenotype correlations in Chinese patients, CDKL5 mutational screening in cases with early-onset epileptic encephalopathies and RTT without MECP2 mutation were performed. The detailed clinical information including clinical manifestation, electroencephalogram (EEG), magnetic resonance imaging (MRI), blood, urine amino acid and organic acid screening of 102 Chinese patients with early-onset epileptic encephalopathies and RTT were collected. CDKL5 gene mutations were analyzed by PCR, direct sequencing and multiplex ligation-dependent probe amplification (MLPA). The patterns of X-chromosome inactivation (XCI) were studied in the female patients with CDKL5 gene mutation. De novo CDKL5 gene mutations were found in ten patients including one missense mutation (c.533G > A, p.R178Q) which had been reported, two splicing mutations (ISV6 + 1A > G, ISV13 + 1A > G), three micro-deletions (c.1111delC, c.2360delA, c.234delA), two insertions (c.1791 ins G, c.891_892 ins TT in a pair of twins) and one nonsense mutation (c.1375C > T, p.Q459X). Out of ten patients, 7 of 9 females with Hanefeld variants of RTT and the remaining 2 females with early onset epileptic encephalopathy, were detected while only one male with infantile spasms was detected. The common features of all female patients with CDKL5 gene mutations included refractory seizures starting before 4 months of age, severe psychomotor retardation, Rett-like features such as hand stereotypies, deceleration of head growth after birth and poor prognosis. In contrast, the only one male patient with CDKL5 mutation showed no obvious Rett-like features as females in our cohort. The X-chromosome inactivation patterns of all the female patients were random. Mutations in CDKL5 gene are responsible for 7 with Hanefeld variants of RTT and 2 with early-onset epileptic encephalopathy in 71 girls as well as for 1 infantile spasms in 31 males. There are some differences in the phenotypes among genders with CDKL5 gene mutations and CDKL5 gene mutation analysis should be considered in both genders.

Mean Flow Augmented Acoustics in Rocket Systems

NASA Technical Reports Server (NTRS)

Fischbach, Sean R.

2014-01-01

Oscillatory motion in solid rocket motors and liquid engines has long been a subject of concern. Many rockets display violent fluctuations in pressure, velocity, and temperature originating from the complex interactions between the combustion process and gas dynamics. The customary approach to modeling acoustic waves inside a rocket chamber is to apply the classical inhomogeneous wave equation to the combustion gas. The assumption of a linear, non-dissipative wave in a quiescent fluid remains valid while the acoustic amplitudes are small and local gas velocities stay below Mach 0.2. The converging section of a rocket nozzle, where gradients in pressure, density, and velocity become large, is a notable region where this approach is not applicable. The expulsion of unsteady energy through the nozzle of a rocket is identified as the predominate source of acoustic damping for most rocket systems. An accurate model of the acoustic behavior within this region where acoustic modes are influenced by the presence of a steady mean flow is required for reliable stability predictions. Recently, an approach to address nozzle damping with mean flow effects was implemented by French [1]. This new approach extends the work originated by Sigman and Zinn [2] by solving the acoustic velocity potential equation (AVPE) formulated by perturbing the Euler equations [3]. The acoustic velocity potential (psi) describing the acoustic wave motion in the presence of an inhomogeneous steady high-speed flow is defined by, (del squared)(psi) - (lambda/c)(exp 2)(psi) - M(dot)[M(dot)(del)(del(psi))] - 2(lambda(M/c) + (M(dot)del(M))(dot)del(psi)-2(lambda)(psi)[M(dot)del(1/c)]=0 (1) with M as the Mach vector, c as the speed of sound, and lambda as the complex eigenvalue. French apply the finite volume method to solve the steady flow field within the combustion chamber and nozzle with inviscid walls. The complex eigenvalues and eigenvector are determined with the use of the ARPACK eigensolver. The present study employs the COMSOL Multphysics framework to solve the coupled eigenvalue problem using the finite element approach. The study requires one way coupling of the CFD High Mach Number Flow (HMNF) and mathematics module. The HMNF module evaluated the gas flow inside of a solid rocket motor using St. Robert's law modeling solid propellant burn rate, slip boundary conditions, and the supersonic outflow condition. Results from the HMNF model are used by the coefficient form of the mathematics module to determine the eigenvalues of the AVPE. The mathematics model is truncated at the nozzle sonic line, where a zero flux boundary condition is self-satisfying. The remaining boundaries are modeled with a zero flux boundary condition, assuming zero acoustic absorption on all surfaces. Pertinent results from these analyses are the complex valued eigenvalue and eigenvectors. Comparisons are made to the French results to evaluate the modeling approach. A comparison of the French results with that of the present analysis is displayed in figures 1 and 2, respectively. The graphic shows the first tangential eigenvector's real (a) and imaginary (b) values.

Whole exome sequencing identified 1 base pair novel deletion in BCL2-associated athanogene 3 (BAG3) gene associated with severe dilated cardiomyopathy (DCM) requiring heart transplant in multiple family members.

PubMed

Rafiq, Muhammad Arshad; Chaudhry, Ayeshah; Care, Melanie; Spears, Danna A; Morel, Chantal F; Hamilton, Robert M

2017-03-01

Dilated cardiomyopathy (DCM) is characterized by dilation and impaired contraction of the left ventricle or both ventricles. Among hereditary DCM, the genetic causes are heterogeneous, and include mutations encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. We report three severely affected males, in a four-generation pedigree, with DCM phenotype who underwent cardiac transplant. Cardiomegaly with marked biventricular dilation and fibrosis were noticeable histopathological findings. The affected males had tested negative on a 46-gene pancardiomyopathy panel. Whole Exome Sequencing (WES) was performed to reveal mutation in the gene responsible in generation of DCM phenotypes. The 1-bp (Chr10:121435979delC; c.913delC) novel heterozygous deletion in exon 4 of BAG3, was identified in three affected males, resulted in frame-shift and a premature termination codon (p.Met306-Stop) producing a truncated BAG3 protein lacking functionally important PXXP and BAG domains. WES data were further utilized to map 10 SNP markers around the discovered mutation to generate shared disease haplotype in all affected individuals encompassing 11 Mb on 10q25.3-26.2 harboring BAG3. Finally genotypes were inferred for the unavailable/deceased individuals in the pedigrees. Here we propose that Chr10:121435979delC in BAG3 is a causal mutation in these subjects. Our and earlier studies indicate that BAG3 mutations are associated with DCM phenotypes. BAG3 should be added to cardiomyopathy gene panels for screening of DCM patients, and patients previously considered gene elusive should undergo sequencing of the BAG3 gene. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Frequency of pathogenic germline mutation in CHEK2, PALB2, MRE11, and RAD50 in patients at high risk for hereditary breast cancer.

PubMed

Kim, Haeyoung; Cho, Dae-Yeon; Choi, Doo Ho; Oh, Mijin; Shin, Inkyung; Park, Won; Huh, Seung Jae; Nam, Seok Jin; Lee, Jeong Eon; Kim, Seok Won

2017-01-01

This study was performed to evaluate the frequency of mutations in CHEK2, PALB2, MRE11, and RAD50 among Korean patients at high risk for hereditary breast cancer. A total of 235 Korean patients with hereditary breast cancer who tested negative for BRCA1/2 mutation were enrolled to this study. Entire coding regions of CHEK2, PALB2, MRE11, and RAD50 were analyzed using massively parallel sequencing (MPS). Sequence variants detected by MPS were confirmed by Sanger sequencing. Six patients (2.5 %) were found to have pathogenic variants in CHEK2 (n = 1), PALB2 (n = 2), MRE11 (n = 1), and RAD50 (n = 2). Among the pathogenic variants, PALB2 c.2257C>T was previously reported in other studies, while CHEK2 c.1245dupC, PALB2 c.1048C>T, MRE11 c.1773_1774delAA, RAD50 c.1276C>T, and RAD50 c.3811_3813delGAA were newly identified in this study. A total of 15 missense variants were found in the four genes among 26 patients; 7 patients had a variant in CHEK2, 11 in PALB2, 2 in MRE11, and 6 in RAD50. When in silico analyses were performed to the 15 missense variants, six variants (CHEK2 c.686A>G, PALB2 c.1492G>T, PALB2 c.3054G>C, MRE11 c.140C>T, RAD50 c.1456C>T, and RAD50 c.3790C>T) were predicted to be deleterious. Pathogenic variants in CHEK2, PALB2, MRE11, and RAD50 were detected in a small proportion of Korean patients with features of hereditary breast cancer.

The p.Leu167del Mutation in APOE Gene Causes Autosomal Dominant Hypercholesterolemia by Down-regulation of LDL Receptor Expression in Hepatocytes.

PubMed

Cenarro, Ana; Etxebarria, Aitor; de Castro-Orós, Isabel; Stef, Marianne; Bea, Ana M; Palacios, Lourdes; Mateo-Gallego, Rocío; Benito-Vicente, Asier; Ostolaza, Helena; Tejedor, Teresa; Martín, César; Civeira, Fernando

2016-05-01

The p.Leu167del mutation in the APOE gene has been associated with hyperlipidemia. Our objective was to determine the frequency of p.Leu167del mutation in APOE gene in subjects with autosomal dominant hypercholesterolemia (ADH) in whom LDLR, APOB, and PCSK9 mutations had been excluded and to identify the mechanisms by which this mutant apo E causes hypercholesterolemia. The APOE gene was analyzed in a case-control study. The study was conducted at a University Hospital Lipid Clinic. Two groups (ADH, 288 patients; control, 220 normolipidemic subjects) were included. We performed sequencing of APOE gene and proteomic and cellular experiments. To determine the frequency of the p.Leu167del mutation and the mechanism by which it causes hypercholesterolemia. In the ADH group, nine subjects (3.1%) were carriers of the APOE c.500_502delTCC, p.Leu167del mutation, cosegregating with hypercholesterolemia in studied families. Proteomic quantification of wild-type and mutant apo E in very low-density lipoprotein (VLDL) from carrier subjects revealed that apo E3 is almost a 5-fold increase compared to mutant apo E. Cultured cell studies revealed that VLDL from mutation carriers had a significantly higher uptake by HepG2 and THP-1 cells compared to VLDL from subjects with E3/E3 or E2/E2 genotypes. Transcriptional down-regulation of LDLR was also confirmed. p.Leu167del mutation in APOE gene is the cause of hypercholesterolemia in the 3.1% of our ADH subjects without LDLR, APOB, and PCSK9 mutations. The mechanism by which this mutation is associated to ADH is that VLDL carrying the mutant apo E produces LDLR down-regulation, thereby raising plasma low-density lipoprotein cholesterol levels.

General anesthetic octanol and related compounds activate wild-type and delF508 cystic fibrosis chloride channels.

PubMed

Marcet, Brice; Becq, Frédéric; Norez, Caroline; Delmas, Patrick; Verrier, Bernard

2004-03-01

1. Cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel is defective during cystic fibrosis (CF). Activators of the CFTR Cl(-) channel may be useful for therapy of CF. Here, we demonstrate that a range of general anesthetics like normal-alkanols (n-alkanols) and related compounds can stimulate the Cl(-) channel activity of wild-type CFTR and delF508-CFTR mutant. 2. The effects of n-alkanols like octanol on CFTR activity were measured by iodide ((125)I) efflux and patch-clamp techniques on three distinct cellular models: (1). CFTR-expressing Chinese hamster ovary cells, (2). human airway Calu-3 epithelial cells and (3). human airway JME/CF15 epithelial cells which express the delF508-CFTR mutant. 3. Our data show for the first time that n-alkanols activate both wild-type CFTR and delF508-CFTR mutant. Octanol stimulated (125)I efflux in a dose-dependent manner in CFTR-expressing cells (wild-type and delF508) but not in cell lines lacking CFTR. (125)I efflux and Cl(-) currents induced by octanol were blocked by glibenclamide but insensitive to 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, as expected for a CFTR Cl(-) current. 4. CFTR activation by octanol was neither due to cell-to-cell uncoupling properties of octanol nor to an intracellular cAMP increase. CFTR activation by octanol requires phosphorylation by protein kinase-A (PKA) since it was prevented by H-89, a PKA inhibitor. 5. n-Alkanols chain length was an important determinant for channel activation, with rank order of potencies: 1-heptanol<1-octanol<2-octanol<1-decanol. Our findings may be of valuable interest for developing novel therapeutic strategies for CF.

Increasing the Endoplasmic Reticulum Pool of the F508del Allele of the Cystic Fibrosis Transmembrane Conductance Regulator Leads to Greater Folding Correction by Small Molecule Therapeutics.

PubMed

Chung, W Joon; Goeckeler-Fried, Jennifer L; Havasi, Viktoria; Chiang, Annette; Rowe, Steven M; Plyler, Zackery E; Hong, Jeong S; Mazur, Marina; Piazza, Gary A; Keeton, Adam B; White, E Lucile; Rasmussen, Lynn; Weissman, Allan M; Denny, R Aldrin; Brodsky, Jeffrey L; Sorscher, Eric J

2016-01-01

Small molecules that correct the folding defects and enhance surface localization of the F508del mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) comprise an important therapeutic strategy for cystic fibrosis lung disease. However, compounds that rescue the F508del mutant protein to wild type (WT) levels have not been identified. In this report, we consider obstacles to obtaining robust and therapeutically relevant levels of F508del CFTR. For example, markedly diminished steady state amounts of F508del CFTR compared to WT CFTR are present in recombinant bronchial epithelial cell lines, even when much higher levels of mutant transcript are present. In human primary airway cells, the paucity of Band B F508del is even more pronounced, although F508del and WT mRNA concentrations are comparable. Therefore, to augment levels of "repairable" F508del CFTR and identify small molecules that then correct this pool, we developed compound library screening protocols based on automated protein detection. First, cell-based imaging measurements were used to semi-quantitatively estimate distribution of F508del CFTR by high content analysis of two-dimensional images. We evaluated ~2,000 known bioactive compounds from the NIH Roadmap Molecular Libraries Small Molecule Repository in a pilot screen and identified agents that increase the F508del protein pool. Second, we analyzed ~10,000 compounds representing diverse chemical scaffolds for effects on total CFTR expression using a multi-plate fluorescence protocol and describe compounds that promote F508del maturation. Together, our findings demonstrate proof of principle that agents identified in this fashion can augment the level of endoplasmic reticulum (ER) resident "Band B" F508del CFTR suitable for pharmacologic correction. As further evidence in support of this strategy, PYR-41-a compound that inhibits the E1 ubiquitin activating enzyme-was shown to synergistically enhance F508del rescue by C18, a small molecule corrector. Our combined results indicate that increasing the levels of ER-localized CFTR available for repair provides a novel route to correct F508del CFTR.

Fiber-optic components for optical communicatios and sensing =

NASA Astrophysics Data System (ADS)

Marques, Carlos Alberto Ferreira

Nos ultimos anos, a Optoelectronica tem sido estabelecida como um campo de investigacao capaz de conduzir a novas solucoes tecnologicas. As conquistas abundantes no campo da optica e lasers, bem como em comunicacoes opticas tem sido de grande importancia e desencadearam uma serie de inovacoes. Entre o grande numero de componentes opticos existentes, os componentes baseados em fibra optica sao principalmente relevantes devido a sua simplicidade e a elevada de transporte de dados da fibra optica. Neste trabalho foi focado um destes componentes opticos: as redes de difraccao em fibra optica, as quais tem propriedades opticas de processamento unicas. Esta classe de componentes opticos e extremamente atraente para o desenvolvimento de dispositivos de comunicacoes opticas e sensores. O trabalho comecou com uma analise teorica aplicada a redes em fibra e foram focados os metodos de fabricacao de redes em fibra mais utilizados. A inscricao de redes em fibra tambem foi abordado neste trabalho, onde um sistema de inscricao automatizada foi implementada para a fibra optica de silica, e os resultados experimentais mostraram uma boa aproximacao ao estudo de simulacao. Tambem foi desenvolvido um sistema de inscricao de redes de Bragg em fibra optica de plastico. Foi apresentado um estudo detalhado da modulacao acustico-optica em redes em fibra optica de silica e de plastico. Por meio de uma analise detalhada dos modos de excitacao mecanica aplicadas ao modulador acustico-optico, destacou-se que dois modos predominantes de excitacao acustica pode ser estabelecidos na fibra optica, dependendo da frequencia acustica aplicada. Atraves dessa caracterizacao, foi possivel desenvolver novas aplicacoes para comunicacoes opticas. Estudos e implementacao de diferentes dispositivos baseados em redes em fibra foram realizados, usando o efeito acustico-optico e o processo de regeneracao em fibra optica para varias aplicacoes tais como rapido multiplexador optico add-drop, atraso de grupo sintonizavel de redes de Bragg, redes de Bragg com descolamento de fase sintonizaveis, metodo para a inscricao de redes de Bragg com perfis complexos, filtro sintonizavel para equalizacao de ganho e filtros opticos notch ajustaveis.

Identifying mutations in Tunisian families with retinal dystrophy.

PubMed

Habibi, Imen; Chebil, Ahmed; Falfoul, Yosra; Allaman-Pillet, Nathalie; Kort, Fedra; Schorderet, Daniel F; El Matri, Leila

2016-11-22

Retinal dystrophies (RD) are a rare genetic disorder with high genetic heterogeneity. This study aimed at identifying disease-causing variants in fifteen consanguineous Tunisian families. Full ophthalmic examination was performed. Index patients were subjected to IROme analysis or whole exome sequencing followed by homozygosity mapping. All detected variations were confirmed by direct Sanger sequencing. Mutation analysis in our patients revealed two compound heterozygous mutations p.(R91W);(V172D) in RPE65, and five novel homozygous mutations: p.R765C in CNGB1, p.H337R in PDE6B, splice site variant c.1129-2A > G and c.678_681delGAAG in FAM161A and c.1133 + 3_1133 + 6delAAGT in CERKL. The latter mutation impacts pre-mRNA splicing of CERKL. The other changes detected were six previously reported mutations in CNGB3 (p.R203*), ABCA4 (p.W782*), NR2E3 (p.R311Q), RPE65 (p.H182Y), PROM1 (c.1354dupT) and EYS (c.5928-2A > G). Segregation analysis in each family showed that all affected individuals were homozygotes and unaffected individuals were either heterozygote carriers or homozygous wild type allele. These results confirm the involvement of a large number of genes in RD in the Tunisian population.

The USH2A c.2299delG mutation: dating its common origin in a Southern European population

PubMed Central

Aller, Elena; Larrieu, Lise; Jaijo, Teresa; Baux, David; Espinós, Carmen; González-Candelas, Fernando; Nájera, Carmen; Palau, Francesc; Claustres, Mireille; Roux, Anne-Françoise; Millán, José M

2010-01-01

Usher syndrome type II is the most common form of Usher syndrome. USH2A is the main responsible gene of the three known to be disease causing. It encodes two isoforms of the protein usherin. This protein is part of an interactome that has an essential role in the development and function of inner ear hair cells and photoreceptors. The gene contains 72 exons spanning over a region of 800 kb. Although numerous mutations have been described, the c.2299delG mutation is the most prevalent in several populations. Its ancestral origin was previously suggested after the identification of a common core haplotype restricted to 250 kb in the 5′ region that encodes the short usherin isoform. By extending the haplotype analysis over the 800 kb region of the USH2A gene with a total of 14 intragenic single nucleotide polymorphisms, we have been able to define 10 different c.2299delG haplotypes, showing high variability but preserving the previously described core haplotype. An exhaustive c.2299delG/control haplotype study suggests that the major source of variability in the USH2A gene is recombination. Furthermore, we have evidenced twice the amount of recombination hotspots located in the 500 kb region that covers the 3′ end of the gene, explaining the higher variability observed in this region when compared with the 250 kb of the 5′ region. Our data confirm the common ancestral origin of the c.2299delG mutation. PMID:20145675

FEASIL Implementation under VAX VMS with Design Information.

DTIC Science & Technology

1986-11-01

desirable to eventually port FEASIL to the HP 9000, the IBM PC, and several other com- puters. However, the flowcharting and VAX conversion efforts have...v W l EU l l~rl EDIIkEL (pg 12) DEL El’F TJ-’LE C rr~PACE 13 HPvrwrH IIUpdate the I Itpe DescrL c ðere tau,1es remaining nthe relatioil ? ye

Curriculum Guide for Spanish Language Arts, Primary Level C = Guia para la ensenanza de las artes del lenguaje espanol, primaria, nivel C. (Grade 1).

ERIC Educational Resources Information Center

Chicago Board of Education, IL. Dept. of Curriculum.

The curriculum guide for teachers of Spanish language arts for native Spanish-speaking primary students in the Chicago public schools' bilingual education program is introduced by a section defining the areas to be emphasized in the program: word attack, comprehension skills, study skills, literature appreciation, and writing skills. Sections…

A Novel Homozygous Mutation in FOXC1 Causes Axenfeld Rieger Syndrome with Congenital Glaucoma

PubMed Central

Micheal, Shazia; Villanueva-Mendoza, Cristina; Cortés-González, Vianney; Khan, Muhammad Imran; den Hollander, Anneke I.

2016-01-01

Background Anterior segment dysgenesis (ASD) disorders are a group of clinically and genetically heterogeneous phenotypes in which frequently cornea, iris, and lens are affected. This study aimed to identify novel mutations in PAX6, PITX2 and FOXC1 in families with anterior segment dysgenesis disorders. Methods We studied 14 Pakistani and one Mexican family with Axenfeld Rieger syndrome (ARS; n = 10) or aniridia (n = 5). All affected and unaffected family members underwent full ophthalmologic and general examinations. Total genomic DNA was isolated from peripheral blood. PCR and Sanger sequencing were performed for the exons and intron-exon boundaries of the FOXC1, PAX6, and PITX2 genes. Results Mutations were identified in five of the 15 probands; four variants were novel and one variant was described previously. A novel de novo variant (c.225C>A; p.Tyr75*) was identified in the PAX6 gene in two unrelated probands with aniridia. In addition, a known variant (c.649C>T; p.Arg217*) in PAX6 segregated in a family with aniridia. In the FOXC1 gene, a novel heterozygous variant (c.454T>C; p.Trp152Arg) segregated with the disease in a Mexican family with ARS. A novel homozygous variant (c.92_100del; p.Ala31_Ala33del) in the FOXC1 gene segregated in a Pakistani family with ARS and congenital glaucoma. Conclusions Our study expands the mutation spectrum of the PAX6 and FOXC1 genes in individuals with anterior segment dysgenesis disorders. In addition, our study suggests that FOXC1 mutations, besides typical autosomal dominant ARS, can also cause ARS with congenital glaucoma through an autosomal recessive inheritance pattern. Our results thus expand the disease spectrum of FOXC1, and may lead to a better understanding of the role of FOXC1 in development. PMID:27463523

A Novel Homozygous Mutation in FOXC1 Causes Axenfeld Rieger Syndrome with Congenital Glaucoma.

PubMed

Micheal, Shazia; Siddiqui, Sorath Noorani; Zafar, Saemah Nuzhat; Villanueva-Mendoza, Cristina; Cortés-González, Vianney; Khan, Muhammad Imran; den Hollander, Anneke I

2016-01-01

Anterior segment dysgenesis (ASD) disorders are a group of clinically and genetically heterogeneous phenotypes in which frequently cornea, iris, and lens are affected. This study aimed to identify novel mutations in PAX6, PITX2 and FOXC1 in families with anterior segment dysgenesis disorders. We studied 14 Pakistani and one Mexican family with Axenfeld Rieger syndrome (ARS; n = 10) or aniridia (n = 5). All affected and unaffected family members underwent full ophthalmologic and general examinations. Total genomic DNA was isolated from peripheral blood. PCR and Sanger sequencing were performed for the exons and intron-exon boundaries of the FOXC1, PAX6, and PITX2 genes. Mutations were identified in five of the 15 probands; four variants were novel and one variant was described previously. A novel de novo variant (c.225C>A; p.Tyr75*) was identified in the PAX6 gene in two unrelated probands with aniridia. In addition, a known variant (c.649C>T; p.Arg217*) in PAX6 segregated in a family with aniridia. In the FOXC1 gene, a novel heterozygous variant (c.454T>C; p.Trp152Arg) segregated with the disease in a Mexican family with ARS. A novel homozygous variant (c.92_100del; p.Ala31_Ala33del) in the FOXC1 gene segregated in a Pakistani family with ARS and congenital glaucoma. Our study expands the mutation spectrum of the PAX6 and FOXC1 genes in individuals with anterior segment dysgenesis disorders. In addition, our study suggests that FOXC1 mutations, besides typical autosomal dominant ARS, can also cause ARS with congenital glaucoma through an autosomal recessive inheritance pattern. Our results thus expand the disease spectrum of FOXC1, and may lead to a better understanding of the role of FOXC1 in development.

[Polymorphisms of inhibin α gene exon 1 in buffalo (Bubalus bubalis), gayal (Bos frontalis) and yak (Bos grunniens)].

PubMed

Miao, Yong-Wang; Ha, Fu; Gao, Hua-Shan; Yuan, Feng; Li, Da-Lin; Yuan, Yue-Yun

2012-08-01

To elucidate the genetic characteristics of the bovine Inhibin α subunit (INHA) gene, the polymorphisms in exon 1 of INHA and its bilateral sequences were assayed using PCR with direct sequencing in buffalo, gayal and yak. A comparative analysis was conducted by pooled the results in this study with the published data of INHA on some mammals including some bovine species together. A synonymous substitution c.73C>A was identified in exon 1 of INHA for buffalo, which results in identical encoding product in river and swamp buffalo. In gayal, two non-synonymous but same property substitutions in exon 1 of INHA, viz. c.62 C>T and c.187 G>A, were detected, which lead to p. P21L, p. V63M changes in INHA, respectively. In yak, nucleotide substitution c.62C> T, c.129A>G were found in exon 1 of INHA, the former still causes p. P21L substitution and the latter is synonymous. For the sequence of the 5'-flanking region of INHA examined, no SNPs were found within the species, but a substitution, c. -6T>G, was found. The nucleotide in this site in gayal, yak and cattle was c. -6G, whereas in buffalo it was c. -6T. Meanwhile, a 6-bp deletion, namely c. 262+31_262+36delTCTGAC, was found in the intron of buffalo INHA gene. For this deletion, wild types (+/+) account for main part in river buffalo while mutant types (-/-) are predominant in swamp buffalo. This deletion was not found in gayal, yak and cattle, though these all have another deletion in the intron of INHA, c. 262+78_262+79delTG. The results of sequence alignment showed that the substitutions c. 43A and c. 67G in exon 1 of INHA are specific to buffalo, whereas the substitutions c. 173A and c. 255G are exclusive to gayal, yak and cattle, and c. 24C, c. 47G, c. 174T and c. 206T are specific to goat. Furthermore, there are few differences among gayal, yak and cattle, but there relatively great differences between buffalo, goat and other bovine species regarding the sequences of INHA exon 1.

Screening of LDLR and APOB gene mutations in Mexican patients with homozygous familial hypercholesterolemia.

PubMed

Hernández Flores, Teresita De Jesús; González García, Juan Ramón; Colima Fausto, Ana Gabriela; Vázquez Cárdenas, Norma Alejandra; Sánchez López, Yoaly; Zarate Morales, César Augusto; Magaña Torres, María Teresa

Familial hypercholesterolemia (FH) is an autosomal dominant disorder that causes accumulation of serum low-density lipoprotein cholesterol and premature cardiovascular disease. It is mainly related to mutations in the LDLR gene. Homozygous FH (HoFH) patients have the most severe form of the disease accounting for a worldwide prevalence of 1:1,000,000. In Mexico, at least 5 cases of HoFH have been reported. The aim of this study was to describe the clinical, biochemical, and molecular data observed in patients with HoFH phenotype. We included 13 patients, belonging to 11 families, with clinical and biochemical diagnoses suggestive of HoFH. Molecular analyses of the LDLR and APOB genes were performed by means of polymerase chain reaction followed by Sanger sequencing. The causal mutation of HoFH was found in 8 of 11 unrelated patients. Excepting 1, all were true homozygotes. Six different variants in LDLR were identified: c.-139delCTCCCCCTGC, p.Glu140Lys, p.Asp360His, p.Asn405Lys, p.Ala755Glyfs*7, and p.Leu759Serfs*6. Of these, p.Asp360His and p.Asn405Lys were detected for the first time in Mexico; p.Leu759Serfs*6 showed to be the most frequent (43.7% of the alleles 7/16), and c.-139delCTCCCCCTGC is a new variant located in the promoter region. This work increases knowledge of biochemical and genetic features in Mexican patients with HoFH. A novel mutation in the LDLR gene promoter was detected: c.-139delCTCCCCCTGC, which possibly inhibits its expression. Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Prevalence of GJB2 Mutations in Affected Individuals from United Arab Emirates with Autosomal Recessive Nonsyndromic Hearing Loss.

PubMed

Tlili, Abdelaziz; Al Mutery, Abdullah; Kamal Eddine Ahmad Mohamed, Walaa; Mahfood, Mona; Hadj Kacem, Hassen

2017-11-01

Mutations in the gap junction protein beta 2 (GJB2) gene are responsible for more cases of nonsyndromic recessive hearing loss than any other gene. The purpose of our study was to evaluate the prevalence of GJB2 mutations among affected individuals from United Arab Emirates (UAE). There were 50 individuals diagnosed with hereditary hearing loss and 120 healthy individuals enrolled in the study. The Sanger sequencing method was used to screen the GJB2 coding region in all affected individuals. The c.-1G>A variant was determined by the polymerase chain reaction-restriction fragment length polymorphism method in normal individuals. Nine cases with bi-allelic mutations and three cases with mono-allelic mutations were detected in 12 out of 50 patients (24%). The homozygous mutation c.35delG was identified as the cause of hearing loss in six participants (12%). The mutation c.506G>A was identified in three affected individuals (6%). The allelic frequency (14%) and low percentage of individuals that were homozygous (2%) for the c.35delG mutation suggest that there are other genes responsible for nonsyndromic deafness in the UAE population. The results reported here are a preliminary step in collecting epidemiological data regarding autosomal recessive nonsyndromic hearing loss related to GJB2 gene mutations among the UAE population. The c.35delG mutation of the GJB2 gene is the most frequently seen causative mutation in the UAE and is followed by the p.Cys169Tyr mutation.

A novel FLNC frameshift and an OBSCN variant in a family with distal muscular dystrophy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rossi, Daniela; Palmio, Johanna; Evilä, Anni

A novel FLNC c.5161delG (p.Gly1722ValfsTer61) mutation was identified in two members of a French family affected by distal myopathy and in one healthy relative. This FLNC c.5161delG mutation is one nucleotide away from a previously reported FLNC mutation (c.5160delC) that was identified in patients and in asymptomatic carriers of three Bulgarian families with distal muscular dystrophy, indicating a low penetrance of the FLNC frameshift mutations. Given these similarities, we believe that the two FLNC mutations alone can be causative of distal myopathy without full penetrance. Moreover, comparative analysis of the clinical manifestations indicates that patients of the French family showmore » an earlier onset and a complete segregation of the disease. As a possible explanation of this, the two French patients also carry a OBSCN c.13330C>T (p.Arg4444Trp) mutation. The p.Arg4444Trp variant is localized within the OBSCN Ig59 domain that, together with Ig58, binds to the ZIg9/ZIg10 domains of titin at Z-disks. Structural and functional studies indicate that this OBSCN p.Arg4444Trp mutation decreases titin binding by ~15-fold. On this line, we suggest that the combination of the OBSCN p.Arg4444Trp variant and of the FLNC c.5161delG mutation, can cooperatively affect myofibril stability and increase the penetrance of muscular dystrophy in the French family.« less

Downstream of downtown: urban wastewater as groundwater recharge

NASA Astrophysics Data System (ADS)

Foster, S. S. D.; Chilton, P. J.

Wastewater infiltration is often a major component of overall recharge to aquifers around urban areas, especially in more arid climates. Despite this, such recharge still represents only an incidental (or even accidental) byproduct of various current practices of sewage effluent handling and wastewater reuse. This topic is reviewed through reference to certain areas of detailed field research, with pragmatic approaches being identified to reduce the groundwater pollution hazard of these practices whilst attempting to retain their groundwater resource benefit. Since urban sewage effluent is probably the only `natural resource' whose global availability is steadily increasing, the socioeconomic importance of this topic for rapidly developing urban centres in the more arid parts of Asia, Africa, Latin America and the Middle East will be apparent. L'infiltration des eaux usées est souvent la composante essentielle de toute la recharge des aquifères des zones urbaines, particulièrement sous les climats les plus arides. Malgré cela, une telle recharge ne constitue encore qu'un sous-produit incident, ou même accidentel, de pratiques courantes variées du traitement de rejets d'égouts et de réutilisation d'eaux usées. Ce sujet est passé en revue en se référant à certaines régions étudiées en détail, par des approches pragmatiques reconnues pour permettre de réduire les risques de pollution des nappes dues à ces pratiques tout en permettant d'en tirer profit pour leur ressource en eau souterraine. Puisque les effluents d'égouts urbains sont probablement la seule « ressource naturelle » dont la disponibilité globale va croissant constamment, l'importance socio-économique de ce sujet est évidente pour les centres urbains à développement rapide de l'Asie, de l'Afrique, de l'Amérique latine et du Moyen-Orient. La infiltración de aguas residuales es a menudo un componente principal de la recarga total en acuíferos ubicados en torno a zonas urbanas, especialmente en los climas más áridos. A pesar de ello, dicho componente todavía es una consecuencia secundaria (o incluso accidental) de diversas prácticas asociadas con la manipulación de las aguas residuales y con la reutilitzación de aguas depuradas. Este tema se revisa mediante referencias a ciertas áreas en las que existen investigación detallada de campo, identificando enfoques pragmáticos con el fin de reducir el riesgo de contaminación de las aguas subterráneas por tales prácticas, a la vez tratando de conservar los beneficios para los recursos del acuífero. Dado que los efluentes de aguas residuales urbanas son probablemente la única `fuente natural' cuya disponibilidad global se halla en del aumento, la importancia socioeconómica de este tema será evidente para los centros urbanos de rápido desarrollo en Asia, Latinoamérica y Oriente Medio.

Quality management systems for fruit fly (Diptera: Tephritidae) sterile insect technique

DOE Office of Scientific and Technical Information (OSTI.GOV)

Caceres, C.; Robinson, A.; McInnis, D.

The papers presented in this issue are focused on developing and validating procedures to improve the overall quality of sterile fruit flies for use in area-wide integrated pest management (AW-IPM) programs with a sterile insect technique (SIT) component. The group was coordinated and partially funded by the Joint FAO/IAEA Programme of Nuclear Techniques in Food and Agriculture, International Atomic Energy Agency, Vienna, Austria, under a five-year Coordinated Research Project (CRP) on 'Quality Assurance in Mass-Reared and Released Fruit Flies for Use in SIT Programmes'. Participants in the CRP from 16 countries came from both basic and applied fields of expertisemore » to ensure that appropriate and relevant procedures were developed. A variety of studies was undertaken to develop protocols to assess strain compatibility and to improve colonization procedures and strain management. Specific studies addressed issues related to insect nutrition, irradiation protocols, field dispersal and survival, field cage behavior assessments, and enhancement of mating competitiveness. The main objective was to increase the efficiency of operational fruit fly programs using sterile insects and to reduce their cost. Many of the protocols developed or improved during the CRP will be incorporated into the international quality control manual for sterile tephritid fruit flies, standardizing key components of the production, sterilization, shipment, handling, and release of sterile insects. (author) [Spanish] Los articulos presentados en este numero se enfocan en el desarrollo y la validacion de procedimientos para mejorar la calidad total de moscas de las frutas esteriles para su uso en programas de manejo integrado de plagas en donde la tecnica del insecto esteril (TIE) es uno de los componentes clave. El grupo fue coordinado y parcialmente financiado por la Division Conjunta de Tecnicas Nucleares para la Alimentacion y la Agricultura de la FAO/OIEA, Viena, Austria, por un periodo de cinco anos bajo el proyecto de Investigacion Coordinada (PIC) sobre 'el Aseguramiento de la Calidad de Moscas de las Frutas Criadas y Liberadas para su Uso en Programas de TIE'. Los participantes en el PIC representan 16 paises con experiencia en campos de investigacion basica y aplicada. Para asegurar que los procedimientos desarrollados fueran apropiados y pertinentes, se realizaron una variedad de estudios para el desarrollo de protocolos para evaluar la compatibilidad y para mejorar los procedimientos de colonizacion y manejo de cepas salvajes. Estudios especificos trataron asuntos relacionados con la nutricion de insectos, los protocolos de irradiacion, la dispersion y supervivencia en el campo, evaluacion del comportamiento en jaulas de campo, y el mejoramiento de la competitividad sexual. Los objetivos fundamentales fueron el aumentar la eficiencia y reducir los costos de los programas operacionales de control de moscas de las frutas donde TIE es utilizada. Muchos de los protocolos desarrollados o mejorados durante el PIC seran incorporados en el Manual Internacional de Control de Calidad para Moscas Estriles de la familia Tephritidae, para estandarizar componentes claves como la produccion, esterilizacion, envio, manejo y liberacion de insectos esteriles. (author)« less

Velocidades radiales Coravel y fotometría UBV de gigantes rojas del cúmulo abierto Melotte71

NASA Astrophysics Data System (ADS)

Mermilliod, J. C.; Clariá, J. J.; Andersen, J.; Mayor, M.

Se presentan velocidades radiales determinadas con el espectrovelocímetro CORAVEL y fotometría UBV de 24 gigantes rojas del cúmulo abierto de edad-intermedia Melotte71. Las observaciones realizadas en La Silla y Cerro Tololo permiten confirmar la pertenencia al cúmulo de 16 estrellas, de las cuales 8 constituyen nuevas binarias espectroscópicas cuyos períodos oscilan entre 74 y 1627 días. La velocidad radial media es +57.17 ± 0.47 km/s. El mejor ajuste con una isócrona teórica se obtiene para log t (edad) = 9.00 y Z = 0.008, no obstante existir algunas discrepancias respecto de la ubicación predicha y observada del ``clump".

Annual Fossil-Fuel CO2 Emissions: Global Stable Carbon Isotopic Signature (1751-2008) (DB1013 V.2011)

DOE Data Explorer

Andres, R. J. [CDIAC, Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (USA); Boden, T. A. [CDIAC, Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (USA); Marland, G. [CDIAC, Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (USA)

1996-01-01

The 2011 revision of this database contains estimates of the annual, global mean value of del 13C of CO2 emissions from fossil-fuel consumption and cement manufacture for 1751-2008. These estimates of the carbon isotopic signature account for the changing mix of coal, petroleum, and natural gas being consumed and for the changing mix of petroleum from various producing areas with characteristic isotopic signatures. This time series of global fossil-fuel del 13C signature provides an additional constraint for balancing the sources and sinks of the global carbon cycle and complements the atmospheric del 13C measurements that are used to partition the uptake of fossil carbon emissions among the ocean, atmosphere, and terrestrial biosphere reservoirs.

Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer.

PubMed

Cybulski, Cezary; Wokołorczyk, Dominika; Jakubowska, Anna; Huzarski, Tomasz; Byrski, Tomasz; Gronwald, Jacek; Masojć, Bartłomiej; Deebniak, Tadeusz; Górski, Bohdan; Blecharz, Paweł; Narod, Steven A; Lubiński, Jan

2011-10-01

To estimate the risk of breast cancer in a woman who has a CHEK2 mutation depending on her family history of breast cancer. Seven thousand four hundred ninety-four BRCA1 mutation-negative patients with breast cancer and 4,346 control women were genotyped for four founder mutations in CHEK2 (del5395, IVS2+1G>A, 1100delC, and I157T). A truncating mutation (IVS2+1G>A, 1100delC, or del5395) was present in 227 patients (3.0%) and in 37 female controls (0.8%; odds ratio [OR], 3.6; 95% CI, 2.6 to 5.1). The OR was higher for women with a first- or second-degree relative with breast cancer (OR, 5.0; 95% CI, 3.3 to 7.6) than for women with no family history (OR, 3.3; 95% CI, 2.3 to 4.7). If both a first- and second-degree relative were affected with breast cancer, the OR was 7.3 (95% CI, 3.2 to 16.8). Assuming a baseline risk of 6%, we estimate the lifetime risks for carriers of CHEK2 truncating mutations to be 20% for a woman with no affected relative, 28% for a woman with one second-degree relative affected, 34% for a woman with one first-degree relative affected, and 44% for a woman with both a first- and second-degree relative affected. CHEK2 mutation screening detects a clinically meaningful risk of breast cancer and should be considered in all women with a family history of breast cancer. Women with a truncating mutation in CHEK2 and a positive family history of breast cancer have a lifetime risk of breast cancer of greater than 25% and are candidates for magnetic resonance imaging screening and for tamoxifen chemoprevention.

Isolation of Breast Tumor Suppressor Genes from Chromosome 11p.

DTIC Science & Technology

1998-09-01

tumors . Figure 7b shows the SSCA pattern of exon 2 amplified from paired normal/ tumor samples from four different Wilms tumor patients. Sample 1 is...G., Chaussain, J.L., Junien, C. Tumor specific loss of IIp 15.5 alleles in del 1 lp 13 Wilms tumor and in familial adrenocortical carcinoma. Proc...Chilton-MacNeill,S., Campbell, C.E., Weksberg, R., Yeger, H., Reeve, A.E. and Williams, B.R.G. Loss of heterozygosity mapping in Wilms tumor

Clinical and genetic characteristics of Pseudohypoparathyroidism in the Chinese population.

PubMed

Chu, Xueying; Zhu, Yan; Wang, Ou; Nie, Min; Quan, Tingting; Xue, Yu; Wang, Wenbo; Jiang, Yan; Li, Mei; Xia, Weibo; Xing, Xiaoping

2018-02-01

Pseudohypoparathyroidism (PHP) is caused by mutations and epimutations in the GNAS locus, and characterized by the possibility of resistance to multiple hormones and Albright's hereditary osteodystrophy. PHP can be classified into the forms 1A/C, sporadic 1B and familial 1B. To obtain an overall view of the clinical and genetic characteristics of the Chinese PHP patient population. From 2000 to 2016, 120 patients were recruited and studied using Sanger sequencing, methylation-specific multiple ligation-dependent probe amplification (MS-MLPA) and combined bisulfite restriction analysis (COBRA). Of these patients, 104 had positive molecular alterations indicative of certain forms of PHP and were included in data analysis. Clinical and laboratory features were compared between PHP1A/C and PHP1B patients. Ten PHP1A/C, 21 familial PHP1B and 73 sporadic PHP1B patients were identified. Four novel GNAS mutations were discovered in these patients, including c.1038+1G>T, c.530+2T>C, c.880_883delCAAG and c.311_312delAAG, insT. The most common symptoms in this series were recurrent tetany (89.4%) and epilepsy (47.1%). The prevalence of weight excess increased with age for PHP1B (10%-35%) and PHP1A/C (50%-75%). Intracranial calcification had a prevalence of 94.6% and correlated with seizures (r = .227, P = .029). Cataracts occurred in 56.2% PHP patients, and there was a trend towards longer disease duration in patients with cataracts (P = .051). Statistically significant differences (P < .05) were observed when comparing certain clinical characteristics between PHP1B and PHP1A/C patients, including age of onset (10 vs 7 year), short stature (21.3% vs 70%), rounded face (60.6% vs 100%), brachydactyly (25.5% vs 100%), ectopic ossification (1.1% vs 40%) and TSH resistance (44.6% vs 90%), respectively. This study is the largest single-centre series of PHP patients and summarizes the clinical and genetic features of the Chinese PHP population. While there was substantial clinical overlap between PHP1A/C and PHP1B, differences in disease progression were observed. © 2017 John Wiley & Sons Ltd.

Magnetohydrodynamic and Paramagnetic Phenomena in Electrochemistry with Diamagnetic and Ferromagnetic Millielectrodes

NASA Technical Reports Server (NTRS)

Leventis, Nicholas; Dass, Amala

2004-01-01

There are three kinds of body forces operating in electrolytic solutions in the magnetic field: the magnetohydrodynamic force F(sub B) (=i x B), the F(sub delB) force (approximately B(raised dot)gradB) and the F(sub delC) force (approximately |B|(sup 2)gradC). These three forces manifest themselves differently, depending on the experimental conditions. Thus, diamagnetic disc millielectrodes (e.g., Au) with their plane parallel to the flux density of the homogeneous magnetic field of an electromagnet yield convective behavior analogous to that observed with rotating electrodes; that response is controlled by F(sub B). The same electrodes placed in the inhomogeneous field of a strong permanent magnet yield also convective behavior that is controlled by both F(sub B) and F(sub delB). Finally, similarly sized millielectrodes made of permanent magnets (e.g., Au-coated Nd-Fe-B discs) yield diffusion-controlled behavior at conditions where a gold disc electrode shows behavior dominated by density gradient driven natural convection; in this case the predominant forces are both F(sub delB) and F(sub delC). Under open circuit conditions, ferromagnetic (i.e., magnetizable) millielectrodes (Co, Fe, Ni) dipped in corrosive solutions and placed in homogeneous magnetic fields yield mass-transfer phenomena that seem to be controlled by magnetophoresis.

The importance of proper bioinformatics analysis and clinical interpretation of tumor genomic profiling: a case study of undifferentiated sarcoma and a constitutional pathogenic BRCA2 mutation and an MLH1 variant of uncertain significance.

PubMed

Varga, Elizabeth; Chao, Elizabeth C; Yeager, Nicholas D

2015-09-01

Next-generation sequencing (NGS) technology is increasingly utilized to identify therapeutic targets for patients with malignancy. This technology also has the capability to reveal the presence of constitutional genetic alterations, which may have significant implications for patients and their family members. Here we present the case of a 23 year old Caucasian patient with recurrent undifferentiated sarcoma who had NGS-based tumor analysis using an assay which simultaneously analyzed the entire coding sequence of 236 cancer-related genes (3769 exons) plus 47 introns from 19 genes often rearranged or altered in cancer. Pathogenic alterations were reported in tumor as the predicted protein alterations, BRCA2 "R645fs*15″ and MLH1 "E694*". Because constitutional BRCA2 and MLH1 gene mutations are associated with Hereditary Breast Ovarian Cancer Syndrome (HBOCS) and Lynch syndrome respectively, sequence analysis of DNA isolated from peripheral blood was performed. The presence of the alterations, BRCA2 c.1929delG and MLH1 c.2080G>T, corresponding to the previously reported predicted protein alterations, were confirmed by Sanger sequencing in the constitutional DNA. An additional DNA finding was reported in this analysis, MLH1 c.2081A>C at the neighboring nucleotide. Further evaluation of the family revealed that all alterations were paternally inherited and the two MLH1 substitutions were in cis, more appropriately referred to as MLH1 c.2080_2081delGAinsTC, which is classified as a variant of uncertain significance. This case illustrates important considerations related to appropriate interpretation of NGS tumor results and follow-up of patients with potentially deleterious constitutional alterations.

Job Language Performance Requirements for MOS-62J, General Construction Equipment Operator, Reference Soldier’s Manual Dated 28 September 1979.

DTIC Science & Technology

1979-09-28

DAAosrt O14.NE VRO1 H__IH_1_________1_______1 1~~hN EIl 1___________ dsknind.o ~~~importance aCCA .Is %1* NU%3E OF REODE D RATA OBTAINED FROM...9~44r £LM2 ae1s ~ Am 424~~del 4e A ~-~. f3 N w ~ Ail 2~ZV41/- t-.. c4 fz d/1,C4t let e -~4Z tz 4L~ fl~4k*1 Wed 4 4-’V 4~bf6144a- 6d>zi.i Z a~ r

A novel mutation in the MITF may be digenic with GJB2 mutations in a large Chinese family of Waardenburg syndrome type II.

PubMed

Yan, Xukun; Zhang, Tianyu; Wang, Zhengmin; Jiang, Yi; Chen, Yan; Wang, Hongyan; Ma, Duan; Wang, Lei; Li, Huawei

2011-12-20

Waardenburg syndrome type II (WS2) is associated with syndromic deafness. A subset of WS2, WS2A, accounting for approximately 15% of patients, is attributed to mutations in the microphthalmia-associated transcription factor (MITF) gene. We examined the genetic basis of WS2 in a large Chinese family. All 9 exons of the MITF gene, the single coding exon (exon 2) of the most common hereditary deafness gene GJB2 and the mitochondrial DNA (mtDNA) 12S rRNA were sequenced. A novel heterozygous mutation c.[742_743delAAinsT;746_747delCA] in exon 8 of the MITF gene co-segregates with WS2 in the family. The MITF mutation results in a premature termination codon and a truncated MITF protein with only 247 of the 419 wild type amino acids. The deaf proband had this MITF gene heterozygous mutation as well as a c.[109G>A]+[235delC] compound heterozygous pathogenic mutation in the GJB2 gene. No pathogenic mutation was found in mtDNA 12S rRNA in this family. Thus, a novel compound heterozygous mutation, c.[742_743delAAinsT;746_747delCA] in MITF exon 8 was the key genetic reason for WS2 in this family, and a digenic effect of MITF and GJB2 genes may contribute to deafness of the proband. Copyright © 2011. Published by Elsevier Ltd.

PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

PubMed Central

Southey, Melissa C; Goldgar, David E; Winqvist, Robert; Pylkäs, Katri; Couch, Fergus; Tischkowitz, Marc; Foulkes, William D; Dennis, Joe; Michailidou, Kyriaki; van Rensburg, Elizabeth J; Heikkinen, Tuomas; Nevanlinna, Heli; Hopper, John L; Dörk, Thilo; Claes, Kathleen BM; Reis-Filho, Jorge; Teo, Zhi Ling; Radice, Paolo; Catucci, Irene; Peterlongo, Paolo; Tsimiklis, Helen; Odefrey, Fabrice A; Dowty, James G; Schmidt, Marjanka K; Broeks, Annegien; Hogervorst, Frans B; Verhoef, Senno; Carpenter, Jane; Clarke, Christine; Scott, Rodney J; Fasching, Peter A; Haeberle, Lothar; Ekici, Arif B; Beckmann, Matthias W; Peto, Julian; dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Bolla, Manjeet K; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Marme, Federik; Burwinkel, Barbara; Yang, Rongxi; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Bojesen, Stig; Nielsen, Sune F; Flyger, Henrik; Benitez, Javier; Zamora, M Pilar; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan; Ziogas, Argyrios; Clarke, Christina A; Brenner, Hermann; Arndt, Volker; Stegmaier, Christa; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon-Dschun; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Bogdanova, Natalia V; Antonenkova, Natalia N; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Spurdle, Amanda B; Investigators, kConFab; Wauters, Els; Smeets, Dominiek; Beuselinck, Benoit; Floris, Giuseppe; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Olson, Janet E; Vachon, Celine; Pankratz, Vernon S; McLean, Catriona; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Kristensen, Vessela; Alnæs, Grethe Grenaker; Zheng, Wei; Hunter, David J; Lindstrom, Sara; Hankinson, Susan E; Kraft, Peter; Andrulis, Irene; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Jukkola-Vuorinen, Arja; Grip, Mervi; Kauppila, Saila; Devilee, Peter; Tollenaar, Robert A E M; Seynaeve, Caroline; Hollestelle, Antoinette; Garcia-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Eccles, Diana M; Rafiq, Sajjad; Tapper, William J; Gerty, Sue M; Hooning, Maartje J; Martens, John W M; Collée, J Margriet; Tilanus-Linthorst, Madeleine; Hall, Per; Li, Jingmei; Brand, Judith S; Humphreys, Keith; Cox, Angela; Reed, Malcolm W R; Luccarini, Craig; Baynes, Caroline; Dunning, Alison M; Hamann, Ute; Torres, Diana; Ulmer, Hans Ulrich; Rüdiger, Thomas; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Slager, Susan; Toland, Amanda E; Ambrosone, Christine B; Yannoukakos, Drakoulis; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Jones, Michael; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Simard, Jacques; Dumont, Martine; Soucy, Penny; Eeles, Rosalind; Muir, Kenneth; Wiklund, Fredrik; Gronberg, Henrik; Schleutker, Johanna; Nordestgaard, Børge G; Weischer, Maren; Travis, Ruth C; Neal, David; Donovan, Jenny L; Hamdy, Freddie C; Khaw, Kay-Tee; Stanford, Janet L; Blot, William J; Thibodeau, Stephen; Schaid, Daniel J; Kelley, Joseph L; Maier, Christiane; Kibel, Adam S; Cybulski, Cezary; Cannon-Albright, Lisa; Butterbach, Katja; Park, Jong; Kaneva, Radka; Batra, Jyotsna; Teixeira, Manuel R; Kote-Jarai, Zsofia; Olama, Ali Amin Al; Benlloch, Sara; Renner, Stefan P; Hartmann, Arndt; Hein, Alexander; Ruebner, Matthias; Lambrechts, Diether; Van Nieuwenhuysen, Els; Vergote, Ignace; Lambretchs, Sandrina; Doherty, Jennifer A; Rossing, Mary Anne; Nickels, Stefan; Eilber, Ursula; Wang-Gohrke, Shan; Odunsi, Kunle; Sucheston-Campbell, Lara E; Friel, Grace; Lurie, Galina; Killeen, Jeffrey L; Wilkens, Lynne R; Goodman, Marc T; Runnebaum, Ingo; Hillemanns, Peter A; Pelttari, Liisa M; Butzow, Ralf; Modugno, Francesmary; Edwards, Robert P; Ness, Roberta B; Moysich, Kirsten B; du Bois, Andreas; Heitz, Florian; Harter, Philipp; Kommoss, Stefan; Karlan, Beth Y; Walsh, Christine; Lester, Jenny; Jensen, Allan; Kjaer, Susanne Krüger; Høgdall, Estrid; Peissel, Bernard; Bonanni, Bernardo; Bernard, Loris; Goode, Ellen L; Fridley, Brooke L; Vierkant, Robert A; Cunningham, Julie M; Larson, Melissa C; Fogarty, Zachary C; Kalli, Kimberly R; Liang, Dong; Lu, Karen H; Hildebrandt, Michelle A T; Wu, Xifeng; Levine, Douglas A; Dao, Fanny; Bisogna, Maria; Berchuck, Andrew; Iversen, Edwin S; Marks, Jeffrey R; Akushevich, Lucy; Cramer, Daniel W; Schildkraut, Joellen; Terry, Kathryn L; Poole, Elizabeth M; Stampfer, Meir; Tworoger, Shelley S; Bandera, Elisa V; Orlow, Irene; Olson, Sara H; Bjorge, Line; Salvesen, Helga B; van Altena, Anne M; Aben, Katja K H; Kiemeney, Lambertus A; Massuger, Leon F A G; Pejovic, Tanja; Bean, Yukie; Brooks-Wilson, Angela; Kelemen, Linda E; Cook, Linda S; Le, Nhu D; Górski, Bohdan; Gronwald, Jacek; Menkiszak, Janusz; Høgdall, Claus K; Lundvall, Lene; Nedergaard, Lotte; Engelholm, Svend Aage; Dicks, Ed; Tyrer, Jonathan; Campbell, Ian; McNeish, Iain; Paul, James; Siddiqui, Nadeem; Glasspool, Rosalind; Whittemore, Alice S; Rothstein, Joseph H; McGuire, Valerie; Sieh, Weiva; Cai, Hui; Shu, Xiao-Ou; Teten, Rachel T; Sutphen, Rebecca; McLaughlin, John R; Narod, Steven A; Phelan, Catherine M; Monteiro, Alvaro N; Fenstermacher, David; Lin, Hui-Yi; Permuth, Jennifer B; Sellers, Thomas A; Chen, Y Ann; Tsai, Ya-Yu; Chen, Zhihua; Gentry-Maharaj, Aleksandra; Gayther, Simon A; Ramus, Susan J; Menon, Usha; Wu, Anna H; Pearce, Celeste L; Van Den Berg, David; Pike, Malcolm C; Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Moes-Sosnowska, Joanna; Kupryjanczyk, Jolanta; Pharoah, Paul DP; Song, Honglin; Winship, Ingrid; Chenevix-Trench, Georgia; Giles, Graham G; Tavtigian, Sean V; Easton, Doug F; Milne, Roger L

2016-01-01

Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important. PMID:27595995

An Experimental Animal Model for the Study of Immunity to Entamoeba Histolytica.

DTIC Science & Technology

1983-04-15

off the injury, amebae were proliferating toc rapidly and starting new lesions by invading normal tissue. Masses of trophozoites were often seen...rnu CC 4C- rr rn r NU n 55- B 0 55 to of5 C -- NN 555 3 0 t is 5’ 1 0 It t toC -@ to . ~413 ofU to -4~ 0000% 00 000 00 of 0. a of .0.~ OIL %De-o Sit 0...del sistema fagocftico mononuclear en hamsters infectados con Entamoeba histolytica. Archivos de Investigaci6n M-dica 11(suppl. 1):235-240; 1980b. 68

Mutation Spectrum of Common Deafness-Causing Genes in Patients with Non-Syndromic Deafness in the Xiamen Area, China.

PubMed

Jiang, Yi; Huang, Shasha; Deng, Tao; Wu, Lihua; Chen, Juan; Kang, Dongyang; Xu, Xiufeng; Li, Ruiyu; Han, Dongyi; Dai, Pu

2015-01-01

In China, approximately 30,000 babies are born with hearing impairment each year. However, the molecular factors causing congenital hearing impairment in the Xiamen area of Fujian province have not been evaluated. To provide accurate genetic testing and counseling in the Xiamen area, we investigated the molecular etiology of non-syndromic deafness in a deaf population from Xiamen. Unrelated students with hearing impairment (n = 155) who attended Xiamen Special Education School in Fujian Province were recruited for this study. Three common deafness-related genes, GJB2, SLC26A4, and mtDNA12SrRNA, were analyzed using all-exon sequencing. GJB2 mutations were detected in 27.1% (42/155) of the entire cohort. The non-syndromic hearing loss (NSHL) hotspot mutations c.109G>A (p.V37I) and c.235delC were found in this population, whereas the Caucasian hotspot mutation c.35delG was not. The allelic frequency of the c.109G>A mutation was 9.03% (28/310), slightly higher than that of c.235delC (8.39%, 26/310), which is the most common GJB2 mutation in most areas of China. The allelic frequency of the c.109G>A mutation was significantly higher in this Xiamen's deaf population than that in previously reported cohorts (P = 0.00). The SLC26A4 mutations were found in 16.77% (26/155) of this cohort. The most common pathogenic allele was c.IVS7-2A>G (6.13%, 19/310), and the second most common was the c.1079C>T (p.A360V) mutation (1.94%, 6/310) which has rarely been reported as a hotspot mutation in other studies. The mutation rate of mtDNA12SrRNA in this group was 3.87% (6/155), all being the m.A1555G mutation. These findings show the specificity of the common deaf gene-mutation spectrum in this area. According to this study, there were specific hotspot mutations in Xiamen deaf patients. Comprehensive sequencing analysis of the three common deaf genes can help portray the mutation spectrum and develop optimal testing strategies for deaf patients in this area.

Sequence variants in four genes underlying Bardet-Biedl syndrome in consanguineous families

PubMed Central

Ullah, Asmat; Umair, Muhammad; Yousaf, Maryam; Khan, Sher Alam; Nazim-ud-din, Muhammad; Shah, Khadim; Ahmad, Farooq; Azeem, Zahid; Ali, Ghazanfar; Alhaddad, Bader; Rafique, Afzal; Jan, Abid; Haack, Tobias B.; Strom, Tim M.; Meitinger, Thomas; Ghous, Tahseen

2017-01-01

Purpose To investigate the molecular basis of Bardet-Biedl syndrome (BBS) in five consanguineous families of Pakistani origin. Methods Linkage in two families (A and B) was established to BBS7 on chromosome 4q27, in family C to BBS8 on chromosome 14q32.1, and in family D to BBS10 on chromosome 12q21.2. Family E was investigated directly with exome sequence analysis. Results Sanger sequencing revealed two novel mutations and three previously reported mutations in the BBS genes. These mutations include two deletions (c.580_582delGCA, c.1592_1597delTTCCAG) in the BBS7 gene, a missense mutation (p.Gln449His) in the BBS8 gene, a frameshift mutation (c.271_272insT) in the BBS10 gene, and a nonsense mutation (p.Ser40*) in the MKKS (BBS6) gene. Conclusions Two novel mutations and three previously reported variants, identified in the present study, further extend the body of evidence implicating BBS6, BBS7, BBS8, and BBS10 in causing BBS. PMID:28761321

General anesthetic octanol and related compounds activate wild-type and delF508 cystic fibrosis chloride channels

PubMed Central

Marcet, Brice; Becq, Frédéric; Norez, Caroline; Delmas, Patrick; Verrier, Bernard

2004-01-01

Cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel is defective during cystic fibrosis (CF). Activators of the CFTR Cl− channel may be useful for therapy of CF. Here, we demonstrate that a range of general anesthetics like normal-alkanols (n-alkanols) and related compounds can stimulate the Cl− channel activity of wild-type CFTR and delF508-CFTR mutant. The effects of n-alkanols like octanol on CFTR activity were measured by iodide (125I) efflux and patch-clamp techniques on three distinct cellular models: (1) CFTR-expressing Chinese hamster ovary cells, (2) human airway Calu-3 epithelial cells and (3) human airway JME/CF15 epithelial cells which express the delF508-CFTR mutant. Our data show for the first time that n-alkanols activate both wild-type CFTR and delF508-CFTR mutant. Octanol stimulated 125I efflux in a dose-dependent manner in CFTR-expressing cells (wild-type and delF508) but not in cell lines lacking CFTR. 125I efflux and Cl− currents induced by octanol were blocked by glibenclamide but insensitive to 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid, as expected for a CFTR Cl− current. CFTR activation by octanol was neither due to cell-to-cell uncoupling properties of octanol nor to an intracellular cAMP increase. CFTR activation by octanol requires phosphorylation by protein kinase-A (PKA) since it was prevented by H-89, a PKA inhibitor. n-Alkanols chain length was an important determinant for channel activation, with rank order of potencies: 1-heptanol<1-octanol<2-octanol<1-decanol. Our findings may be of valuable interest for developing novel therapeutic strategies for CF. PMID:14967738

The interaction of reward genes with environmental factors in contribution to alcoholism in mexican americans.

PubMed

Du, Yanlei; Wan, Yu-Jui Yvonne

2009-12-01

Alcoholism is a polygenic disorder resulting from reward deficiency; polymorphisms in reward genes including serotonin transporter (5-HTT)-linked polymorphic region (5-HTTLPR), A118G in opioid receptor mu1 (OPRM1), and -141C Insertion/Deletion (Ins/Del) in dopamine receptor D2 (DRD2) as well as environmental factors (education and marital status) might affect the risk of alcoholism. Objective of the current study was to examine the main and interacting effect of these 3 polymorphisms and 2 environmental factors in contribution to alcoholism in Mexican Americans. Genotyping of 5-HTTLPR, OPRM1 A118G, and DRD2-141C Ins/Del was performed in 365 alcoholics and 338 nonalcoholic controls of Mexican Americans who were gender- and age-matched. Alcoholics were stratified according to tertiles of MAXDRINKS, which denotes the largest number of drinks consumed in one 24-hour period. Data analysis was done in the entire data set and in each alcoholic stratum. Multinomial logistic regression was conducted to explore the main effect of 3 polymorphisms and 2 environmental factors (education and marital status); classification tree, generalized multifactor dimensionality reduction (GMDR) analysis, and polymorphism interaction analysis version 2.0 (PIA 2) program were used to study factor interaction. Main effect of education, OPRM1, and DRD2 was detected in alcoholic stratum of moderate and/or largest MAXDRINKS with education < or =12 years, OPRM1 118 A/A, and DRD2 -141C Ins/Ins being risk factors. Classification tree analysis, GMDR analysis, and PIA 2 program all supported education*OPRM1 interaction in alcoholics of largest MAXDRINKS with education < or =12 years coupled with OPRM1 A/A being a high risk factor; dendrogram showed synergistic interaction between these 2 factors; dosage-effect response was also observed for education*OPRM1 interaction. No definite effect of marital status and 5-HTTLPR in pathogenesis of alcoholism was observed. Our results suggest main effect of education background, OPRM1 A118G, and DRD2 -141C Ins/Del as well as education*OPRM1 interaction in contribution to moderate and/or severe alcoholism in Mexican Americans. Functional relevance of these findings still needs to be explored.

Role of CYP1A2 polymorphisms on lung cancer risk in a prospective study.

PubMed

Pavanello, Sofia; Fedeli, Ugo; Mastrangelo, Giuseppe; Rota, Federica; Overvad, Kim; Raaschou-Nielsen, Ole; Tjønneland, Anne; Vogel, Ulla

2012-06-01

Cytochrome P4501A2 (CYP1A2) is a key enzyme for lung carcinogen activation and lung inflammation. We studied the interactions of the CYP1A2 functional variants -3860G/A(rs2069514),-2467T/delT(rs3569413),-163C/A(rs762551)] with occupational/environmental carcinogenic exposures in the development of lung cancer in a case-control study nested in the Danish prospective cohort "Diet, Cancer and Health." At enrollment (1993-1997), blood samples for genotype analyses and information on lifestyle were collected 5 (mean value) years before the onset of the disease. The study population included 425 lung cancer cases and 786 subcohort members, who were gender- and age-matched. We found that -163A carriers were at increased risk of lung cancer (P=0.035) in a multivariate COX regression model, which was adjusted for personal habits (i.e., cumulative smoking, passive smoke at home, alcohol intake, and fruit intake) and occupational exposure. Additionally, the interaction between -2467delT and smoking increases lung cancer risk in males, especially light smokers (<21.5 pack-years, P=0.004). The increased lung cancer risk found in -163C carriers, independent of smoking status, and in -2467delT male smokers, suggests that these variants could influence lung cancer development through different mechanisms (i.e. lung carcinogen activation and lung inflammation). Copyright © 2012 Elsevier Inc. All rights reserved.

Endogenous developmental endothelial locus-1 limits ischemia-related angiogenesis by blocking inflammation

PubMed Central

Klotzsche - von Ameln, Anne; Cremer, Sebastian; Hoffmann, Jedrzej; Schuster, Peggy; Khedr, Sherif; Korovina, Irina; Troulinaki, Maria; Neuwirth, Ales; Sprott, David; Chatzigeorgiou, Antonios; Economopoulou, Matina; Orlandi, Alessia; Hain, Andreas; Zeiher, Andreas M.; Deussen, Andreas; Hajishengallis, George; Dimmeler, Stefanie; Chavakis, Triantafyllos; Chavakis, Emmanouil

2017-01-01

We have recently identified endothelial cell-secreted developmental endothelial locus-1 (Del-1) as an endogenous inhibitor of β2-integrin–dependent leukocyte infiltration. Del-1 was previously also implicated in angiogenesis. Here, we addressed the role of endogenously produced Del-1 in ischemia-related angiogenesis. Intriguingly, Del-1–deficient mice displayed increased neovascularization in two independent ischemic models (retinopathy of prematurity and hind-limb ischemia), as compared to Del-1–proficient mice. On the contrary, angiogenic sprouting in vitro or ex vivo (aortic ring assay) and physiological developmental retina angiogenesis were not affected by Del-1 deficiency. Mechanistically, the enhanced ischemic neovascularization in Del-1-deficiency was linked to higher infiltration of the ischemic tissue by CD45+ hematopoietic and immune cells. Moreover, Del-1-deficiency promoted β2-integrin–dependent adhesion of hematopoietic cells to endothelial cells in vitro, and the homing of hematopoietic progenitor cells and of immune cell populations to ischemic muscles in vivo. Consistently, the increased hind limb ischemia-related angiogenesis in Del-1 deficiency was completely reversed in mice lacking both Del-1 and the β2-integrin LFA-1. Additionally, enhanced retinopathy-associated neovascularization in Del-deficient mice was reversed by LFA-1 blockade. Our data reveal a hitherto unrecognized function of endogenous Del-1 as a local inhibitor of ischemia-induced angiogenesis by restraining LFA-1–dependent homing of pro-angiogenic hematopoietic cells to ischemic tissues. Our findings are relevant for the optimization of therapeutic approaches in the context of ischemic diseases. PMID:28447099

Autoguía para el telescopio 2,15 mts de CASLEO

NASA Astrophysics Data System (ADS)

Aballay, J. A.; Casagrande, A. R.; Pereyra, P. F.; Marún, A. H.

Se está desarrollando un sistema de autoguía para el telescopio de 2,15 mts. El mismo se realizará aprovechando el Offset Guider. Al ocular móvil de éste se vinculará alguna cámara digital (ST4-ST7-CH250) para lograr la visión del objeto. El funcionamiento del equipo será el siguiente: primero, dadas las coordenadas del objeto a observar, se tomarán las coordenadas del telescopio para que, a través de una base de datos, se determine un campo de objetos que sirvan para la cámara de visión, luego, la PC obtendrá el offset entre la estrella de observación y la estrella seleccionada como guía, este valor será trasladado a los motores que posicionarán en forma automática el ocular. Una vez que la estrella es visualizada en la cámara (monitor de PC ) se correrá el programa que guiará el telescopio automáticamente.

Novel germline PALB2 truncating mutations in African-American breast cancer patients

PubMed Central

Zheng, Yonglan; Zhang, Jing; Niu, Qun; Huo, Dezheng; Olopade, Olufunmilayo I.

2011-01-01

Background It has been demonstrated that PALB2 acts as a bridging molecule between the BRCA1 and BRCA2 proteins and is responsible for facilitating BRCA2-mediated DNA repair. Truncating mutations in the PALB2 gene have been reported to be enriched in Fanconi anemia and breast cancer patients in various populations. Methods We evaluated the contribution of PALB2 germline mutations in 279 African-American breast cancer patients including 29 patients with a strong family history, 29 patients with a moderate family history, 75 patients with a weak family history, and 146 non-familial or sporadic breast cancer cases. Results After direct sequencing of all the coding exons, exon/intron boundaries, 5′UTR and 3′UTR of PALB2, three (1.08%; 3 in 279) novel monoallelic truncating mutations were identified: c.758dupT (exon4), c.1479delC (exon4) and c.3048delT (exon 10); together with 50 sequence variants, 27 of which are novel. None of the truncating mutations were found in 262 controls from the same population. Conclusions PALB2 mutations are present in both familial and non-familial breast cancer among African-Americans. Rare PALB2 mutations account for a small but substantial proportion of breast cancer patients. PMID:21932393

Deletion of Late Cornified Envelope 3B and 3C genes is not associated with atopic dermatitis.

PubMed

Bergboer, Judith G M; Zeeuwen, Patrick L J M; Irvine, Alan D; Weidinger, Stephan; Giardina, Emiliano; Novelli, Giuseppe; Den Heijer, Martin; Rodriguez, Elke; Illig, Thomas; Riveira-Munoz, Eva; Campbell, Linda E; Tyson, Jess; Dannhauser, Emma N; O'Regan, Gráinne M; Galli, Elena; Klopp, Norman; Koppelman, Gerard H; Novak, Natalija; Estivill, Xavier; McLean, W H Irwin; Postma, Dirkje S; Armour, John A L; Schalkwijk, Joost

2010-08-01

Atopic dermatitis (AD) and psoriasis are common skin diseases characterized by cutaneous inflammation and disturbed epidermal differentiation. Genome-wide analyses have shown overlapping susceptibility loci, such as the epidermal differentiation complex on chromosome 1q21. Recently, a deletion on 1q21 (LCE3C_LCE3B-del), comprising LCE3B and LCE3C, two members of the late cornified envelope (LCE) gene cluster, was found to be associated with psoriasis. Although the mechanistic role of LCE proteins in psoriasis has not been identified, these proteins are putatively involved in skin barrier formation and repair. Considering the potential genetic overlap between the two diseases and the recent finding that mutations in the skin barrier protein filaggrin are associated with AD, we investigated a possible association between LCE3C_LCE3B-del and AD. Evaluation of four different cohorts of European ancestry, containing a total of 1075 AD patients and 1658 controls, did not provide evidence for such an association. Subgroup analysis did not reveal an association with concomitant asthma. Our data suggest that the potential roles of skin barrier defects in the pathogenesis of AD and psoriasis are based on distinct genetic causes.

Poblacion estelar joven embebida en la nube molecular galactica asociada a la fuente IRAS 18236-1205

NASA Astrophysics Data System (ADS)

Romero, Ricardo Retes

2008-06-01

En esta tesis presento una metodología de seleccion y estudio de la población estelar embebida en la nube molecular galactica asociada a la fuente IRAS 18236-1205. La fuente IRAS posee colores de region Ultra Compacta HII (UCHII) y tiene deteccióon en monosulfuro de carbono (CS), trazador molecular de alta densidad, lo cual da la posibilidad de definir la nube molecular asociada hacia esta region. Lo anterior muestra que esta es buena candidata a región de formación estelar masiva. La metodología de seleccion de la población embebida, est à basada por una parte, en la distribución del gas molecular monoxido de carbono (13CO) asociado a la fuente IRAS, nube molecular seleccionada del mapeo Galactic Ring Survey (GRS) realizado en 13CO. Otros pasos de la seleccion, se basan en los diagramas color-color y color-magnitud con datos del cercano infrarrrojo de 2MASS. Para el estudio de la componente estelar se usaron los catalogos de fuentes puntuales en el cercano, medio y lejano infrarrojo de 2MASS, SPITZER e IRAS, respectivamente. De los diagramas color-color y color-magnitud, usando datos de 2MASS, se construyo un criterio fotométrico para identificar los objetos estelares j ovenes embebidos en la region molecular. Aplicando modelos a la distribución espectral de energía (SED) de algunos ellos, se encontraron parametros estelares de objetos estelares j ovenes embebidos de masa intermedia y alta. Adicionalmente, se encontro un objeto de masa ´ intermedia no identifiado por el catalogo de 2MASS y su efecto sobre el medio interestelar, emision en la banda de [4.5] μm de IRAC-Spitzer asociado a un outflow. Dos de los objetos seleccionados por el criterio fotometrico resultaron ser objetos estelares jovenes de alta e intermedia masa (B1V/B2V y B8V/A0V respectivamente), los cuales deben estar asociados a la emision radiativa responsable de los colores de región UC HII. Otro objeto estelar joven de baja masa (F0V/F5V) fue encontrado en la region de estudio. Este parece estar asociado con la presencia de un disco circumestelar y material excitado por choque (IRAC-Spitzer [4.5]μm). Se concluye que el escenario de region de formación estelar masiva factible para esta region molecular es el de una asociación estelar joven embebida en una densa región molecular (AV . 30) hacia la fuente IRAS 18236-1205.

[Study of generational risk in deafness inflicted couples using deafness gene microarray technique].

PubMed

Wang, Ping; Zhao, Jia; Yu, Shu-yuan; Jin, Peng; Zhu, Wei; DU, Bo

2011-06-01

To explored the significance of screening the gene mutations of deafness related in deaf-mute (deaf & dumb) family using DNA microarray. Total of 52 couples of deaf-mute were recruited from Changchun deaf-mute community. With an average age of (58.3 ± 6.7) years old (x(-) ± s). Blood samples were obtained with informed consent. Their genomic DNA was extracted from peripheral blood and PCR was performed. Nine of hot spot mutations in four most common deafness pathologic gene were examined with the DNA microarray, including GJB2, GJB3, PDS and mtDNA 12S rRNA genes. At the same time, the results were verified with the traditional methods of sequencing. Fifty of normal people served as a control group. All patients were diagnosed non-syndromic sensorineural hearing loss by subjective pure tone audiometry. Thirty-two of 104 cases appeared GJB2 gene mutation (30.7%), the mutation sites included 35delG, 176del16, 235delC and 299delAT. Eighteen of 32 cases of GJB2 mutations were 235delC (59.1%). Seven of 104 cases appeared SLC26A4 gene IVS7-2 A > G mutation. Questionnaire survey and gene diagnosis revealed that four of 52 families have deaf offspring (7.6%). When a couple carries the same gene mutation, the risk of their children deafness was 100%. The results were confirmed with the traditional methods of sequencing. There is a high risk of deafness if a deaf-mute family is planning to have a new baby. It is very important and helpful to avoid deaf newborns again in deaf-mute family by DNA microarray.

Amniotic fluid digestive enzyme analysis is useful for identifying CFTR gene mutations of unclear significance.

PubMed

Oca, Florine; Dreux, Sophie; Gérard, Bénédicte; Simon-Bouy, Brigitte; de Becdelièvre, Alix; Ferec, Claude; Girodon, Emmanuelle; Muller, Françoise

2009-12-01

The large number of CFTR [cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)] mutations and the existence of variants of unclear significance complicate the prenatal diagnosis of cystic fibrosis (CF). The aim of this study was to determine whether the pattern of amniotic fluid digestive enzymes (AF-DEs) could be correlated with the severity of CFTR mutations. The AF-DE pattern (gamma-glutamyltranspeptidase, aminopeptidase M, and the intestinal isoform of alkaline phosphatase) was retrospectively analyzed in 43 AF samples. All fetuses presented 2 CFTR mutations, which were classified according to the severity of the disease: CF/CF (n = 38); CF/CFTR-related disorders (n = 1); and CF/unknown variant (n = 4). The relationships between clinical CF status, CFTR mutations, and AF-DE pattern were studied. Of 38 severely affected CF fetuses, an "obstructive" AF-DE pattern was observed in 15 of 15 samples collected before 22 weeks, irrespective of the CFTR mutation (diagnostic sensitivity, 100%; diagnostic specificity, 99.8%). In the 23 fetuses evaluated after 22 weeks, the AF-DE pattern was abnormal in 7 cases and noncontributive in 16 (diagnostic sensitivity, 30.4%; diagnostic specificity, 99.8%). Of the 5 questionable cases (F508del/N1224K, F508del/L73F, 3849+10kbC>T/G1127E, F508del/S1235R, F508del/G622D), all were CF symptom free at 2-4 years of follow-up. The AF-DE pattern (<22 weeks) was typical in 3 cases but abnormal in the last 2 cases. AF-DE analysis is of value for prenatal CF diagnosis in classic forms of CF and could be helpful in nonclassic CF.

Characterization of novel RS1 exonic deletions in juvenile X-linked retinoschisis

PubMed Central

D’Souza, Leera; Cukras, Catherine; Antolik, Christian; Craig, Candice; He, Hong; Li, Shibo; Hejtmancik, James F.; Sieving, Paul A.; Wang, Xinjing

2013-01-01

Purpose X-linked juvenile retinoschisis (XLRS) is a vitreoretinal dystrophy characterized by schisis (splitting) of the inner layers of the neuroretina. Mutations within the retinoschisis (RS1) gene are responsible for this disease. The mutation spectrum consists of amino acid substitutions, splice site variations, small indels, and larger genomic deletions. Clinically, genomic deletions are rarely reported. Here, we characterize two novel full exonic deletions: one encompassing exon 1 and the other spanning exons 4–5 of the RS1 gene. We also report the clinical findings in these patients with XLRS with two different exonic deletions. Methods Unrelated XLRS men and boys and their mothers (if available) were enrolled for molecular genetics evaluation. The patients also underwent ophthalmologic examination and in some cases electroretinogram (ERG) recording. All the exons and the flanking intronic regions of the RS1 gene were analyzed with direct sequencing. Two patients with exonic deletions were further evaluated with array comparative genomic hybridization to define the scope of the genomic aberrations. After the deleted genomic region was identified, primer walking followed by direct sequencing was used to determine the exact breakpoints. Results Two novel exonic deletions of the RS1 gene were identified: one including exon 1 and the other spanning exons 4 and 5. The exon 1 deletion extends from the 5′ region of the RS1 gene (including the promoter) through intron 1 (c.(−35)-1723_c.51+2664del4472). The exon 4–5 deletion spans introns 3 to intron 5 (c.185–1020_c.522+1844del5764). Conclusions Here we report two novel exonic deletions within the RS1 gene locus. We have also described the clinical presentations and hypothesized the genomic mechanisms underlying these schisis phenotypes. PMID:24227916

Characterization of novel RS1 exonic deletions in juvenile X-linked retinoschisis.

PubMed

D'Souza, Leera; Cukras, Catherine; Antolik, Christian; Craig, Candice; Lee, Ji-Yun; He, Hong; Li, Shibo; Smaoui, Nizar; Hejtmancik, James F; Sieving, Paul A; Wang, Xinjing

2013-01-01

X-linked juvenile retinoschisis (XLRS) is a vitreoretinal dystrophy characterized by schisis (splitting) of the inner layers of the neuroretina. Mutations within the retinoschisis (RS1) gene are responsible for this disease. The mutation spectrum consists of amino acid substitutions, splice site variations, small indels, and larger genomic deletions. Clinically, genomic deletions are rarely reported. Here, we characterize two novel full exonic deletions: one encompassing exon 1 and the other spanning exons 4-5 of the RS1 gene. We also report the clinical findings in these patients with XLRS with two different exonic deletions. Unrelated XLRS men and boys and their mothers (if available) were enrolled for molecular genetics evaluation. The patients also underwent ophthalmologic examination and in some cases electroretinogram (ERG) recording. All the exons and the flanking intronic regions of the RS1 gene were analyzed with direct sequencing. Two patients with exonic deletions were further evaluated with array comparative genomic hybridization to define the scope of the genomic aberrations. After the deleted genomic region was identified, primer walking followed by direct sequencing was used to determine the exact breakpoints. Two novel exonic deletions of the RS1 gene were identified: one including exon 1 and the other spanning exons 4 and 5. The exon 1 deletion extends from the 5' region of the RS1 gene (including the promoter) through intron 1 (c.(-35)-1723_c.51+2664del4472). The exon 4-5 deletion spans introns 3 to intron 5 (c.185-1020_c.522+1844del5764). Here we report two novel exonic deletions within the RS1 gene locus. We have also described the clinical presentations and hypothesized the genomic mechanisms underlying these schisis phenotypes.

Neonatal Marfan Syndrome: Report of a Case with an Inherited Splicing Mutation outside the Neonatal Domain

PubMed Central

Le Gloan, Laurianne; Hauet, Quentin; David, Albert; Hanna, Nadine; Arfeuille, Chloé; Arnaud, Pauline; Boileau, Catherine; Romefort, Bénédicte; Benbrik, Nadir; Gournay, Véronique; Joram, Nicolas; Baron, Olivier; Isidor, Bertrand

2016-01-01

We report a child and her mother affected by Marfan syndrome. The child presented with a phenotype of neonatal Marfan syndrome, revealed by acute and refractory heart failure, finally leading to death within the first 4 months of life. Her mother had a common clinical presentation. Genetic analysis revealed an inherited FBN1 mutation. This intronic mutation (c.6163+3_6163+6del), undescribed to date, leads to exon 49 skipping, corresponding to in-frame deletion of 42 amino acids (p.Ile2014_Asp2055del). FBN1 next-generation sequencing did not show any argument for mosaicism. Association in the same family of severe neonatal and classical Marfan syndrome illustrates the intrafamilial phenotype variability. PMID:27022329

Neonatal Marfan Syndrome: Report of a Case with an Inherited Splicing Mutation outside the Neonatal Domain.

PubMed

Le Gloan, Laurianne; Hauet, Quentin; David, Albert; Hanna, Nadine; Arfeuille, Chloé; Arnaud, Pauline; Boileau, Catherine; Romefort, Bénédicte; Benbrik, Nadir; Gournay, Véronique; Joram, Nicolas; Baron, Olivier; Isidor, Bertrand

2016-02-01

We report a child and her mother affected by Marfan syndrome. The child presented with a phenotype of neonatal Marfan syndrome, revealed by acute and refractory heart failure, finally leading to death within the first 4 months of life. Her mother had a common clinical presentation. Genetic analysis revealed an inherited FBN1 mutation. This intronic mutation (c.6163+3_6163+6del), undescribed to date, leads to exon 49 skipping, corresponding to in-frame deletion of 42 amino acids (p.Ile2014_Asp2055del). FBN1 next-generation sequencing did not show any argument for mosaicism. Association in the same family of severe neonatal and classical Marfan syndrome illustrates the intrafamilial phenotype variability.

International Conference on the Physics of Electronic and Atomic Collisions. Participants List (16th), Held in New York, New York on 26 July-1 August 1989

DTIC Science & Technology

1989-08-01

SOPHIA UNIVERSITY INST. DE ASTRONOMIA OSSERVATERIO ASTROLOGIC DEPARTMENT OF PHYSICS Y FISICA DEL ESPACIO DE BRERA 7-1 KIOI-CHO C.C. 67, SUC. 28 VIA...ISLAM STATE UNIVERSITY OF Y . ITIKAWA WALRAVEN J. NEW YORK COLLEGE-POTSDAM INST OF SPACE & ASTRN SCI UN7’,ERSITY OF 136 MAPLE STREET 3-1-1 YOSHINODAI...S.UNIVERSITY DR USA PRINCETON, NJ 08544 FT. WORTH, TI 76129 USA USA ALEXANDER KALAMARIDES EMANUEL Y . KAMBER WOLFGANG KAMKE RICE UNIVERSITY PHYSICS DEPT

A clinical and molecular characterisation of CRB1-associated maculopathy.

PubMed

Khan, Kamron N; Robson, Anthony; Mahroo, Omar A R; Arno, Gavin; Inglehearn, Chris F; Armengol, Monica; Waseem, Naushin; Holder, Graham E; Carss, Keren J; Raymond, Lucy F; Webster, Andrew R; Moore, Anthony T; McKibbin, Martin; van Genderen, Maria M; Poulter, James A; Michaelides, Michel

2018-05-01

To date, over 150 disease-associated variants in CRB1 have been described, resulting in a range of retinal disease phenotypes including Leber congenital amaurosis and retinitis pigmentosa. Despite this, no genotype-phenotype correlations are currently recognised. We performed a retrospective review of electronic patient records to identify patients with macular dystrophy due to bi-allelic variants in CRB1. In total, seven unrelated individuals were identified. The median age at presentation was 21 years, with a median acuity of 0.55 decimalised Snellen units (IQR = 0.43). The follow-up period ranged from 0 to 19 years (median = 2.0 years), with a median final decimalised Snellen acuity of 0.65 (IQR = 0.70). Fundoscopy revealed only a subtly altered foveal reflex, which evolved into a bull's-eye pattern of outer retinal atrophy. Optical coherence tomography identified structural changes-intraretinal cysts in the early stages of disease, and later outer retinal atrophy. Genetic testing revealed that one rare allele (c.498_506del, p.(Ile167_Gly169del)) was present in all patients, with one patient being homozygous for the variant and six being heterozygous. In trans with this, one variant recurred twice (p.(Cys896Ter)), while the four remaining alleles were each observed once (p.(Pro1381Thr), p.(Ser478ProfsTer24), p.(Cys195Phe) and p.(Arg764Cys)). These findings show that the rare CRB1 variant, c.498_506del, is strongly associated with localised retinal dysfunction. The clinical findings are much milder than those observed with bi-allelic, loss-of-function variants in CRB1, suggesting this in-frame deletion acts as a hypomorphic allele. This is the most prevalent disease-causing CRB1 variant identified in the non-Asian population to date.

Founder and Recurrent Mutations in BRCA1 and BRCA2 Genes in Latin American Countries: State of the Art and Literature Review

PubMed Central

Torres, Diana

2016-01-01

Background. Numerous epidemiological factors affect the probability of developing breast or ovarian cancer, but no predictor is as determinant as inheriting a mutation in BRCA1 or BRCA2. The concept of the founder effect explains the reduced genetic variability in some populations, according to the theory that new populations can be formed from a reduced number of individuals, so the new population would carry only a small fraction of the genetic variability of the original population. The main purpose of this review is to provide an update on the state of the art in founder mutations and some recurrent mutations that have recently been described in Latin America. Methods. A literature search was performed in the electronic databases of PUBMED, EMBASE, LILACS, and BIREME using the terms BRCA1, BRCA2, founder mutation, Latin American population, and Hispanic. Sixty-two papers were identified, of which 38 were considered relevant for this review. Each result is shown per country. Results. In Latin America, clear founder effects have been reported in Mexico (BRCA1 del exons 9–12), Brazil (BRCA1 5382insC and BRCA2 c.156_157insAlu), and Colombia (BRCA1 3450del4, A1708E, and BRCA2 3034del4) and in Latinas residing in Southern California (BRCA1 185delAG, IVS5+1G>A, S955x, and R1443x). Of these, mutation BRCA1 3450del4 has also been reported in Brazil and Chile, whereas mutation BRCA2 3034del4 has been reported in Argentina and Peru. These data support the idea that although most Hispanic populations are the result of a mixture between Europeans, Africans, and Amerindians, the relative proportion of each genetic component varies throughout the Hispanic populations, making it necessary to identify the mutations characteristic of each population to generate mutation profiles adjusted to each one of them. Conclusion. In Latin American countries, and even among regions of the same country, there is great heterogeneity of ancestors. Therefore, Latinas should not be analyzed like other population groups without taking into account their genetic ancestry. The presence of founder mutations in specific population groups represents a cost-effective analysis. The importance of determining the founder mutations lies mainly in the decrease in costs. If we manage to decrease costs, screenings could be offered more widely and cover a larger number of women. Implications for Practice: Hispanic and African-American populations are four to five times less likely than other populations worldwide to receive screening for BRCA mutations, a main reason being the high costs of these tools. The present study seeks to identify the prevalent mutations and the founder effect in the BRCA gene in the Hispanic population to address specific panels for this population group in the future and develop strategies for population screening. PMID:27286788

Founder and Recurrent Mutations in BRCA1 and BRCA2 Genes in Latin American Countries: State of the Art and Literature Review.

PubMed

Ossa, Carlos Andrés; Torres, Diana

2016-07-01

Numerous epidemiological factors affect the probability of developing breast or ovarian cancer, but no predictor is as determinant as inheriting a mutation in BRCA1 or BRCA2. The concept of the founder effect explains the reduced genetic variability in some populations, according to the theory that new populations can be formed from a reduced number of individuals, so the new population would carry only a small fraction of the genetic variability of the original population. The main purpose of this review is to provide an update on the state of the art in founder mutations and some recurrent mutations that have recently been described in Latin America. A literature search was performed in the electronic databases of PUBMED, EMBASE, LILACS, and BIREME using the terms BRCA1, BRCA2, founder mutation, Latin American population, and Hispanic. Sixty-two papers were identified, of which 38 were considered relevant for this review. Each result is shown per country. In Latin America, clear founder effects have been reported in Mexico (BRCA1 del exons 9-12), Brazil (BRCA1 5382insC and BRCA2 c.156_157insAlu), and Colombia (BRCA1 3450del4, A1708E, and BRCA2 3034del4) and in Latinas residing in Southern California (BRCA1 185delAG, IVS5+1G>A, S955x, and R1443x). Of these, mutation BRCA1 3450del4 has also been reported in Brazil and Chile, whereas mutation BRCA2 3034del4 has been reported in Argentina and Peru. These data support the idea that although most Hispanic populations are the result of a mixture between Europeans, Africans, and Amerindians, the relative proportion of each genetic component varies throughout the Hispanic populations, making it necessary to identify the mutations characteristic of each population to generate mutation profiles adjusted to each one of them. In Latin American countries, and even among regions of the same country, there is great heterogeneity of ancestors. Therefore, Latinas should not be analyzed like other population groups without taking into account their genetic ancestry. The presence of founder mutations in specific population groups represents a cost-effective analysis. The importance of determining the founder mutations lies mainly in the decrease in costs. If we manage to decrease costs, screenings could be offered more widely and cover a larger number of women. Hispanic and African-American populations are four to five times less likely than other populations worldwide to receive screening for BRCA mutations, a main reason being the high costs of these tools. The present study seeks to identify the prevalent mutations and the founder effect in the BRCA gene in the Hispanic population to address specific panels for this population group in the future and develop strategies for population screening. ©AlphaMed Press.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Seung-Hwan; Kim, Dong-Young; Jing, Feifeng

Developmental endothelial locus-1 (Del-1) is an endogenous anti-inflammatory molecule that is highly expressed in the lung and the brain and limits leukocyte migration to these tissues. We previously reported that the expression of Del-1 is positively regulated by p53 in lung endothelial cells. Although several reports have implicated the altered expression of Del-1 gene in cancer patients, little is known about its role in tumor cells. We here investigated the effect of Del-1 on the features of human lung carcinoma cells. Del-1 mRNA was found to be significantly decreased in the human lung adenocarcinoma cell lines A549 (containing wild typemore » of p53), H1299 (null for p53) and EKVX (mutant p53), compared to in human normal lung epithelial BEAS-2B cells and MRC-5 fibroblasts. The decrease of Del-1 expression was dependent on the p53 activity in the cell lines, but not on the expression of p53. Neither treatment with recombinant human Del-1 protein nor the introduction of adenovirus expressing Del-1 altered the expression of the apoptosis regulators BAX, PUMA and Bcl-2. Unexpectedly, the adenovirus-mediated overexpression of Del-1 gene into the lung carcinoma cell lines promoted proliferation and invasion of the lung carcinoma cells, as revealed by BrdU incorporation and transwell invasion assays, respectively. In addition, overexpression of the Del-1 gene enhanced features of epithelial–mesenchymal transition (EMT), such as increasing vimentin while decreasing E-cadherin in A549 cells, and increases in the level of Slug, an EMT-associated transcription regulator. Our findings demonstrated for the first time that there are deleterious effects of high levels of Del-1 in lung carcinoma cells, and suggest that Del-1 may be used as a diagnostic or prognostic marker for cancer progression, and as a novel therapeutic target for lung carcinoma. - Highlights: • Developmental Endothelial Locus-1 (Del-1) expression is downregulated in human lung cancer cells. • Overexpression of the Del-1 gene potentiates proliferation and invasion of lung carcinoma cells. • Del-1 may be used as a diagnostic or prognostic marker for lung cancer progression.« less

Towards a prevention program for β-thalassemia. The molecular spectrum in East Java, Indonesia.

PubMed

Hernanda, Pratika Yuhyi; Tursilowati, Luluk; Arkesteijn, Sandra G J; Ugrasena, I Dewa Gede; Larasati, Marian C Shanty; Soeatmadji, Sentot Mustajab; Giordano, Piero C; Harteveld, Cornelis L

2012-01-01

Defining the spectrum of specific thalassemia mutations is an important issue when planning prevention programs in large multi ethnic countries as is Indonesia. In a first attempt to define the prevalence of the common mutations in East Java we selected a cohort of 17 transfusion-dependent patients attending the Dr. Soetomo Hospital, Surabaya, Indonesia. After basic diagnostics we performed direct DNA sequencing for all β-globin genes. The results obtained on 34 independent chromosomes revealed the following prevalence rates: c.79 G>A p. Glu27Lys (Hb E) 47.0%; c.92+5G>C (IVS-I-5 G>C) 20.6%; c.109_110 delC p.Pro37Leu fs X7 [codon 35 (-C)] 17.6%; c.46del T p.Trp16Gly fsX4 [codon 15 (-T)] 5.9%; c.126_129delCTTT p. Phe42Leu fs X19 (codons 41/42) 2.9%; c.316-197 C>T [IVS-II-654 (C>T)] 2.9%; c*112 A>G (PolyA) 2.9%. Our preliminary results show that the distribution of the prevalent mutations in our cohort is quite homogeneous but with different forms than previously reported. This indicates that more studies on a larger scale and in different geographical areas are needed to refine our provisional results and to characterize the molecular background of the disease in the whole country.

Two Small Molecules Restore Stability to a Subpopulation of the Cystic Fibrosis Transmembrane Conductance Regulator with the Predominant Disease-causing Mutation.

PubMed

Meng, Xin; Wang, Yiting; Wang, Xiaomeng; Wrennall, Joe A; Rimington, Tracy L; Li, Hongyu; Cai, Zhiwei; Ford, Robert C; Sheppard, David N

2017-03-03

Cystic fibrosis (CF) is caused by mutations that disrupt the plasma membrane expression, stability, and function of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl - channel. Two small molecules, the CFTR corrector lumacaftor and the potentiator ivacaftor, are now used clinically to treat CF, although some studies suggest that they have counteracting effects on CFTR stability. Here, we investigated the impact of these compounds on the instability of F508del-CFTR, the most common CF mutation. To study individual CFTR Cl - channels, we performed single-channel recording, whereas to assess entire CFTR populations, we used purified CFTR proteins and macroscopic CFTR Cl - currents. At 37 °C, low temperature-rescued F508del-CFTR more rapidly lost function in cell-free membrane patches and showed altered channel gating and current flow through open channels. Compared with purified wild-type CFTR, the full-length F508del-CFTR was about 10 °C less thermostable. Lumacaftor partially stabilized purified full-length F508del-CFTR and slightly delayed deactivation of individual F508del-CFTR Cl - channels. By contrast, ivacaftor further destabilized full-length F508del-CFTR and accelerated channel deactivation. Chronic (prolonged) co-incubation of F508del-CFTR-expressing cells with lumacaftor and ivacaftor deactivated macroscopic F508del-CFTR Cl - currents. However, at the single-channel level, chronic co-incubation greatly increased F508del-CFTR channel activity and temporal stability in most, but not all, cell-free membrane patches. We conclude that chronic lumacaftor and ivacaftor co-treatment restores stability in a small subpopulation of F508del-CFTR Cl - channels but that the majority remain destabilized. A fuller understanding of these effects and the characterization of the small F508del-CFTR subpopulation might be crucial for CF therapy development. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Del-1 Expression as a Potential Biomarker in Triple-Negative Early Breast Cancer.

PubMed

Lee, Soo Jung; Lee, Jeeyeon; Kim, Wan Wook; Jung, Jin Hyang; Park, Ho Yong; Park, Ji-Young; Chae, Yee Soo

2018-01-01

A differential diagnostic role for plasma Del-1 was proposed for early breast cancer (EBC) in our previous study. We examined tumoral Del-1 expression and analyzed its prognostic impact among patients with EBC. Del-1 mRNA expression was assessed in breast epithelial and cancer cells. Meanwhile, the tumoral expression of Del-1 was determined based on tissue microarrays and immunohistochemistry results from 440 patients. While a high Del-1 mRNA expression was found in all the breast cancer cell lines, the expression was significantly higher in MDA-MB-231. Tumoral expression of Del-1 was also significantly associated with a negative expression of estrogen receptor or progesterone receptor, and low expression of Ki-67, particularly in the case of triple-negative breast cancer (TNBC) (p < 0.036). Furthermore, a correlation was found between Del-1 expression and an aggressive histological grade, nuclear mitosis, and polymorphism, suggesting a possible role in tumor progression. In the survival analysis, a worse distant disease-free survival trend was noted for the group overexpressing Del-1. While all the investigated breast cancer cell lines exhibited Del-1 expression, the expression rate and intensity were specifically prominent in TNBC. In addition, based on its relationship to an unfavorable histology and worse survival trend, Del-1 could act as a molecular target in TNBC patients. © 2018 S. Karger AG, Basel.

Is there a genetic anticipation in breast and/or ovarian cancer families with the germline c.3481_3491del11 mutation?

PubMed

El Tannouri, R; Albuisson, E; Jonveaux, P; Luporsi, E

2018-01-01

The aim of the current analysis is to evaluate any differences of breast or ovarian cancer age at diagnosis between mothers and daughters carrying the c.3481_3491del11 mutation in the BRCA1 gene. A study cohort of 38 women carrying the c.3481_3491del11 mutation and affected by first breast or ovarian cancer who reported a first breast or ovarian cancer in their mother carrying the c.3481_3491del11 mutation, was identified in 37 different families including members with breast and/or ovarian cancer at the Oncology Institute of Lorraine. Twelve mothers underwent genetic testing. Twenty-five pairs of the 38 mothers-daughters pairs with c.3481_3491del11 mutation were affected by breast cancer and 13 pairs by ovarian cancer. Clinical and genetic data were collected from medical files and family pedigrees. Analyses were conducted for each cancer type. We investigated an early breast cancer detection effect due to early screening programs and also an increased breast tumor aggression. Since major improvements in breast cancer clinical management and imaging techniques appeared after 1980, we compared the age at breast cancer diagnosis and the age at death in mothers and daughters before and after 1980, first, in the group of women including mothers and daughters taken together and then in mothers and daughters separately. The mean age at breast cancer diagnosis was 45.28 ± 10.27 years in mothers and 39.80 ± 7.79 years in daughters (p = 0.026). The difference of age at ovarian cancer diagnosis in mother-daughter pairs was 8.62 ± 12.76 years (p = 0.032). When considering the group of women including mothers and daughters taken together, no significant difference of age at breast cancer diagnosis was found between women affected before 1980 and those affected after 1980 (p = 0.577). However, the age at death increased in these women after 1980 (p = 0.026). Comparison of age at breast cancer diagnosis in mothers and daughters separately, showed that daughters were affected at an earlier age after 1980 (p = 0.002). Daughters had a poor prognosis and died earlier than mothers after 1980. Our results may have reflected genetic anticipation in c.3481_3491del11 mutation breast and ovarian cancer families. In order to confirm our findings, a larger cohort would provide more precision to the difference of ages at breast or ovarian cancer diagnosis between mothers and daughters and more powerful statistical analyses. Increased aggression in daughters' tumors compared to those of mothers could be also considered as a parameter of genetic anticipation. Complete information on tumor profile and proliferation would allow us to study genetic anticipation by comparing the tumor phenotypes between mothers and daughters in the future.

Association of Ugrp2 gene polymorphisms with adenoid hypertrophy in the pediatric population.

PubMed

Atilla, Mahmut Huntürk; Özdaş, Sibel; Özdaş, Talih; Baştimur, Sibel; Muz, Sami Engin; Öz, Işılay; Kurt, Kenan; İzbirak, Afife; Babademez, Mehmet Ali; Vatandaş, Nilgün

2017-08-01

Adenoid hypertrophy is a condition that presents itself as the chronic enlargement of adenoid tissues; it is frequently observed in the pediatric population. The Ugrp2 gene, a member of the secretoglobin superfamily, encodes a low-molecular weight protein that functions in the differentiation of upper airway epithelial cells. However, little is known about the association of Ugrp2 genetic variations with adenoid hypertrophy. The aim of this study is to investigate the association of single nucleotide polymorphisms in the Ugrp2 gene with adenoid hypertrophy and its related phenotypes. A total of 219 children, comprising 114 patients suffering from adenoid hypertrophy and 105 healthy patients without adenoid hypertrophy, were enrolled in this study. Genotypes of the Ugrp2 gene were determined by DNA sequencing. We identified four single nucleotide polymorphisms (IVS1-189G>A, IVS1-89T>G, c.201delC, and IVS2-15G>A) in the Ugrp2 gene. Our genotype analysis showed that the Ugrp2 (IVS1-89T>G) TG and (c.201delC) CdelC genotypes and their minor alleles were associated with a considerable increase in the risk of adenoid hypertrophy compared with the controls (p=0.012, p=0.009, p=0.013, and p=0.037, respectively). Furthermore, Ugrp2 (GTdelCG, GTdelCA) haplotypes were significantly associated with adenoid hypertrophy (four single nucleotide polymorphisms ordered from 5' to 3'; p=0.0001). Polymorfism-Polymorfism interaction analysis indicated a strong interaction between combined genotypes of the Ugrp2 gene contributing to adenoid hypertrophy, as well as an increased chance of its diagnosis (p<0.0001). In addition, diplotypes carrying the mutant Ugrp2 (c.201delC) allele were strongly associated with an increased risk of adenoid hypertrophy with asthma and adenoid hypertrophy with allergies (p=0.003 and p=0.0007, respectively). Some single nucleotide polymorphisms and their combinations in the Ugrp2 gene are associated with an increased risk of developing adenoid hypertrophy. Therefore, we tried to underline the importance of genetic factors associated with adenoid hypertrophy and adenoid hypertrophy-related clinical phenotypes. Copyright © 2017 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

Identification of Genetic Defects Underlying FXII Deficiency in Four Unrelated Chinese Patients.

PubMed

Yang, Lihong; Wang, Yingyu; Zhou, Jianpin; Cheng, Xiaoli; Hao, Xiuping; Xie, Haixiao; Jin, Yanhui; Wang, Mingshan

2016-01-01

Congenital factor XII (FXII) dexFB01;ciency is a rare autosomal recessive disorder, characterized by a great variability in its clinical manifestations. In this study, we screened for mutations in the F12 gene of 4 unrelated patients with FXII coagulant activity <10% of that of normal human plasma. To investigate the molecular defects in these FXII-deficient patients, we performed FXII mutation screening. By sequencing all coding exons as well as xFB02;anking intronic regions of the F12 gene, 6 different mutations, including 3 missense mutations (Gly341Arg, Glu502Lys and Gly542 Ser), 1 insertion (7142insertC) and 2 deletions (5741-5742 delCA and 6753-6755delACA), were identixFB01;ed on the F12 gene. Three of them (Gly341Arg, 5741-5742delCA and 6753-6755delACA) are reported here for the first time. Computer-based algorithms predicted these missense mutations to be deleterious. This study has increased our knowledge of the mutational spectrum underlying FXII deficiency. © 2016 S. Karger AG, Basel.

An USH2A founder mutation is the major cause of Usher syndrome type 2 in Canadians of French origin and confirms common roots of Quebecois and Acadians.

PubMed

Ebermann, Inga; Koenekoop, Robert K; Lopez, Irma; Bou-Khzam, Lara; Pigeon, Renée; Bolz, Hanno J

2009-01-01

Congenital hearing loss affects approximately one child in 1000. About 10% of the deaf population have Usher syndrome (USH). In USH, hearing loss is complicated by retinal degeneration with onset in the first (USH1) or second (USH2) decade. In most populations, diagnostic testing is hampered by a multitude of mutations in nine genes. We have recently shown that in French Canadians from Quebec, USH1 largely results from a single USH1C founder mutation, c.216G>A ('Acadian allele'). The genetic basis of USH2 in Canadians of French descent, however, has remained elusive. Here, we have investigated nine USH2 families from Quebec and New Brunswick (the former Acadia) by haplotype analyses of the USH2A locus and sequencing of the three known USH2 genes. Seven USH2A mutations were identified in eight patients. One of them, c.4338_4339delCT, accounts for 10 out of 18 disease alleles (55.6%). This mutation has previously been reported in an Acadian USH2 family, and it was found in homozygous state in the three Acadians of our sample. As in the case of c.216G>A (USH1C), a common haplotype is associated with c.4338_4339delCT. With a limited number of molecular tests, it will now be possible in these populations to estimate whether children with congenital hearing impairment of different degrees will develop retinal disease - with important clinical and therapeutic implications. USH2 is the second example that reveals a significant genetic overlap between Quebecois and Acadians: in contrast to current understanding, other genetic disorders present in both populations are likely based on common founder mutations as well.

Major repeat components covering one-third of the ginseng (Panax ginseng C.A. Meyer) genome and evidence for allotetraploidy.

PubMed

Choi, Hong-Il; Waminal, Nomar E; Park, Hye Mi; Kim, Nam-Hoon; Choi, Beom Soon; Park, Minkyu; Choi, Doil; Lim, Yong Pyo; Kwon, Soo-Jin; Park, Beom-Seok; Kim, Hyun Hee; Yang, Tae-Jin

2014-03-01

Ginseng (Panax ginseng) is a famous medicinal herb, but the composition and structure of its genome are largely unknown. Here we characterized the major repeat components and inspected their distribution in the ginseng genome. By analyzing three repeat-rich bacterial artificial chromosome (BAC) sequences from ginseng, we identified complex insertion patterns of 34 long terminal repeat retrotransposons (LTR-RTs) and 11 LTR-RT derivatives accounting for more than 80% of the BAC sequences. The LTR-RTs were classified into three Ty3/gypsy (PgDel, PgTat and PgAthila) and two Ty1/Copia (PgTork and PgOryco) families. Mapping of 30-Gbp Illumina whole-genome shotgun reads to the BAC sequences revealed that these five LTR-RT families occupy at least 34% of the ginseng genome. The Ty3/Gypsy families were predominant, comprising 74 and 33% of the BAC sequences and the genome, respectively. In particular, the PgDel family accounted for 29% of the genome and presumably played major roles in enlargement of the size of the ginseng genome. Fluorescence in situ hybridization (FISH) revealed that the PgDel1 elements are distributed throughout the chromosomes along dispersed heterochromatic regions except for ribosomal DNA blocks. The intensity of the PgDel2 FISH signals was biased toward 24 out of 48 chromosomes. Unique gene probes showed two pairs of signals with different locations, one pair in subtelomeric regions on PgDel2-rich chromosomes and the other in interstitial regions on PgDel2-poor chromosomes, demonstrating allotetraploidy in ginseng. Our findings promote understanding of the evolution of the ginseng genome and of that of related species in the Araliaceae. © 2014 The Authors The Plant Journal © 2014 John Wiley & Sons Ltd.

Investigation of Complex Angle Processing to Reduce Radome Induced Angle Pointing Errors.

DTIC Science & Technology

1979-10-01

PAfNGv 0 -. 0DIF19DIF2vDELsNO9Dlv2 I -ARG/DL+. o 5 IF (I eE~o 1) 1=2 IF( I r-0,N) I N-1 DIF0=tRG-ANG( 1-1) rO! F3 . -ARG-4N.G(! ) C!F2uARG-ANG( I 41...1) C n0 35 !=2,NL APRPR=APP’wAPERP(I I+SPP*CP.:RP(I) BPI Pr’t.Dp* BPP ’ P( TI +SOP.*op’qp( I! CPRPR=CPP*. PRP(I)+OPP*CP--P(!) APRFAP*APRA(I)+BPRCpR

A Visual Reporter System for Virus-Induced Gene Silencing in Tomato Fruit Based on Anthocyanin Accumulation1[C][W

PubMed Central

Orzaez, Diego; Medina, Aurora; Torre, Sara; Fernández-Moreno, Josefina Patricia; Rambla, José Luis; Fernández-del-Carmen, Asun; Butelli, Eugenio; Martin, Cathie; Granell, Antonio

2009-01-01

Virus-induced gene silencing (VIGS) is a powerful tool for reverse genetics in tomato (Solanum lycopersicum). However, the irregular distribution of the effects of VIGS hampers the identification and quantification of nonvisual phenotypes. To overcome this limitation, a visually traceable VIGS system was developed for fruit, comprising two elements: (1) a transgenic tomato line (Del/Ros1) expressing Antirrhinum majus Delila and Rosea1 transcription factors under the control of the fruit-specific E8 promoter, showing a purple-fruited, anthocyanin-rich phenotype; and (2) a modified tobacco rattle virus VIGS vector incorporating partial Rosea1 and Delila sequences, which was shown to restore the red-fruited phenotype upon agroinjection in Del/Ros1 plants. Dissection of silenced areas for subsequent chemometric analysis successfully identified the relevant metabolites underlying gene function for three tomato genes, phytoene desaturase, TomloxC, and SlODO1, used for proof of concept. The C-6 aldehydes derived from lipid 13-hydroperoxidation were found to be the volatile compounds most severely affected by TomloxC silencing, whereas geranial and 6-methyl-5-hepten-2-one were identified as the volatiles most severely reduced by phytoene desaturase silencing in ripening fruit. In a third example, silencing of SlODO1, a tomato homolog of the ODORANT1 gene encoding a myb transcription factor, which regulates benzenoid metabolism in petunia (Petunia hybrida) flowers, resulted in a sharp accumulation of benzaldehyde in tomato fruit. Together, these results indicate that fruit VIGS, enhanced by anthocyanin monitoring, can be a powerful tool for reverse genetics in the study of the metabolic networks operating during fruit ripening. PMID:19429602

Fotometría UBVI en NGC 6231

NASA Astrophysics Data System (ADS)

Baume, G. L.; Vázquez, R. A.; Feinstein, A.

Se ha realizado fotometría CCD UBVI en la zona del cúmulo abierto NGC 6231, habiéndose observado 1062 estrellas hasta una magnitud V≈ 19. Esto posibilita tener una imagen clara de la parte inferior de la secuencia principal del cúmulo. Combinando nuestros datos con tipos espectrales tomados de la literatura pudimos re-derivar la ley de absorción en dirección a este cúmulo y encontrar que los valores de R muestran variaciones de estrella a estrella. La secuencia principal inferior muestra también algunos rasgos intrigantes: hay un codo notorio en V≈ 13.5 seguido por un gran ``spread'' de magnitudes a color constante entre las estrellas débiles y una inusualmente alta densidad de estrellas a lo largo de una banda que se extiende 1.5 mag encima de la ZAMS. Los cálculos indican que el número esperado de estrellas de campo en dirección al cúmulo debería ser menor que el observado. Una re-evaluación de las funciones de luminosidad y masa dentro de los límites -7.5 < MV < 1.5 mag y 2 Msolar < M arroja pendientes planas para ambas funciones, lo que parece ser típico de cúmulos muy jóvenes. Todos estos rasgos son congruentes con un escenario joven donde las estrellas en fase de contracción están arribando a la secuencia principal.

Gelsolin functions as a metastasis suppressor in B16-BL6 mouse melanoma cells and requirement of the carboxyl-terminus for its effect.

PubMed

Fujita, H; Okada, F; Hamada , J; Hosokawa, M; Moriuchi, T; Koya, R C; Kuzumaki, N

2001-09-01

Gelsolin, an actin-binding protein, is implicated as a critical regulator in cell motility. In addition, we have reported that cellular levels of gelsolin are decreased in various tumor cells, and overexpression of gelsolin by gene transfer suppresses tumorigenicity. We sought to assess the effects of gelsolin overexpression on metastasis and to determine the importance of a carboxyl-terminus that confers Ca(2+) dependency on gelsolin for effects of its overexpression. Expression vectors with cDNA encoding either full-length wild-type or His321 mutant form, isolated from a flat revertant of Ras-transformed cells and a carboxyl-terminal truncate, C-del of gelsolin, were transfected into a highly metastatic murine melanoma cell line, B16-BL6. Expression of introduced cDNA in transfectants was confirmed using Western blotting, 2-dimensional gel electrophoresis and reverse transcription-polymerase chain reaction (RT-PCR). We characterized phenotypes of transfectants, such as growth rate, colony formation in soft agar, cell motility and metastasis formation in vivo. Transfectants expressing the wild-type, His321 mutant and C-del gelsolin exhibited reduced growth ability in soft agar. Although expression of integrin beta1 or alpha4 on the cell surface of transfectants was not changed, wild-type and His321 mutant gelsolin, except for C-del gelsolin, exhibited retardation of cell spreading, reduced chemotatic migration to fibronectin and suppressed lung colonization in spontaneous metastasis assay. Gelsolin may function as a metastasis suppressor as well as a tumor suppressor gene. The carboxyl-terminus of gelsolin is important for retardation of cell spreading, reduced chemotasis and metastasis suppression. Copyright 2001 Wiley-Liss, Inc.

Phytoreovirus-like sequences isolated from salivary glands of the glassy-winged sharpshooter Homolodisca vitripennis (Hemiptera: Cicadellidae)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Katsar, C.S.; Hunter, W.B.; Sinisterra, X.H.

The salivary glands of the Glassy-winged sharpshooter (GWSS), Homalodisca vitripennis Germar 1821, (syn. H. coagulata, Hemiptera: Cicadellidae) were collected and used to produce a cDNA library. Examination by BLASTX analyses identified 2 viral sequences, one a 610-base pair fragment and a second 839-base pair fragment, both of which had significant homology to viruses within the genus Phytoreovirus. Resequencing of the fragments confirmed sequence validities. These sequences were used for in silico protein translation and BLASTP analysis confirming the established homology. While the GWSS is the primary vector of Pierce's disease of grapes, this is the first report that GWSS maymore » be a vector of a phytoreoviruses. Phylogenetic and homology comparisons with BLASTX, BLASTP, and PAUP analyses indicated that the viral sequences isolated from GWSS were closely related to the viruses in the Family Reoviridae, Genus Phytoreovirus, specifically Rice Dwarf Phytoreovirus (RDV). RDV is the only plant reovirus that is not limited to the phloem. Phytoreoviruses are transmitted in a propagative manner by cicadellid leafhoppers (Hemiptera: Cicadellidae), which acquire and transmit them during feeding. Phytoreoviruses have been reported from Agallian, Agalliopsis, Nephotettix, and Recilia, genera of leafhoppers, with evidence for transovarial transmission. The GWSS, although considered to feed primarily from the xylem, ingests from other plant tissues, such as the phloem and mesophyll during probing similar to other leafhoppers. The feeding behavior and wide host range of the GWSS provides an overlapping condition for these two organisms, leafhopper and virus. GWSS will feed from grasses as a transitory host, and on herbaceous and woody plants as primary hosts, which may favor the acquisition and transmission of Phytoreovirus by this leafhopper. Monitoring for an increase of Phytoreovirus spread in graminaceous crops that are in proximity to vineyards or tree crop orchards, where GWSS occurs, such as in southern California, will provide a better understanding of the potential role of the GWSS as a disease vector in the spread of phytoreoviruses and other plant pathogens. The sequences have been deposited in NCBI database under the accession numbers (EF058280) for GWSS-V1, WHSg013C11 and (EF058281) for GWSS-V2, WHSg024H02. (author) [Spanish] Dos fragmentos de 610 y 839 pares de bases fueron aislados apartir de una genoteca de expresion derivada de las glandulas salivales del cucarron de las alas cristalinas (GWSS), Homalodisca vitripennis, Germar 1821 (syn. H. coagulata) el cual es vector de la enfermedad de Pierce de las uvas. Los resultados de alineamiento utilizando BLASTX, BLASTP y el analisis filogenetico utilizando PAUP indicaron que los fragmentos de DNA estaban relacionado de manera mas cercana a viruses en la familia Reoviridae, genero Phytoreovirus, y especificamente a los virus del enanismo del arroz (RDV) y al virus del tumor de las grietas (WTV). El cucarron de las alas cristalinas es un saltahoja que se alimenta no solo del xilema sino tambien del floema y del mesofilo. Saltahojas del genero Agallian, son los principales vectores de WTV, el cual infecta el floema de plantas dicotiledoneas tumoraciones en las hojas y en las raices. WTV es transmitido por saltahojas y es el unico reovirus que es capaz de infectar tanto tejidos del xilema como del floema. El comportamiento alimentario del GWSS y su amplio rango de hospederos que incluye pastos y plantas herbaceas y lenosas podria proveer la interaccion entre estos dos organismos facilitando la adquisicion y tranmision de fitoreovirus por el GWSS. Un adecuado monitoreo de el incremento en la expansion de reoviruses en cultivos de gramineas asociados al los vinedos en donde GWSS ocurre en regiones tales como el sur de California, y en general el sur de los Estados Unidos, podria proveer un mejor entendimiento del papel del GWSS como vector de fitoreovirus y otros patogenos de plantas. Las sequencias se depositaron en la base de datos NCBI con los siguientes numeros de identificacion: (EF058280) para GWSS-V1, WHSg013C11 y (EF058281) para GWSSV2, WHSg024H02. (author)« less

Strategies for genetic study of hearing loss in the Brazilian northeastern region

PubMed Central

Melo, Uirá S; Santos, Silvana; Cavalcanti, Hannalice G; Andrade, Wagner T; Dantas, Vitor G; Rosa, Marine RD; Mingroni-Netto, Regina C

2014-01-01

The overall aim of this study was to estimate the contribution of genetic factors to the etiology of hearing loss (HL) in two counties in the Brazilian northeastern region. A cross-sectional study, based on the key informant approach (KI) was conducted in Queimadas and Gado Bravo counties (Paraíba, Northeast Brazil). The sample consisted of 182 patients with HL. Genetic screening of the most frequent mutations associated with HL was performed for all samples. DFNB1 mutations were the most frequently found in both counties. The c.35delG mutation was detected in homozygosis in seven non-syndromic probands in Queimadas (7/76, 9.2%) and only a single homozygote with this mutation was found in Gado Bravo (1/44, 2.3%). We also detected the del(GJB6-D13S1854) mutation in non-syndromic probands from Gado Bravo (2/44, 4.5%). The c.189C>A (p.TyrY63*) mutation in the CLRN1 gene was detected in homozygosis in 21/23 Usher syndrome patients from Gado Bravo and it was not found in Queimadas. Cases with probable genetic etiology contributed approximately to half of HL probands in each county (54.6% in Gado Bravo and 45.7% in Queimadas). We confirm the importance of DFNB1 locus to non-syndromic HL but we show that the frequency of mutations in the northeastern region differs somewhat from those reported in southeastern Brazil and other populations. In addition, the extremely high frequency of individuals with Usher syndrome with c.189C>A variation in CLRN1 indicates the need for a specific screening of this mutation. PMID:24596593

The prevalence of ABCB1:c.227_230delATAG mutation in affected dog breeds from European countries.

PubMed

Firdova, Zuzana; Turnova, Evelina; Bielikova, Marcela; Turna, Jan; Dudas, Andrej

2016-06-01

Deletion of 4-base pairs in the canine ABCB1 (MDR1) gene, responsible for encoding P-glycoprotein, leads to nonsense frame-shift mutation, which causes hypersensitivity to macrocyclic lactones drugs (e.g. ivermectin). To date, at least 12 purebred dog breeds have been found to be affected by this mutation. The aim of this study was to update information about the prevalence of ABCB1 mutation (c.227_230delATAG) in predisposed breeds in multiple European countries. This large scale survey also includes countries which were not involved in previous studies. The samples were collected in the period from 2012 to 2014. The overview is based on genotyping data of 4729 individuals. The observed mutant allele frequencies were 58.5% (Smooth Collie), 48.3% (Rough Collie), 35% (Australian Shepherd), 30.3% (Shetland Sheepdog), 28.1% (Silken Windhound), 26.1% (Miniature Australian Shepherd), 24.3% (Longhaired Whippet), 16.2% (White Swiss Shepherd) and 0% (Border Collie). The possible presence of an ABCB1 mutant allele in Akita-Inu breed has been investigated with negative results. This information could be helpful for breeders in optimization of their breeding strategy and for veterinarians when prescribing drug therapy for dogs of predisposed breeds. Copyright © 2016 Elsevier Ltd. All rights reserved.

Operational tools and applications of EO satellite data to retrieve surface fluxes in semi-arid countries

NASA Astrophysics Data System (ADS)

Tanguy, Maliko

The objective of the thesis is to develop and evaluate useful tools and applications of Earth Observation (EO) satellite data to estimate surface fluxes in semi-arid countries. In a first part (Chapter 4), we assess the performance of a new parameterisation scheme of ground heat flux (G) to be used in remote sensing (RS) evapotranspiration (ET) estimation methods. The G-parameterisation optimized with AMMA flux data performs well and improves the sensible heat flux (H) and ET retrieved by means of the triangle method (Jiang & Islam, 2001). In a second part (Chapter 5), the triangle method is compared with ET estimated by means of a land surface model (JULES). An attempt is made to calibrate JULES using the triangle method through Monte Carlo simulations, but the two methods supply rather different results, indicating that further intercomparison tasks should be carried out to assess the performance of RS-based algorithms and land surface models in estimating the components of the land surface energy balance. Chapter 6 presents a set of operational examples for retrieving surface fluxes using RS data. The first example is the study of temporal evolution of ET-maps in Western Africa under monsoonal influence. In a second example, we apply the new scheme proposed in Chapter 4 to retrieve and analyse the long term evolution (2000-2009) of the surface energy balance components, G, H and ET at several sites of the Segura Basin (S-E Spain) using MODIS-Terra data (land surface temperature and NDVI). Temporal and spatial distribution of evapotranspiration reveals different controls on ET. (Chapter 6). In the last example, MODIS-Aqua Sea Surface Temperature (SST) is used to validate a mathematical model to retrieve surface fluxes in a Mediterranean coastal lagoon (Mar Menor, S-E Spain). El objetivo de esta tesis es de desarrollar y evaluar herramientas y aplicaciones de la teledetección para estimar flujos de superficie en zonas semiáridas. En una primera parte (Capítulo 4), se evalúa la fiabilidad de una nueva parametrización para estimar el flujo de calor en el suelo (G) con el fin de ser utilizado en métodos de estimación de la evapotranspiración (ET) usando datos de teledetección. La parametrización de G se optimiza usando datos de flujo de energía obtenido durante las campañas del proyecto AMMA, y muestra buenos resultados y una mejora de las estimaciones del flujo de calor sensible (H) y de ET cuando se utiliza conjuntamente con el método del triángulo (Jiang & Islam, 2001). En una segunda parte (Capítulo 5), el método del triángulo se compara con valores de ET estimado por un modelo de superficie terrestre (JULES). Se intenta calibrar JULES usando el método del triángulo mediante simulaciones de Monte Carlo, pero los dos métodos muestran resultados muy diferentes, indicando que se necesita tareas de comparación profundizadas para poder evaluar la eficacia de estos modelos (de superficie terrestre y basados en la teledetección) para estimar los flujos de energía a la superficie. El capítulo 6 presenta un conjunto de ejemplos de aplicaciones operacionales para estimar los flujos de superficie usando datos de teledetección. El primer ejemplo consiste en el estudio de la evolución temporal de mapas de ET en África occidental bajo la influencia del monzón africano. En el segundo ejemplo, se aplica la nueva parametrización de G descrita en el capítulo 4 para calcular y analizar la evolución a largo plazo (2000-2009) de los componentes del balance de energía a la superficie, G, H y ET, en diferentes puntos de la cuenca del río Segura (Sureste español) utilizando datos del sensor MODIS-Terra (temperatura superficial y NDVI). La distribución temporal y espacial de ET revela diferentes controles sobre ET. En el último ejemplo, datos de temperatura superficial del mar del sensor MODIS-Aqua se utilizaron para validar un modelo matemático para calcular los flujos superficiales de una laguna costera del Mediterráneo (Mar Menor en el Sureste español).

Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies

PubMed Central

Antoniou, A; Pharoah, P; Narod, S; Risch, H; Eyfjord, J; Hopper, J; Olsson, H; Johannsson, O; Borg, A; Pasini, B; Radice, P; Manoukian, S; Eccles, D; Tang, N; Olah, E; Anton-Culver, H; Warner, E; Lubinski, J; Gronwald, J; Gorski, B; Tulinius, H; Thorlacius, S; Eerola, H; Nevanlinna, H; Syrjakoski, K; Kallioniemi, O; Thompson, D; Evans, C; Peto, J; Lalloo, F; Evans, D; Easton, D

2005-01-01

A recent report estimated the breast cancer risks in carriers of the three Ashkenazi founder mutations to be higher than previously published estimates derived from population based studies. In an attempt to confirm this, the breast and ovarian cancer risks associated with the three Ashkenazi founder mutations were estimated using families included in a previous meta-analysis of populatrion based studies. The estimated breast cancer risks for each of the founder BRCA1 and BRCA2 mutations were similar to the corresponding estimates based on all BRCA1 or BRCA2 mutations in the meta-analysis. These estimates appear to be consistent with the observed prevalence of the mutations in the Ashkenazi Jewish population. PMID:15994883

Distribution of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mutations in a Cohort of Patients Residing in Palestine.

PubMed

Siryani, Issa; Jama, Mohamed; Rumman, Nisreen; Marzouqa, Hiyam; Kannan, Moein; Lyon, Elaine; Hindiyeh, Musa

2015-01-01

Cystic fibrosis (CF) is an autosomal recessive inherited life-threatening disorder that causes severe damage to the lungs and the digestive system. In Palestine, mutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) that contributes to the clinical presentation of CF are ill defined. A cohort of thirty three clinically diagnosed CF patients from twenty one different Palestinian families residing in the central and southern part of Palestine were incorporated in this study. Sweat chloride testing was performed using the Sweat Chek Conductivity Analyzer (ELITECH Group, France) to confirm the clinical diagnosis of CF. In addition, nucleic acid from the patients' blood samples was extracted and the CFTR mutation profiles were assessed by direct sequencing of the CFTR 27 exons and the intron-exon boundaries. For patient's DNA samples where no homozygous or two heterozygous CFTR mutations were identified by exon sequencing, DNA samples were tested for deletions or duplications using SALSA MLPA probemix P091-D1 CFTR assay. Sweat chloride testing confirmed the clinical diagnosis of CF in those patients. All patients had NaCl conductivity >60 mmol/l. In addition, nine different CFTR mutations were identified in all 21 different families evaluated. These mutations were c.1393-1G>A, F508del, W1282X, G85E, c.313delA, N1303K, deletion exons 17a-17b-18, deletion exons 17a-17b and Q1100P. c.1393-1G>A was shown to be the most frequent occurring mutation among tested families. We have profiled the underling mutations in the CFTR gene of a cohort of 21 different families affected by CF. Unlike other studies from the Arab countries where F508del was reported to be the most common mutation, in southern/central Palestine, the c.1393-1G>A appeared to be the most common. Further studies are needed per sample size and geographic distribution to account for other possible CFTR genetic alterations and their frequencies. Genotype/phenotype assessments are also recommended and finally carrier frequency should be ascertained.

Presence of a deletion mutation (c.716delA) in the ligand binding domain of the vitamin D receptor in an Indian patient with vitamin D-dependent rickets type II.

PubMed

Kanakamani, Jeyaraman; Tomar, Neeraj; Kaushal, Esha; Tandon, Nikhil; Goswami, Ravinder

2010-01-01

Vitamin D-dependent rickets type II (VDDR-type II) is a rare disorder caused by mutations in the vitamin D receptor (VDR) gene. Here, we describe a patient with VDDR-type II with severe alopecia and rickets. She had hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and elevated serum alkaline phosphatase and 1,25-dihydroxyvitamin D(3). Sequence analysis of the lymphocyte VDR cDNA revealed deletion mutation c.716delA. Sequence analysis of her genomic DNA fragment amplified from exon 6 of the VDR gene incorporating this mutation confirmed the presence of the mutation in homozygous form. This frameshift mutation in the ligand binding domain (LBD) resulted in premature termination (p.Lys240Argfs) of the VDR protein. The mutant protein contained 246 amino acids, with 239 normal amino acids at the N terminus, followed by seven changed amino acids resulting in complete loss of its LBD. The mutant VDR protein showed evidence of 50% reduced binding with VDR response elements on electrophoretic mobility assay in comparison to the wild-type VDR protein. She was treated with high-dose calcium infusion and oral phosphate. After 18 months of treatment, she gained 6 cm of height, serum calcium and phosphorus improved, alkaline phosphatase levels decreased, and intact PTH normalized. Radiologically, there were signs of healing of rickets. Her parents and one of her siblings had the same c.716delA mutation in heterozygous form. Despite the complete absence of LBD, the rickets showed signs of healing with intravenous calcium.

Phylogeographic and population genetic structure of bighorn sheep ( Ovis canadensis ) in North American deserts.

PubMed

Buchalski, Michael R; Sacks, Benjamin N; Gille, Daphne A; Penedo, Maria Cecilia T; Ernest, Holly B; Morrison, Scott A; Boyce, Walter M

2016-06-09

Fossil data are ambiguous regarding the evolutionary origin of contemporary desert bighorn sheep ( Ovis canadensis subspecies). To address this uncertainty, we conducted phylogeographic and population genetic analyses on bighorn sheep subspecies found in southwestern North America. We analyzed 515 base pairs of mtDNA control region sequence and 39 microsatellites in 804 individuals from 58 locations. Phylogenetic analyses revealed 2 highly divergent clades concordant with Sierra Nevada ( O. c. sierrae ) and Rocky Mountain ( O. c. canadensis ) bighorn and showed that these 2 subspecies both diverged from desert bighorn prior to or during the Illinoian glaciation (~315-94 thousand years ago [kya]). Desert bighorn comprised several more recently diverged haplogroups concordant with the putative Nelson ( O. c. nelsoni ), Mexican ( O. c. mexicana ), and Peninsular ( O. c. cremnobates ) subspecies. Corresponding estimates of effective splitting times (~17-3 kya), and haplogroup ages (~85-72 kya) placed the most likely timeframe for divergence among desert bighorn subspecies somewhere within the last glacial maximum. Median-joining haplotype network and Bayesian skyline analyses both indicated that desert bighorn collectively comprised a historically large and haplotype-diverse population, which subsequently lost much of its diversity through demographic decline. Using microsatellite data, discriminant analysis of principle components (DAPC) and Bayesian clustering analyses both indicated genetic structure concordant with the geographic distribution of 3 desert subspecies. Likewise, microsatellite and mitochondrial-based F ST comparisons revealed significant fixation indices among the desert bighorn genetic clusters. We conclude these desert subspecies represent ancient lineages likely descended from separate Pleistocene refugial populations and should therefore be managed as distinct taxa to preserve maximal biodiversity. Los datos de fósiles sobre el origen evolutivo de las ovejas del desierto ( Ovis canadensis subespecies) contemporáneas son ambiguos. Para dilucidar esta incertidumbre, llevamos a cabo análisis filogeográficos y de genética de poblaciones entre cinco subespecies de ovejas del suroccidente de Norteamérica. Analizamos 515 pb de secuencia de la región control del ADN mitocondrial y 39 microsatélites en 804 ovejas de 58 localidades. Los análisis filogenéticos revelaron 2 clados altamente divergentes concordantes con ovejas de la Sierra Nevada ( O. c. sierrae ) y de las Montañas Rocosas ( O. c. canadensis ), y demostraron que estas dos subespecies divergieron antes o durante la glaciación de Illinois (315,000-94,000 años). Las ovejas del desierto formaron varios haplogrupos recientemente derivados concordantes con las subespecies de Nelson ( O. c. nelsoni ), México ( O. c. mexicana ) y peninsular ( O. c. cremnobates ). Las estimaciones correspondientes al tiempo de separación efectiva (17,000-3,000 años) y edades de haplogrupos (85,000-72,000 años) son los plazos más probables para las divergencias entre subespecies de ovejas del desierto dentro de la última glaciación máxima. Análisis de redes de haplotipos de unión de medias y análisis bayesianos de líneas de horizonte indicaron que las ovejas del desierto formaron una población históricamente grande y diversa en términos de haplotipos, que luego perdieron gran parte de su diversidad a través de un descenso demográfico. Utilizando datos de microsatélites los análisis DAPC y TESS indicaron agrupamiento genético concordante con la distribución geográfica actual de las tres subespecies. Asimismo, comparaciones de F ST con datos de microsatélites y mitocondriales revelaron índices de fijación significativos entre los grupos genéticos de ovejas del desierto. Concluimos que estas subespecies de ovejas del desierto representan linajes antiguos que probablemente descienden de poblaciones de distintos refugios del Pleistoceno, y que por lo tanto deben ser manejadas como taxones distintos para preservar su biodiversidad máxima.

Deletion of P399{sub E}401 in NADPH cytochrome P450 oxidoreductase results in partial mixed oxidase deficiency

DOE Office of Scientific and Technical Information (OSTI.GOV)

Flueck, Christa E., E-mail: christa.flueck@dkf.unibe.ch; Mallet, Delphine; Hofer, Gaby

2011-09-09

Highlights: {yields} Mutations in human POR cause congenital adrenal hyperplasia. {yields} We are reporting a novel 3 amino acid deletion mutation in POR P399{sub E}401del. {yields} POR mutation P399{sub E}401del decreased P450 activities by 60-85%. {yields} Impairment of steroid metabolism may be caused by multiple hits. {yields} Severity of aromatase inhibition is related to degree of in utero virilization. -- Abstract: P450 oxidoreductase (POR) is the electron donor for all microsomal P450s including steroidogenic enzymes CYP17A1, CYP19A1 and CYP21A2. We found a novel POR mutation P399{sub E}401del in two unrelated Turkish patients with 46,XX disorder of sexual development. Recombinant PORmore » proteins were produced in yeast and tested for their ability to support steroid metabolizing P450 activities. In comparison to wild-type POR, the P399{sub E}401del protein was found to decrease catalytic efficiency of 21-hydroxylation of progesterone by 68%, 17{alpha}-hydroxylation of progesterone by 76%, 17,20-lyase action on 17OH-pregnenolone by 69%, aromatization of androstenedione by 85% and cytochrome c reduction activity by 80%. Protein structure analysis of the three amino acid deletion P399{sub E}401 revealed reduced stability and flexibility of the mutant. In conclusion, P399{sub E}401del is a novel mutation in POR that provides valuable genotype-phenotype and structure-function correlation for mutations in a different region of POR compared to previous studies. Characterization of P399{sub E}401del provides further insight into specificity of different P450s for interaction with POR as well as nature of metabolic disruptions caused by more pronounced effect on specific P450s like CYP17A1 and aromatase.« less

33 CFR 80.1118 - Marina Del Rey, CA.

Code of Federal Regulations, 2010 CFR

2010-07-01

... NAVIGATION RULES COLREGS DEMARCATION LINES Pacific Coast § 80.1118 Marina Del Rey, CA. (a) A line drawn from Marina Del Rey Breakwater South Light 1 to Marina Del Rey Light 4. (b) A line drawn from Marina Del Rey... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Marina Del Rey, CA. 80.1118...

33 CFR 80.1118 - Marina Del Rey, CA.

Code of Federal Regulations, 2012 CFR

2012-07-01

... NAVIGATION RULES COLREGS DEMARCATION LINES Pacific Coast § 80.1118 Marina Del Rey, CA. (a) A line drawn from Marina Del Rey Breakwater South Light 1 to Marina Del Rey Light 4. (b) A line drawn from Marina Del Rey... 33 Navigation and Navigable Waters 1 2012-07-01 2012-07-01 false Marina Del Rey, CA. 80.1118...

33 CFR 80.1118 - Marina Del Rey, CA.

Code of Federal Regulations, 2013 CFR

2013-07-01

... NAVIGATION RULES COLREGS DEMARCATION LINES Pacific Coast § 80.1118 Marina Del Rey, CA. (a) A line drawn from Marina Del Rey Breakwater South Light 1 to Marina Del Rey Light 4. (b) A line drawn from Marina Del Rey... 33 Navigation and Navigable Waters 1 2013-07-01 2013-07-01 false Marina Del Rey, CA. 80.1118...

33 CFR 80.1118 - Marina Del Rey, CA.

Code of Federal Regulations, 2011 CFR

2011-07-01

... NAVIGATION RULES COLREGS DEMARCATION LINES Pacific Coast § 80.1118 Marina Del Rey, CA. (a) A line drawn from Marina Del Rey Breakwater South Light 1 to Marina Del Rey Light 4. (b) A line drawn from Marina Del Rey... 33 Navigation and Navigable Waters 1 2011-07-01 2011-07-01 false Marina Del Rey, CA. 80.1118...

33 CFR 80.1118 - Marina Del Rey, CA.

Code of Federal Regulations, 2014 CFR

2014-07-01

... NAVIGATION RULES COLREGS DEMARCATION LINES Pacific Coast § 80.1118 Marina Del Rey, CA. (a) A line drawn from Marina Del Rey Breakwater South Light 1 to Marina Del Rey Light 4. (b) A line drawn from Marina Del Rey... 33 Navigation and Navigable Waters 1 2014-07-01 2014-07-01 false Marina Del Rey, CA. 80.1118...

Coping with Cosmetic Effects of Cancer Treatment

MedlinePlus

... for Educators Search English Español Coping With Cosmetic Effects of Cancer Treatment KidsHealth / For Parents / Coping With ... estéticos del tratamiento del cáncer What Are Cosmetic Effects of Cancer Treatment? Cancer treatment can bring about ...

Probing Conformational Rescue Induced by a Chemical Corrector of F508del-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mutant*

PubMed Central

Yu, Wilson; Chiaw, Patrick Kim; Bear, Christine E.

2011-01-01

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that cause loss of function of the CFTR channel on the apical surface of epithelial cells. The major CF-causing mutation, F508del-CFTR, is misfolded, retained in the endoplasmic reticulum, and degraded. Small molecule corrector compounds have been identified using high throughput screens, which partially rescue the trafficking defect of F508del-CFTR, allowing a fraction of the mutant protein to escape endoplasmic reticulum retention and traffic to the plasma membrane, where it exhibits partial function as a cAMP-regulated chloride channel. A subset of such corrector compounds binds directly to the mutant protein, prompting the hypothesis that they rescue the biosynthetic defect by inducing improved protein conformation. We tested this hypothesis directly by evaluating the consequences of a corrector compound on the conformation of each nucleotide binding domain (NBD) in the context of the full-length mutant protein in limited proteolytic digest studies. Interestingly, we found that VRT-325 was capable of partially restoring compactness in NBD1. However, VRT-325 had no detectable effect on the conformation of the second half of the molecule. In comparison, ablation of the di-arginine sequence, R553XR555 (F508del-KXK-CFTR), modified protease susceptibility of NBD1, NBD2, and the full-length protein. Singly, each intervention led to a partial correction of the processing defect. Together, these interventions restored processing of F508del-CFTR to near wild type. Importantly, however, a defect in NBD1 conformation persisted, as did a defect in channel activation after the combined interventions. Importantly, this defect in channel activation can be fully corrected by the addition of the potentiator, VX-770. PMID:21602569

Spontaneous control of HIV-1 viremia in a subject with protective HLA-B plus HLA-C alleles and HLA-C associated single nucleotide polymorphisms.

PubMed

Moroni, Marco; Ghezzi, Silvia; Baroli, Paolo; Heltai, Silvia; De Battista, Davide; Pensieroso, Simone; Cavarelli, Mariangela; Dispinseri, Stefania; Vanni, Irene; Pastori, Claudia; Zerbi, Pietro; Tosoni, Antonella; Vicenzi, Elisa; Nebuloni, Manuela; Wong, Kim; Zhao, Hong; McHugh, Sarah; Poli, Guido; Lopalco, Lucia; Scarlatti, Gabriella; Biassoni, Roberto; Mullins, James I; Malnati, Mauro S; Alfano, Massimo

2014-12-05

Understanding the mechanisms by which some individuals are able to naturally control HIV-1 infection is an important goal of AIDS research. We here describe the case of an HIV-1(+) woman, CASE1, who has spontaneously controlled her viremia for the last 14 of her 20 years of infection. CASE1 has been clinically monitored since 1993. Detailed immunological, virological and histological analyses were performed on samples obtained between 2009 and 2011. As for other Elite Controllers, CASE1 is characterized by low to undetectable levels of plasma HIV-1 RNA, peripheral blood mononuclear cell (PBMC) associated HIV-1 DNA and reduced in vitro susceptibility of target cells to HIV-1 infection. Furthermore, a slow rate of virus evolution was demonstrated in spite the lack of assumption of any antiretroviral agent. CASE1 failed to transmit HIV-1 to either her sexual male partner or to her child born by vaginal delivery. Normal values and ratios of T and B cells were observed, along with normal histology of the intestinal mucosa. Attempts to isolate HIV-1 from her PBMC and gut-derived cells were unsuccessful, despite expression of normal cell surface levels of CD4, CCRC5 and CXCR4. CASE1 did not produce detectable anti-HIV neutralizing antibodies in her serum or genital mucosal fluid although she displayed potent T cell responses against HIV-1 Gag and Nef. CASE1 also possessed multiple genetic polymorphisms, including HLA alleles (B*14, B*57, C*06 and C*08.02) and HLA-C single nucleotide polymorphisms (SNPs, rs9264942 C/C and rs67384697 del/del), that have been previously individually associated with spontaneous control of plasma viremia, maintenance of high CD4(+) T cell counts and delayed disease progression. CASE1 has controlled her HIV-1 viremia below the limit of detection in the absence of antiretroviral therapy for more than 14 years and has not shown any sign of immunologic deterioration or disease progression. Co-expression of multiple protective HLA alleles, HLA-C SNPs and strong T cell responses against HIV-1 proteins are the most likely explanation of this very benign case of spontaneous control of HIV-1 disease progression.

Breast Cancer Family History and Contralateral Breast Cancer Risk in Young Women: An Update From the Women's Environmental Cancer and Radiation Epidemiology Study.

PubMed

Reiner, Anne S; Sisti, Julia; John, Esther M; Lynch, Charles F; Brooks, Jennifer D; Mellemkjær, Lene; Boice, John D; Knight, Julia A; Concannon, Patrick; Capanu, Marinela; Tischkowitz, Marc; Robson, Mark; Liang, Xiaolin; Woods, Meghan; Conti, David V; Duggan, David; Shore, Roy; Stram, Daniel O; Thomas, Duncan C; Malone, Kathleen E; Bernstein, Leslie; Bernstein, Jonine L

2018-05-20

Purpose The Women's Environmental Cancer and Radiation Epidemiology (WECARE) study demonstrated the importance of breast cancer family history on contralateral breast cancer (CBC) risk, even for noncarriers of deleterious BRCA1/2 mutations. With the completion of WECARE II, updated risk estimates are reported. Additional analyses that exclude women negative for deleterious mutations in ATM, CHEK2*1100delC, and PALB2 were performed. Patients and Methods The WECARE Study is a population-based case-control study that compared 1,521 CBC cases with 2,212 individually matched unilateral breast cancer (UBC) controls. Participants were younger than age 55 years when diagnosed with a first invasive breast cancer between 1985 and 2008. Women were interviewed about breast cancer risk factors, including family history. A subset of women was screened for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2. Rate ratios (RRs) were estimated using multivariable conditional logistic regression. Cumulative absolute risks (ARs) were estimated by combining RRs from the WECARE Study and population-based SEER*Stat cancer incidence data. Results Women with any first-degree relative with breast cancer had a 10-year AR of 8.1% for CBC (95% CI, 6.7% to 9.8%). Risks also were increased if the relative was diagnosed at an age younger than 40 years (10-year AR, 13.5%; 95% CI, 8.8% to 20.8%) or with CBC (10-year AR, 14.1%; 95% CI, 9.5% to 20.7%). These risks are comparable with those seen in BRCA1/2 deleterious mutation carriers (10-year AR, 18.4%; 95% CI, 16.0% to 21.3%). In the subset of women who tested negative for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2, estimates were unchanged. Adjustment for known breast cancer single-nucleotide polymorphisms did not affect estimates. Conclusion Breast cancer family history confers a high CBC risk, even after excluding women with deleterious mutations. Clinicians are urged to use detailed family histories to guide treatment and future screening decisions for young women with breast cancer.

Associations between CD24 gene polymorphisms and inflammatory bowel disease: A meta-analysis.

PubMed

Huang, Xiao-Li; Xu, Dong-Hua; Wang, Guo-Pin; Zhang, Shu; Yu, Cheng-Gong

2015-05-21

To evaluate the relationships between CD24 gene polymorphisms and the risk of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD). The PubMed, Web of Science and Cochrane Library databases were searched (up to May 30, 2014). The search terms "CD24", "inflammatory bowel disease", "Crohn's disease", "Ulcerative colitis", "IBD", "CD" or "UC"; and "polymorphism", "mutation" or "variant" were used. Association studies were limited to the English language, but no limitations in terms of race, ethnicity or geographic area were employed. Stata SE12 software was used to calculate the pooled odds ratios (ORs) with 95% confidence intervals (CIs). P < 0.05 was considered statistically significant. The information was independently extracted from each eligible study by two investigators. Two common polymorphisms, C170T (rs8734) and TG1527del (rs3838646), in the CD24 gene were assessed. A total of three case-control studies including 2342 IBD patients and 1965 healthy controls were involved in this meta-analysis. The patients and controls were from Caucasian cohorts. The three articles included in this meta-analysis all conformed to Hardy-Weinberg equilibrium. This meta-analysis revealed that there were no significant associations between the two CD24 polymorphisms and the risk for IBD (all P > 0.05). However, in a disease subgroup analysis, we found that the CD24 C170T polymorphism was associated with an increased risk of UC in a dominant model (OR = 1.79, 95%CI: 1.15-2.77, P = 0.009) and an additive model (OR = 1.87, 95%CI: 1.19-2.93, P = 0.007), but this relationship was not present for CD. The CD24 TG1570del polymorphism was significantly associated with CD in the additive model (OR = 1.24, 95%CI: 1.01-1.52, P = 0.037). Our findings provide evidence that the CD24 C170T polymorphism might contribute to the susceptibility to UC, and the CD24 TG1527del polymorphism might be associated with the risk of CD.

Compound heterozygous HAX1 mutations in a Swedish patient with severe congenital neutropenia and no neurodevelopmental abnormalities.

PubMed

Carlsson, Göran; Elinder, Göran; Malmgren, Helena; Trebinska, Alicja; Grzybowska, Ewa; Dahl, Niklas; Nordenskjöld, Magnus; Fadeel, Bengt

2009-12-01

Kostmann disease or severe congenital neutropenia (SCN) is an autosomal recessive disorder of neutrophil production. Homozygous HAX1 mutations were recently identified in SCN patients belonging to the original family in northern Sweden described by Kostmann. Moreover, recent studies have suggested an association between neurological dysfunction and HAX1 deficiency. Here we describe a patient with a compound heterozygous HAX1 mutation consisting of a nonsense mutation (c.568C > T, p.Glu190X) and a frame-shift mutation (c.91delG, p.Glu31LysfsX54) resulting in a premature stop codon. The patient has a history of neutropenia and a propensity for infections, but has shown no signs of neurodevelopmental abnormalities.

Breast and Ovarian Cancer Risk and Risk Reduction in Jewish BRCA1/2 Mutation Carriers

PubMed Central

Finkelman, Brian S.; Rubinstein, Wendy S.; Friedman, Sue; Friebel, Tara M.; Dubitsky, Shera; Schonberger, Niecee Singer; Shoretz, Rochelle; Singer, Christian F.; Blum, Joanne L.; Tung, Nadine; Olopade, Olufunmilayo I.; Weitzel, Jeffrey N.; Lynch, Henry T.; Snyder, Carrie; Garber, Judy E.; Schildkraut, Joellen; Daly, Mary B.; Isaacs, Claudine; Pichert, Gabrielle; Neuhausen, Susan L.; Couch, Fergus J.; van't Veer, Laura; Eeles, Rosalind; Bancroft, Elizabeth; Evans, D. Gareth; Ganz, Patricia A.; Tomlinson, Gail E.; Narod, Steven A.; Matloff, Ellen; Domchek, Susan; Rebbeck, Timothy R.

2012-01-01

Purpose Mutations in BRCA1/2 dramatically increase the risk of both breast and ovarian cancers. Three mutations in these genes (185delAG, 5382insC, and 6174delT) occur at high frequency in Ashkenazi Jews. We evaluated how these common Jewish mutations (CJMs) affect cancer risks and risk reduction. Methods Our cohort comprised 4,649 women with disease-associated BRCA1/2 mutations from 22 centers in the Prevention and Observation of Surgical End Points Consortium. Of these women, 969 were self-identified Jewish women. Cox proportional hazards models were used to estimate breast and ovarian cancer risks, as well as risk reduction from risk-reducing salpingo-oophorectomy (RRSO), by CJM and self-identified Jewish status. Results Ninety-one percent of Jewish BRCA1/2-positive women carried a CJM. Jewish women were significantly more likely to undergo RRSO than non-Jewish women (54% v 41%, respectively; odds ratio, 1.87; 95% CI, 1.44 to 2.42). Relative risks of cancer varied by CJM, with the relative risk of breast cancer being significantly lower in 6174delT mutation carriers than in non-CJM BRCA2 carriers (hazard ratio, 0.35; 95% CI, 0.18 to 0.69). No significant difference was seen in cancer risk reduction after RRSO among subgroups. Conclusion Consistent with previous results, risks for breast and ovarian cancer varied by CJM in BRCA1/2 carriers. In particular, 6174delT carriers had a lower risk of breast cancer. This finding requires additional confirmation in larger prospective and population-based cohort studies before being integrated into clinical care. PMID:22430266

Adaptor Protein Complex 4 Deficiency Causes Severe Autosomal-Recessive Intellectual Disability, Progressive Spastic Paraplegia, Shy Character, and Short Stature

PubMed Central

Abou Jamra, Rami; Philippe, Orianne; Raas-Rothschild, Annick; Eck, Sebastian H.; Graf, Elisabeth; Buchert, Rebecca; Borck, Guntram; Ekici, Arif; Brockschmidt, Felix F.; Nöthen, Markus M.; Munnich, Arnold; Strom, Tim M.; Reis, Andre; Colleaux, Laurence

2011-01-01

Intellectual disability inherited in an autosomal-recessive fashion represents an important fraction of severe cognitive-dysfunction disorders. Yet, the extreme heterogeneity of these conditions markedly hampers gene identification. Here, we report on eight affected individuals who were from three consanguineous families and presented with severe intellectual disability, absent speech, shy character, stereotypic laughter, muscular hypotonia that progressed to spastic paraplegia, microcephaly, foot deformity, decreased muscle mass of the lower limbs, inability to walk, and growth retardation. Using a combination of autozygosity mapping and either Sanger sequencing of candidate genes or next-generation exome sequencing, we identified one mutation in each of three genes encoding adaptor protein complex 4 (AP4) subunits: a nonsense mutation in AP4S1 (NM_007077.3: c.124C>T, p.Arg42∗), a frameshift mutation in AP4B1 (NM_006594.2: c.487_488insTAT, p.Glu163_Ser739delinsVal), and a splice mutation in AP4E1 (NM_007347.3: c.542+1_542+4delGTAA, r.421_542del, p.Glu181Glyfs∗20). Adaptor protein complexes (AP1-4) are ubiquitously expressed, evolutionarily conserved heterotetrameric complexes that mediate different types of vesicle formation and the selection of cargo molecules for inclusion into these vesicles. Interestingly, two mutations affecting AP4M1 and AP4E1 have recently been found to cause cerebral palsy associated with severe intellectual disability. Combined with previous observations, these results support the hypothesis that AP4-complex-mediated trafficking plays a crucial role in brain development and functioning and demonstrate the existence of a clinically recognizable syndrome due to deficiency of the AP4 complex. PMID:21620353

Novel Variations of FANCA Gene Provokes Fanconi Anemia: Molecular Diagnosis in a Special Chinese Family.

PubMed

Li, Niu; Song, Aiyun; Ding, Lixia; Zhu, Hua; Li, Guoqiang; Miao, Yan; Wang, Jian; Li, Benshang; Chen, Jing

2018-07-01

Fanconi anemia (FA) is a rare autosomal recessive or X-linked disorder with highly variable clinical manifestations and an incidence of ∼1 to 5 in 1 million births. To date, 15 bona fide FA genes have been reported to be responsible for the known FA complementation groups and the FANCA gene accounts for almost 60%. In the present study, we report a special Chinese family, which has 2 children with classic FA characteristics. Via 2-step analysis of the whole-exome sequencing data and verification using multiplex ligation-dependent probe amplification test, one child was found to have a novel compound heterozygous mutation of a splicing variant (c.1471-1G>A) and a large intragenic deletion (exons 23-30 del) of the FANCA gene. The other child had the same splicing variant and another novel large deletion (exons 1-18 del) in the FANCA gene. Clone sequencing showed the c.1471-1G>A variant generate an altered transcript with 1 cryptic splice site in intron 15, resulting in a premature termination codon (p.Val490HisfsX6). This study not only shows the complexity of FA molecular diagnosis via comprehensively studying the FA pathogenic genes and the mutational spectrum, but also has significant reference value for the future molecular diagnosis of FA.

Novel Compound Heterozygous CLCNKB Gene Mutations (c.1755A>G/ c.848_850delTCT) Cause Classic Bartter Syndrome.

PubMed

Wang, Chunli; Chen, Ying; Zheng, Bixia; Zhu, Mengshu; Fan, Jia; Wang, Juejin; Jia, Zhanjun; Huang, Songming; Zhang, Aihua

2018-02-14

Inactivated variants in CLCNKB gene encoding the basolateral chloride channel ClC-Kb cause classic Bartter syndrome characterized by hypokalemic metabolic alkalosis and hyperreninemic hyperaldosteronism. Here we identified two cBS siblings presenting hypokalemia in a Chinese family due to novel compound heterozygous CLCNKB mutations (c.848_850delTCT/c.1755A>G). Compound heterozygosity was confirmed by amplifying and sequencing the patient's genomic DNA. The synonymous mutation c.1755A>G (Thr585Thr) was located at +2bp from the 5' splice donor site in exon 15, further transcript analysis demonstrated that this single nucleotide mutation causes exclusion of exon 15 in the cDNA from the proband and his mother. Furthermore, we investigated the expression and protein trafficking change of c.848_850delTCT (TCT) and exon 15 deletion（E15）mutation in vitro. The E15 mutation markedly decreased the expression of ClC-Kb and resulted in a low-molecular-weight band (~55kD) trapping in the endoplasmic reticulum, while the TCT mutant only decreased the total and plasma membrane ClC-Kb protein expression but did not affect the subcellular localization. Finally, we studied the physiological functions of mutations by using whole-cell patch clamp and found that E15 or TCT mutation decreased the current of ClC-Kb/barttin channel. These results suggested that the compound defective mutations of CLCNKB gene are the molecular mechanism of the two cBS siblings.

Identification of a secondary mutation in the KIT kinase domain correlated with imatinib-resistance in a canine mast cell tumor.

PubMed

Nakano, Yuko; Kobayashi, Masato; Bonkobara, Makoto; Takanosu, Masamine

2017-06-01

Imatinib-resistance is a major therapeutic problem in human chronic myeloid leukemia, human gastrointestinal stromal tumors, and canine mast cell tumors. In the present study, we identified the secondary mutation c.2006C>T in c-KIT exon 14 in a mast cell tumor obtained from a dog carrying c.1663-1671del in exon 11 and showing resistance to imatinib. The mutation in exon 14 resulted in substitution of threonine with isoleucine at position 669, which was located at the center of the ATP binding site as a gatekeeper and played an important role in binding to imatinib. Transfectants were constructed to survey the functions of these mutations in exons 11 and 14. The transfectant with mutant KIT encoded by c-KIT carrying c.1663-1671del showed constitutive ligand-independent phosphorylation that was suppressed by imatinib, indicating a gain-of-function mutation. Furthermore, the transfectant with mutant KIT encoded by c-KIT carrying both c.1663-1671del and c.2006C>T caused ligand-independent phosphorylation, which was not suppressed by imatinib. From these results, we concluded that the mutation c.2006C>T in c-KIT exon 14 was an imatinib-resistance mutation in a canine mast cell tumor. These findings revealed, for the first time, a mechanism of imatinib resistance in a clinical case of canine mast cell tumor. Copyright © 2017 Elsevier B.V. All rights reserved.

PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.

PubMed

Southey, Melissa C; Goldgar, David E; Winqvist, Robert; Pylkäs, Katri; Couch, Fergus; Tischkowitz, Marc; Foulkes, William D; Dennis, Joe; Michailidou, Kyriaki; van Rensburg, Elizabeth J; Heikkinen, Tuomas; Nevanlinna, Heli; Hopper, John L; Dörk, Thilo; Claes, Kathleen Bm; Reis-Filho, Jorge; Teo, Zhi Ling; Radice, Paolo; Catucci, Irene; Peterlongo, Paolo; Tsimiklis, Helen; Odefrey, Fabrice A; Dowty, James G; Schmidt, Marjanka K; Broeks, Annegien; Hogervorst, Frans B; Verhoef, Senno; Carpenter, Jane; Clarke, Christine; Scott, Rodney J; Fasching, Peter A; Haeberle, Lothar; Ekici, Arif B; Beckmann, Matthias W; Peto, Julian; Dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Bolla, Manjeet K; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Marme, Federik; Burwinkel, Barbara; Yang, Rongxi; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Bojesen, Stig; Nielsen, Sune F; Flyger, Henrik; Benitez, Javier; Zamora, M Pilar; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan; Ziogas, Argyrios; Clarke, Christina A; Brenner, Hermann; Arndt, Volker; Stegmaier, Christa; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon-Dschun; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Bogdanova, Natalia V; Antonenkova, Natalia N; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Spurdle, Amanda B; Investigators, kConFab; Wauters, Els; Smeets, Dominiek; Beuselinck, Benoit; Floris, Giuseppe; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Olson, Janet E; Vachon, Celine; Pankratz, Vernon S; McLean, Catriona; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Kristensen, Vessela; Alnæs, Grethe Grenaker; Zheng, Wei; Hunter, David J; Lindstrom, Sara; Hankinson, Susan E; Kraft, Peter; Andrulis, Irene; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Jukkola-Vuorinen, Arja; Grip, Mervi; Kauppila, Saila; Devilee, Peter; Tollenaar, Robert A E M; Seynaeve, Caroline; Hollestelle, Antoinette; Garcia-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Eccles, Diana M; Rafiq, Sajjad; Tapper, William J; Gerty, Sue M; Hooning, Maartje J; Martens, John W M; Collée, J Margriet; Tilanus-Linthorst, Madeleine; Hall, Per; Li, Jingmei; Brand, Judith S; Humphreys, Keith; Cox, Angela; Reed, Malcolm W R; Luccarini, Craig; Baynes, Caroline; Dunning, Alison M; Hamann, Ute; Torres, Diana; Ulmer, Hans Ulrich; Rüdiger, Thomas; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Slager, Susan; Toland, Amanda E; Ambrosone, Christine B; Yannoukakos, Drakoulis; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Jones, Michael; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Simard, Jacques; Dumont, Martine; Soucy, Penny; Eeles, Rosalind; Muir, Kenneth; Wiklund, Fredrik; Gronberg, Henrik; Schleutker, Johanna; Nordestgaard, Børge G; Weischer, Maren; Travis, Ruth C; Neal, David; Donovan, Jenny L; Hamdy, Freddie C; Khaw, Kay-Tee; Stanford, Janet L; Blot, William J; Thibodeau, Stephen; Schaid, Daniel J; Kelley, Joseph L; Maier, Christiane; Kibel, Adam S; Cybulski, Cezary; Cannon-Albright, Lisa; Butterbach, Katja; Park, Jong; Kaneva, Radka; Batra, Jyotsna; Teixeira, Manuel R; Kote-Jarai, Zsofia; Olama, Ali Amin Al; Benlloch, Sara; Renner, Stefan P; Hartmann, Arndt; Hein, Alexander; Ruebner, Matthias; Lambrechts, Diether; Van Nieuwenhuysen, Els; Vergote, Ignace; Lambretchs, Sandrina; Doherty, Jennifer A; Rossing, Mary Anne; Nickels, Stefan; Eilber, Ursula; Wang-Gohrke, Shan; Odunsi, Kunle; Sucheston-Campbell, Lara E; Friel, Grace; Lurie, Galina; Killeen, Jeffrey L; Wilkens, Lynne R; Goodman, Marc T; Runnebaum, Ingo; Hillemanns, Peter A; Pelttari, Liisa M; Butzow, Ralf; Modugno, Francesmary; Edwards, Robert P; Ness, Roberta B; Moysich, Kirsten B; du Bois, Andreas; Heitz, Florian; Harter, Philipp; Kommoss, Stefan; Karlan, Beth Y; Walsh, Christine; Lester, Jenny; Jensen, Allan; Kjaer, Susanne Krüger; Høgdall, Estrid; Peissel, Bernard; Bonanni, Bernardo; Bernard, Loris; Goode, Ellen L; Fridley, Brooke L; Vierkant, Robert A; Cunningham, Julie M; Larson, Melissa C; Fogarty, Zachary C; Kalli, Kimberly R; Liang, Dong; Lu, Karen H; Hildebrandt, Michelle A T; Wu, Xifeng; Levine, Douglas A; Dao, Fanny; Bisogna, Maria; Berchuck, Andrew; Iversen, Edwin S; Marks, Jeffrey R; Akushevich, Lucy; Cramer, Daniel W; Schildkraut, Joellen; Terry, Kathryn L; Poole, Elizabeth M; Stampfer, Meir; Tworoger, Shelley S; Bandera, Elisa V; Orlow, Irene; Olson, Sara H; Bjorge, Line; Salvesen, Helga B; van Altena, Anne M; Aben, Katja K H; Kiemeney, Lambertus A; Massuger, Leon F A G; Pejovic, Tanja; Bean, Yukie; Brooks-Wilson, Angela; Kelemen, Linda E; Cook, Linda S; Le, Nhu D; Górski, Bohdan; Gronwald, Jacek; Menkiszak, Janusz; Høgdall, Claus K; Lundvall, Lene; Nedergaard, Lotte; Engelholm, Svend Aage; Dicks, Ed; Tyrer, Jonathan; Campbell, Ian; McNeish, Iain; Paul, James; Siddiqui, Nadeem; Glasspool, Rosalind; Whittemore, Alice S; Rothstein, Joseph H; McGuire, Valerie; Sieh, Weiva; Cai, Hui; Shu, Xiao-Ou; Teten, Rachel T; Sutphen, Rebecca; McLaughlin, John R; Narod, Steven A; Phelan, Catherine M; Monteiro, Alvaro N; Fenstermacher, David; Lin, Hui-Yi; Permuth, Jennifer B; Sellers, Thomas A; Chen, Y Ann; Tsai, Ya-Yu; Chen, Zhihua; Gentry-Maharaj, Aleksandra; Gayther, Simon A; Ramus, Susan J; Menon, Usha; Wu, Anna H; Pearce, Celeste L; Van Den Berg, David; Pike, Malcolm C; Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Moes-Sosnowska, Joanna; Kupryjanczyk, Jolanta; Pharoah, Paul Dp; Song, Honglin; Winship, Ingrid; Chenevix-Trench, Georgia; Giles, Graham G; Tavtigian, Sean V; Easton, Doug F; Milne, Roger L

2016-12-01

The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10 -5 ), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10 -8 ) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Propriedades de estruturas temporais rápidas submilimétricas durante uma grande explosão solar

NASA Astrophysics Data System (ADS)

Raulin, J.-P.; Kaufmann, P.; Gimenez de Castro, C. G.; Pacini, A. A.; Makhmutov, V.; Levato, H.; Rovira, M.

2003-08-01

Apresentamos novas propriedades de variações rápidas da emissão submilimétrica durante uma das maiores explosões solares do ciclo solar 23. Os dados analisados neste estudo foram obtidos com o Telescópio Solar Submilimétrico (SST), que observa o Sol em 212 GHz e 405 GHz, e comparados com emissões em Raios-X duros e Raios-gama (fótons de energia > 10 MeV), que foram obtidas pelo experimento GRS do Yohkoh. Aplicamos diferentes metodologias para detectar e caracterizar, ao longo do evento, os pulsos submilimétricos (duração de 50-300 ms) detectados acima de uma componente mais lenta (alguns minutos). Os resultados mostram que durante a fase impulsiva, num instante próximo ao tempo do máximo do evento, houve um aumento da ocorrência de maiores e de mais rápidas estruturas temporais. Também identificamos uma boa correlação com as emissões em raios-X e raios-gama (até a faixa de energia 10-100 MeV), indicando que os pulsos rápidos submilimétricos refletiram injeções primárias de energia durante o evento.O espectro do fluxo desses pulsos é crescente com a freqüência entre 212 and 405 GHz, na maioria dos casos, ao contrário do observado para a componente gradual. As posições calculadas para as estruturas rápidas são discretas, compactas e localizadas em toda a área da região ativa, o que é previsto nos modelos de explosões solares decorrentes de instabilidades múltiplas em diferentes pequenas regiões. Por outro lado, a posição calculada para a componente lenta é estável durante a fase impulsiva. Assim, a comparação entre as características do espectro de fluxo e da localização da emissão, para os pulsos rápidos e para a componente gradual, sugere que as respectivas emissões são de natureza diferente.

Report on 2005 Defense Base Closure and Realignment Implementation

DTIC Science & Technology

2007-04-01

Marcos 559 ARNG RC Seguin 560 ARNG RC Snyder 561 ARNG RC Taylor 562 ARNG RC Terrell 563 ARNG RC Texarkana 564 ARNG RC Tyler 565 Benavidez USARC, El...realignment actions: Sep 1 2011 563 ARNG RC Texarkana , TX Commission recommendation(s) affected by this installation: Number Title 44 Reserve Component...AL421382002700 State: Alabama Sites Sites RC Total 51 38 Phase Beg. End <=2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Genetic Analysis of 13 Iranian Families With Leukocyte Adhesion Deficiency Type 1.

PubMed

Teimourian, Shahram; De Boer, Martin; Roos, Dirk; Isaian, Anna; Bemanian, Mohammad Hassan; Lashkary, Sharhzad; Nabavi, Mohammad; Arshi, Saba; Nateghian, Alireza; Sayyahfar, Shirin; Sazgara, Faezeh; Taheripak, Gholamreza; Alipour Fayez, Elham

2018-05-10

Leukocyte adhesion deficiency type 1 is a rare, autosomal recessive disorder that results from mutations in the ITGB2 gene. This gene encodes the CD18 subunit of β2 integrin leukocyte adhesion cell molecules. Leukocyte adhesion deficiency type 1 is characterized by recurrent bacterial infections, impaired wound healing, inadequate pus formation, and delayed separation of the umbilical cord. Blood samples were taken from 13 patients after written consent had been obtained. Genomic DNA was extracted, and ITGB2 exons and exon-intron boundaries were amplified by polymerase chain reaction. The products were examined by Sanger sequencing. In this study, 8 different previously reported mutations (intron7+1G>A, c.715G>A, c.1777 C>T, c.843del C, c.1768T>C, c.1821C>A, Intron7+1G>A, c.1885G>A) and 2 novel mutations (c.1821C>A; p.Tyr607Ter and c.1822C>T; p.Gln608Ter) were found. c.1821C>A (p.Tyr607Ter) and c.1822C>T (p.Gln608Ter) mutations should be included in the panel of carrier detection and prenatal diagnosis.

Effect of anomalous transport on kinetic simulations of the H-mode pedestal

NASA Astrophysics Data System (ADS)

Bateman, G.; Pankin, A. Y.; Kritz, A. H.; Rafiq, T.; Park, G. Y.; Ku, S.; Chang, C. S.

2009-11-01

The MMM08 and MMM95 Multi-Mode transport models [1,2], are used to investigate the effect of anomalous transport in XGC0 gyrokinetic simulations [3] of tokamak H-mode pedestal growth. Transport models are implemented in XGC0 using the Framework for Modernization and Componentization of Fusion Modules (FMCFM). Anomalous transport is driven by steep temperature and density gradients and is suppressed by high values of flow shear in the pedestal. The radial electric field, used to calculate the flow shear rate, is computed self-consistently in the XGC0 code with the anomalous transport, Lagrangian charged particle dynamics and neutral particle effects. XGC0 simulations are used to provide insight into how thermal and particle transport, together with the sources of heat and charged particles, determine the shape and growth rate of the temperature and density profiles. [1] F.D. Halpern et al., Phys. Plasmas 15 (2008) 065033; J.Weiland et al., Nucl. Fusion 49 (2009) 965933; A.Kritz et al., EPS (2009) [2] G. Bateman, et al, Phys. Plasmas 5 (1998) 1793 [3] C.S. Chang, S. Ku, H. Weitzner, Phys. Plasmas 11 (2004) 2649

Genetic diagnosis of polycystic kidney disease, Alport syndrome, and thalassemia minor in a large Chinese family.

PubMed

Miao, Yun; Xiong, Jun; Zhang, Xuelian; Huang, Huajie; Yu, Lixin; Chen, Jianfan; Deng, Wenfeng; Xu, Huiling; Liu, Rumin; Xiang, Chenglin; Xu, Xiangmin; Xiong, Fu

2017-10-01

Polycystic kidney disease (PKD) and Alport syndrome (AS) are serious inherited disorders associated with renal disease, and thalassemia is a hereditary blood disease with a high prevalence in south China. Here, we report an exceptional PKD coincidence of thalassemia minor and AS (diagnosed genetically) in a large Chinese family. Whole genome next-generation sequencing (NGS) was performed on the proband, and all family members underwent clinical evaluation. Sanger sequencing was used to validate the mutations distinguished by NGS. The pathogenic potential of the variants were evaluated by Polymorphism Phenotyping v2 (PolyPhen-2), Sorting Intolerant From Tolerant (SIFT) algorithm, and MutationTaster. Immunohistochemical, Western blot, immunofluorescent, and TdT-mediated dUTP nick-end labeling (TUNEL) analyses were performed to investigate polycystin 1 (PC1) expression, and cell proliferation and apoptosis in kidney tissues from the proband and normal control. A novel frameshift polycystic kidney disease 1 ( PKD1 ) mutation (c.3903delC, p.A1302Pfs) was identified to be responsible for renal disease in this family. PC1 expression, and cell proliferation and apoptosis were significantly increased in the kidney tissues of the proband. Moreover, a deletion of approximately 19.3 kb of DNA with α-globin genes ( _ _SEA ) was associated with thalassemia minor in the family. In addition, a collagen type IV α 5 chain ( COL4A5 ) variant (c.2858G>T, rs78972735), annotated as a pathogenic mutation in dbSNP and human gene mutation database (HGMD), was found in four family members with no clinical traits of AS. A novel pathogenic PKD1 mutation (c.3903delC) and ( _ _SEA ) thalassemia deletion were found to be responsible for the clinical symptoms in this family. The reported pathogenic COL4a5 variant (c.2858G>T, rs78972735) was not pathogenic alone. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Hydrology of the coastal sabkhas of Abu Dhabi, United Arab Emirates

NASA Astrophysics Data System (ADS)

Sanford, Ward; Wood, Warren

2001-05-01

Water fluxes were estimated and a water budget developed for the land surface and a surficial 10-m-deep section of the coastal sabkhas that extend from the city of Abu Dhabi, United Arab Emirates, west to the border with Saudi Arabia. The fluxes were estimated on the basis of water levels and hydraulic conductivities measured in wells and evaporation rates measured with a humidity chamber. In contrast with conceptual models proposed in earlier studies, groundwater inflow is estimated to be small, whereas the largest components of the water budget are recharge from rainfall and evaporation from the water table. Estimates within a rectilinear volume of sabkha, defined as 1 m wide by 10 km long by 10 m deep, indicate that about 1 m3/year of water enters and exits by lateral groundwater flow; 40-50 m3/year enters by upward leakage; and 640 m3/year enters by recharge from rainfall. Based on the water and solute fluxes estimated for the upward leakage into the sabkha, 7-8 pore volumes of brine have entered the sabkha from below since the time the sabkha became saturated (7,000 years ago) as a result of the last global sea-level rise. Résumé. Les flux d'eau ont été estimés et le bilan hydrique a été réalisé pour la surface et les dix premiers mètres sous la surface de sebkhas littorales qui s'étendent à partir de la ville d'Abou Dhabi (Émirats Arabes Unis) à l'ouest de la frontière avec l'Arabie Saoudite. Les flux ont été estimés à partir des niveaux piézométriques et des conductivités hydrauliques mesurés dans les puits et à partir de mesures d'évaporation au moyen de capteurs d'humidité. En opposition avec les modèles conceptuels proposés dans les premières études, on estime que les apports par les eaux souterraines sont faibles, alors que les termes du bilan hydrique les plus importants sont la recharge par la pluie et l'évaporation à partir de la nappe. Les estimations dans un parallélépipède rectangle de sebkha, d'1 m de large, de 10 km de long et de 10 m d'épaisseur, indiquent qu'environ 1 m3/an d'eau entre et sort par écoulement souterrain latéral, que 40 à 50 m3/an entrent par drainance ascendante, et que 640 m3/an pénètrent par recharge à partir de la pluie. À partir des flux estimés d'eau et de solutés pour la drainance ascendante dans la sebkha, 7 à 8 volumes de pores de saumure sont entrés par en bas dans la sebkha depuis le moment où la sebkha est devenue saturée, il y a 7.000 ans, du fait de la dernière remontée du niveau marin. Resumen. Se ha estimado el flujo de agua y se ha efectuado un balance de agua en la superficie del terreno y en una sección superficial de 10 m de profundidad de los sabkhasAmbiente de sedimentación costera que se caracteriza por: (1) sus condiciones de aridez o semi-aridez por encima del nivel de mareas altas y (2) la ausencia de vegetación. Son habituales las evaporitas, depósitos eólicos y depósitos de inundación de marea. costeros cercanos a la ciudad de Abu Dhabi (Emiratos Árabes Unidos), al este de la frontera con Arabia Saudí. La estimación de los flujos se ha hecho con base en los niveles y conductividades hidráulicas medidos en pozos, y en las tasas de evaporación medidas mediante una cámara de humedad. Contrariamente a los modelos conceptuales propuestos en estudios previos, se ha estimado que la entrada de agua subterránea es pequeña, mientras que las componentes principales del balance son la recarga de agua de lluvia y la evaporación desde el nivel freático. Las estimaciones hechas en un volumen de sabkha de 1 m de anchura por 10 km de longitud y 10 m de profundidad indican que alrededor de 1 m3/a de agua entra y sale por flujo subterráneo lateral, 40-50 m3/a lo hacen por recarga desde niveles inferiores, y 650 m3/a proceden de la recarga de agua de lluvia. Teniendo en cuenta la estimación del flujo de agua y solutos para la recarga desde los niveles inferiores, se calcula que entre 7 y 8 volúmenes de poro de salmuera han entrado a la sabkha desde el momento en que ésta se saturó, hace 7.000 años, como resultado del último ascenso global de los océanos.

The molecular basis of Canavan (Aspartoacylase deficiency) disease in European non-Jewish patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shaag, A.; Anikster, Y.; Glustein, J.Z.

Canavan disease is an infantile neurodegenerative disease that is due to aspartoacylase deficiency. The disease has been reported mainly in Ashkenazi Jews but also occurs in other ethnic groups. Determination of enzymatic activity for carrier detection and prenatal diagnosis is considered unreliable. In the present study, nine mutations were found in the aspartoacylase gene of 19 non-Jewish patients. These included four point mutations (A305E [39.5% of the mutated alleles], C218X [15.8%], F2955 [2.6%], and G274R [5.3%]); four deletion mutations (827delGT [5.3%], 870del4 [2.6%], 566del7 [2.6%], and 527del6 [2.6%]); and one exon skip (527del108 [5.3%]). The A305E mutation is pan-European andmore » probably the most ancient mutation, identified in patients of Greek, Polish, Danish, French, Spanish, Italian, and British origin. In contrast, the G274R and 527del108 mutations were found only in patients of Turkish origin, and the C218X mutation was identified only in patients of Gypsy origin. Homozygosity for the A305E mutation was identified in patients with both the severe and the mild forms of Canavan disease. Mutations were identified in 31 of the 38 alleles, resulting in an overall detection rate of 81.6%. All nine mutations identified in non-Jewish patients reside in exons 4-6 of the aspartoacylase gene. The results would enable accurate genetic counseling in the families of 13 (68.4%) of 19 patients, in whom two mutations were identified in the aspartoacylase cDNA. 19 refs., 9 figs., 3 tabs.« less

Insights into Mutation Effect in Three Poikiloderma with Neutropenia Patients by Transcript Analysis and Disease Evolution of Reported Patients with the Same Pathogenic Variants.

PubMed

Colombo, Elisa A; Elcioglu, Nursel H; Graziano, Claudio; Farinelli, Pamela; Di Fede, Elisabetta; Neri, Iria; Facchini, Elena; Greco, Mariangela; Gervasini, Cristina; Larizza, Lidia

2018-05-16

Poikiloderma with neutropenia (PN) is a genodermatosis currently described in 77 patients, all presenting with early-onset poikiloderma, neutropenia, and several additional signs. Biallelic loss-of-function mutations in USB1 gene are detected in all molecularly tested patients but genotype-phenotype correlation remains elusive. Cancer predisposition is recognized among PN features and pathogenic variants found in patients who developed early in life myelodysplasia (n = 12), acute myeloid leukemia (n = 2), and squamous cell carcinoma (n = 2) should be kept into account in management and follow-up of novel patients. This will hopefully allow achieving data clustered on specific mutations relevant to oncological surveillance of the carrier patients. We describe the clinical features of three unreported PN patients and characterize their USB1 pathogenic variants by transcript analysis to get insights into the effect on the overall phenotype and disease evolution. A Turkish boy is homozygous for the c.531delA deletion, a recurrent mutation in Turkey; an adult Italian male is compound heterozygous for two nonsense mutations, c.243G>A and c.541C>T, while an Italian boy is homozygous for the splicing c.683_693+1del variant. The identified mutations have already been reported in PN patients who developed hematologic or skin cancer. Aberrant mRNAs of all four mutated alleles could be identified confirming that transcripts of USB1 main isoform either carrying stop codons or mis-spliced may at least partially escape nonsense-mediated decay. Our study addresses the need of gathering insights on genotype-phenotype correlations in newly described PN patients, by transcript analysis and information on disease evolution of reported patients with the same pathogenic variants.

Differential Effects of HNF-1α Mutations Associated with Familial Young-Onset Diabetes on Target Gene Regulation

PubMed Central

Galán, Maria; García-Herrero, Carmen-Maria; Azriel, Sharona; Gargallo, Manuel; Durán, Maria; Gorgojo, Juan-Jose; Andía, Victor-Manuel; Navas, Maria-Angeles

2011-01-01

Hepatocyte nuclear factor 1-α (HNF-1α) is a homeodomain transcription factor expressed in a variety of tissues (including liver and pancreas) that regulates a wide range of genes. Heterozygous mutations in the gene encoding HNF-1α (HNF1A) cause familial young-onset diabetes, also known as maturity-onset diabetes of the young, type 3 (MODY3). The variability of the MODY3 clinical phenotype can be due to environmental and genetic factors as well as to the type and position of mutations. Thus, functional characterization of HNF1A mutations might provide insight into the molecular defects explaining the variability of the MODY3 phenotype. We have functionally characterized six HNF1A mutations identified in diabetic patients: two novel ones, p.Glu235Gly and c-57-64delCACGCGGT;c-55G>C; and four previously described, p.Val133Met, p.Thr196Ala, p.Arg271Trp and p.Pro379Arg. The effects of mutations on transcriptional activity have been measured by reporter assays on a subset of HNF-1α target promoters in Cos7 and Min6 cells. Target DNA binding affinities have been quantified by electrophoretic mobility shift assay using bacterially expressed glutathione-S-transferase (GST)-HNF-1α fusion proteins and nuclear extracts of transfected Cos7 cells. Our functional studies revealed that mutation c-57-64delCACGCGGT;c-55G>C reduces HNF1A promoter activity in Min6 cells and that missense mutations have variable effects. Mutation p.Arg271Trp impairs HNF-1α activity in all conditions tested, whereas mutations p.Val133Met, p.Glu235Gly and p.Pro379Arg exert differential effects depending on the target promoter. In contrast, substitution p.Thr196Ala does not appear to alter HNF-1α function. Our results suggest that HNF1A mutations may have differential effects on the regulation of specific target genes, which could contribute to the variability of the MODY3 clinical phenotype. PMID:21170474

Dominant KCNA2 mutation causes episodic ataxia and pharmacoresponsive epilepsy.

PubMed

Corbett, Mark A; Bellows, Susannah T; Li, Melody; Carroll, Renée; Micallef, Silvana; Carvill, Gemma L; Myers, Candace T; Howell, Katherine B; Maljevic, Snezana; Lerche, Holger; Gazina, Elena V; Mefford, Heather C; Bahlo, Melanie; Berkovic, Samuel F; Petrou, Steven; Scheffer, Ingrid E; Gecz, Jozef

2016-11-08

To identify the genetic basis of a family segregating episodic ataxia, infantile seizures, and heterogeneous epilepsies and to study the phenotypic spectrum of KCNA2 mutations. A family with 7 affected individuals over 3 generations underwent detailed phenotyping. Whole genome sequencing was performed on a mildly affected grandmother and her grandson with epileptic encephalopathy (EE). Segregating variants were filtered and prioritized based on functional annotations. The effects of the mutation on channel function were analyzed in vitro by voltage clamp assay and in silico by molecular modeling. KCNA2 was sequenced in 35 probands with heterogeneous phenotypes. The 7 family members had episodic ataxia (5), self-limited infantile seizures (5), evolving to genetic generalized epilepsy (4), focal seizures (2), and EE (1). They had a segregating novel mutation in the shaker type voltage-gated potassium channel KCNA2 (CCDS_827.1: c.765_773del; p.255_257del). A rare missense SCN2A (rs200884216) variant was also found in 2 affected siblings and their unaffected mother. The p.255_257del mutation caused dominant negative loss of channel function. Molecular modeling predicted repositioning of critical arginine residues in the voltage-sensing domain. KCNA2 sequencing revealed 1 de novo mutation (CCDS_827.1: c.890G>A; p.Arg297Gln) in a girl with EE, ataxia, and tremor. A KCNA2 mutation caused dominantly inherited episodic ataxia, mild infantile-onset seizures, and later generalized and focal epilepsies in the setting of normal intellect. This observation expands the KCNA2 phenotypic spectrum from EE often associated with chronic ataxia, reflecting the marked variation in severity observed in many ion channel disorders. © 2016 American Academy of Neurology.

Hydrophobic imbalance in the cytoplasmic domain of phospholamban is a determinant for lethal dilated cardiomyopathy.

PubMed

Ceholski, Delaine K; Trieber, Catharine A; Young, Howard S

2012-05-11

The sarco(endo)plasmic reticulum calcium ATPase (SERCA) and its regulatory partner phospholamban (PLN) are essential for myocardial contractility. Arg(9) → Cys (R9C) and Arg(14) deletion (R14del) mutations in PLN are associated with lethal dilated cardiomyopathy in humans. To better understand these mutations, we made a series of amino acid substitutions in the cytoplasmic domain of PLN and tested their ability to inhibit SERCA. R9C is a complete loss-of-function mutant of PLN, whereas R14del is a mild loss-of-function mutant. When combined with wild-type PLN to simulate heterozygous conditions, the mutants had a dominant negative effect on SERCA function. A series of targeted mutations in this region of the PLN cytoplasmic domain ((8)TRSAIRR(14)) demonstrated the importance of hydrophobic balance in proper PLN regulation of SERCA. We found that Arg(9) → Leu and Thr(8) → Cys substitutions mimicked the behavior of the R9C mutant, and an Arg(14) → Ala substitution mimicked the behavior of the R14del mutant. The results reveal that the change in hydrophobicity resulting from the R9C and R14del mutations is sufficient to explain the loss of function and persistent interaction with SERCA. Hydrophobic imbalance in the cytoplasmic domain of PLN appears to be a predictor for the development and progression of dilated cardiomyopathy.

The Physical Oceanography of the Alboran Sea.

DTIC Science & Technology

1987-03-01

concentrated in Lanoix, 1974) fluctuated about 38.47 ppt and 13.15’C , ie northern part (Fig. 20). Its path in the eastern basin (in situ ). Bryden et al...inclinacion transversal de las W ater. aguas atlanticas y Mediterraneas en el Estrecho de Gibraltar. Boletin del Instituto Espaiol de X1. References

USSR Report, International Affairs

DTIC Science & Technology

1986-12-03

moviraiento popular." Lima, 1981, p 430. 12. "Habla la Direccion de la Vanguardia ." Managua, 1981, p 81. 13. C. Fonseca. "Obras," Vol 1, p 237. 14...CUADERNOS DEL TERCER MÜNDO. Mexico, No 63, 1983 (Separata Especial), p 5. 15. "Habla la Direccion de la Vanguardia ," p 34. 16. BARRICADA INTERNACIONAL

Clinical and genetic investigation of families with type II Waardenburg syndrome.

PubMed

Chen, Yong; Yang, Fuwei; Zheng, Hexin; Zhou, Jianda; Zhu, Ganghua; Hu, Peng; Wu, Weijing

2016-03-01

The present study aimed to investigate the molecular pathology of Waardenburg syndrome type II in three families, in order to provide genetic diagnosis and hereditary counseling for family members. Relevant clinical examinations were conducted on the probands of the three pedigrees. Peripheral blood samples of the probands and related family members were collected and genomic DNA was extracted. The coding sequences of paired box 3 (PAX3), microphthalmia‑associated transcription factor (MITF), sex‑determining region Y‑box 10 (SOX10) and snail family zinc finger 2 (SNAI2) were analyzed by polymerase chain reaction and DNA sequencing. The heterozygous mutation, c.649_651delAGA in exon 7 of the MITF gene was detected in the proband and all patients of pedigree 1; however, no pathological mutation of the relevant genes (MITF, SNAI2, SOX10 or PAX3) was detected in pedigrees 2 and 3. The heterozygous mutation c.649_651delAGA in exon 7 of the MITF gene is therefore considered the disease‑causing mutation in pedigree 1. However, there are novel disease‑causing genes in Waardenburg syndrome type II, which require further research.

International Workshop on Glasses and Ceramics, Hybrids and Nanocomposites from Gels (9th); Sol-Gel 󈨥 Held in Centre for Glass Research, The University of Sheffield, UK on 31 August-5 September 1997

DTIC Science & Technology

1998-01-01

Ormosils E. Blanco, M. Garcia-Hernändez, R. Jimenez-Rioböo, R. Liträn, C. Prieto and M. Ramirez -del-Solar 451 Hybrid Xerogel Structure and...Garcia M., E. Ramirez J., M.A. Mondragon, R. Ortega, P. Loza and A. Campero 657 Thermochromic Properties of Silver Colloids Embedded in Si02...C.S.I.C, Cantoblanco, E-28049-Madrid, Spain M. RAMIREZ -DEL-SOLAR Departamento de Fisica de la Materia Condensada, Universidad de Cadiz, Apartado

Funciones de partición atómicas: Fuentes confiables de datos

NASA Astrophysics Data System (ADS)

Merlo, D. C.; Milone, L. A.

Se llevó a cabo una revisión minuciosa del cálculo de funciones de partición atómicas de átomos livianos, en estados neutro y una vez ionizados, partiendo del Hidrógeno y llegando al Sodio, incluyendo también al K I y el Ca II. Al respecto, se realizó una investigación exhaustiva de referencias bibliográficas existentes hasta el presente, las cuales fueron cotejadas con cálculos propios llevados a cabo mediante el procedimiento de depresión del contínuo (0.001 a 0.5 eV). Nuestros resultados muestran un muy buen acuerdo con las expresiones interpolatorias de Traving et al (1966), al presente, la referencia más completa en cuanto a especies atómicas consideradas. Puntualizamos, además, ciertas deficiencias de estas relaciones de ajuste para decrementos del potencial de ionización altos (Δ χ >= 0.5) eV).

High Incidence of ACE/PAI-1 in Association to a Spectrum of Other Polymorphic Cardiovascular Genes Involving PBMCs Proinflammatory Cytokines in Hypertensive Hypercholesterolemic Patients: Reversibility with a Combination of ACE Inhibitor and Statin.

PubMed

AlBacha, Jeanne d'Arc; Khoury, Mira; Mouawad, Charbel; Haddad, Katia; Hamoui, Samar; Azar, Albert; Fajloun, Ziad; Makdissy, Nehman

2015-01-01

Cardiovascular diseases (CVDs) are significantly high in the Lebanese population with the two most predominant forms being atherosclerosis and venous thrombosis. The purpose of our study was to assess the association of a spectrum of CVD related genes and combined state of hypertension hypercholesterolemia (HH) in unrelated Lebanese. Twelve polymorphisms were studied by multiplex PCR and reverse hybridization of DNA from 171 healthy individuals and 144 HH subjects. Two genes were significantly associated with HH: ACE (OR: 9.20, P<0.0001) and PAI-1 (OR: 2.29, P = 0.007), respectively with the occurrence of the risky alleles "Del" and "4G". The frequencies of the Del and 4G alleles were found to be 0.98 and 0.90 in the HH group versus 0.84 and 0.79 in the healthy group, respectively. Serum ACE activity and PAI-I increased significantly with Del/Del and 4G/5G genotypes. The co-expression of Del/4G(+/+) was detected in 113 out of 171 (66.0%) controls and 125 out of 144 (86.8%) HH subjects. Del/4G(-/-) was detected in only 6 (3.5%) controls and undetected in the HH group. Three venous thrombosis related genes [FV(Leiden), MTHFR(A1298C) and FXIII(V34L)] were significantly related to the prominence of the co-expression of Del/4G(+/+). A range of 2 to 8 combined polymorphisms co-expressed per subject where 5 mutations were the most detected. In Del/4G(+/+) subjects, peripheral blood mononuclear cells (PBMCs) produced significant elevated levels of IFN-γ and TNF-α contrary to IL-10, and no variations occurred for IL-4. ACE inhibitor (ramipril) in combination with statin (atorvastatin) and not alone reversed significantly the situation. This first report from Lebanon sheds light on an additional genetic predisposition of a complex spectrum of genes involved in CVD and suggests that the most requested gene FVL by physicians may not be sufficient to diagnose eventual future problems that can occur in the cardiovascular system. Subjects expressing the double mutations (Del/4G) are at high risk for the onset of CVDs.

Association between methylene tetrahydrofolate reductase and glutathione S-transferase M1 gene polymorphisms and chronic myeloid leukemia in a Brazilian population.

PubMed

Lordelo, G S; Miranda-Vilela, A L; Akimoto, A K; Alves, P C Z; Hiragi, C O; Nonino, A; Daldegan, M B; Klautau-Guimarães, M N; Grisolia, C K

2012-04-19

Chronic myeloid leukemia is a hematopoietic stem cell disorder that causes uncontrolled proliferation of white blood cells. Although the clinical and biological aspects are well documented, little is known about individual susceptibility to this disease. We conducted a case-control study analyzing the prevalence of the polymorphisms MTHFR C677T, MTHFR A1298C, del{GSTM1}, del{GSTT1}, and haptoglobin in 105 patients with chronic myeloid leukemia (CML) and 273 healthy controls, using PCR-based methods. A significant association with risk of developing CML was found for MTHFR 1298AA (odds ratio (OR) = 1.794; 95% confidence interval (CI) = 1.14-2.83) and GSTM1 non-null (OR = 1.649; 95%CI = 1.05-2.6) genotypes, while MTHFR 1298AC (OR = 0.630; 95%CI = 0.40-0.99) and GSTM1 null (OR = 0.606; 95%CI = 0.21-0.77) genotypes significantly decreased this risk. There appeared to be selection for heterozygosity at the MTHFR 1298 locus. The considerable range of variation in this and other human populations may be a consequence of distinctive processes of natural selection and adaptation to variable environmental conditions. The Brazilian population is very mixed and heterogeneous; we found these two loci to be associated with CML in this population.

Complete Chloroplast Genome Sequence of Tartary Buckwheat (Fagopyrum tataricum) and Comparative Analysis with Common Buckwheat (F. esculentum)

PubMed Central

Cho, Kwang-Soo; Yun, Bong-Kyoung; Yoon, Young-Ho; Hong, Su-Young; Mekapogu, Manjulatha; Kim, Kyung-Hee; Yang, Tae-Jin

2015-01-01

We report the chloroplast (cp) genome sequence of tartary buckwheat (Fagopyrum tataricum) obtained by next-generation sequencing technology and compared this with the previously reported common buckwheat (F. esculentum ssp. ancestrale) cp genome. The cp genome of F. tataricum has a total sequence length of 159,272 bp, which is 327 bp shorter than the common buckwheat cp genome. The cp gene content, order, and orientation are similar to those of common buckwheat, but with some structural variation at tandem and palindromic repeat frequencies and junction areas. A total of seven InDels (around 100 bp) were found within the intergenic sequences and the ycf1 gene. Copy number variation of the 21-bp tandem repeat varied in F. tataricum (four repeats) and F. esculentum (one repeat), and the InDel of the ycf1 gene was 63 bp long. Nucleotide and amino acid have highly conserved coding sequence with about 98% homology and four genes—rpoC2, ycf3, accD, and clpP—have high synonymous (Ks) value. PCR based InDel markers were applied to diverse genetic resources of F. tataricum and F. esculentum, and the amplicon size was identical to that expected in silico. Therefore, these InDel markers are informative biomarkers to practically distinguish raw or processed buckwheat products derived from F. tataricum and F. esculentum. PMID:25966355

The pleiotropic mouse phenotype extra-toes spotting is caused by translation initiation factor Eif3c mutations and is associated with disrupted sonic hedgehog signaling.

PubMed

Gildea, Derek E; Luetkemeier, Erin S; Bao, Xiaozhong; Loftus, Stacie K; Mackem, Susan; Yang, Yingzi; Pavan, William J; Biesecker, Leslie G

2011-05-01

Polydactyly is a common malformation and can be an isolated anomaly or part of a pleiotropic syndrome. The elucidation of the mutated genes that cause polydactyly provides insight into limb development pathways. The extra-toes spotting (Xs) mouse phenotype manifests anterior polydactyly, predominantly in the forelimbs, with ventral hypopigmenation. The mapping of Xs(J) to chromosome 7 was confirmed, and the interval was narrowed to 322 kb using intersubspecific crosses. Two mutations were identified in eukaryotic translation initiation factor 3 subunit C (Eif3c). An Eif3c c.907C>T mutation (p.Arg303X) was identified in Xs(J), and a c.1702_1758del mutation (p.Leu568_Leu586del) was identified in extra-toes spotting-like (Xsl), an allele of Xs(J). The effect of the Xs(J) mutation on the SHH/GLI3 pathway was analyzed by in situ hybridization analysis, and we show that Xs mouse embryos have ectopic Shh and Ptch1 expression in the anterior limb. In addition, anterior limb buds show aberrant Gli3 processing, consistent with perturbed SHH/GLI3 signaling. Based on the occurrence of Eif3c mutations in 2 Xs lines and haploinsufficiency of the Xs(J) allele, we conclude that the Xs phenotype is caused by a mutation in Eif3c, a component of the translation initiation complex, and that the phenotype is associated with aberrant SHH/GLI3 signaling.

Sistema Planeta-Satélite. Simulación orbital y potenciales gravitatorios

NASA Astrophysics Data System (ADS)

Medina, C.; Carrillo, M.

Se presenta un programa (desarrollado en Quick Basic 4.5) que simula, en tres dimensiones, el movimiento orbital de un satélite (o luna) alrededor de un planeta, al tiempo que calcula y grafica, en un plano, el potencial gravitatorio del sistema en función de la distancia al planeta. Para la simulación orbital, se emplea la matriz de transformación entre el sistema del planeta y el plano orbital. Para el cálculo y graficación del potencial se aplica un desarrollo en serie hasta el segundo orden, que da cuenta del efecto de achatamiento de los polos, en caso de que éste exista. Las longitudes de los ejes del planeta, la masa de éste y del satélite, sus tamaños aparentes, y los parámetros orbitales son introducidos por el usuario.

Measurement of the Neutron Flux of the Reaction C$sup 12$(d,n)N$sup 13$ Based on the Activity of N$sup 13$. Report No. 28; MEDICION DEL FLUJO NEUTRONICO DE LA REACCION C$sup 12$(d,n)N$sup 13$ A BASE DE LA ACTIVIDAD DEL N$sup 13$. INFORME NO 28

DOE Office of Scientific and Technical Information (OSTI.GOV)

Keller, A.

1960-08-01

The principal problem in the measurement of neutron flux from the reaction C/sup 12/(d,n)N/sup 13/, based on the activity of N/sup 13/, is the possibility of nitrogen escape. A method for the measurement of possibie N/sup 13/ losses is described, and measurements with TiC targets irradiated with 600- kev deuterons are reported. The formulas for the calculation of the neutron flux are indicated. (tr-auth)

BRCA1 and BRCA2 mutations in ovarian cancer patients from China: ethnic-related mutations in BRCA1 associated with an increased risk of ovarian cancer.

PubMed

Shi, Tingyan; Wang, Pan; Xie, Caixia; Yin, Sheng; Shi, Di; Wei, Congchong; Tang, Wenbin; Jiang, Rong; Cheng, Xi; Wei, Qingyi; Wang, Qing; Zang, Rongyu

2017-05-01

BRCA1/2 are cancer predisposition genes involved in hereditary breast and ovarian cancer (HBOC). Mutation carriers display an increased sensitivity to inhibitors of poly(ADP-ribose) polymerase (PARP). Despite a number of small-size hospital-based studies being previously reported, there is not yet, to our knowledge, precise data of BRCA1/2 mutations among Chinese ovarian cancer patients. We performed a multicenter cohort study including 916 unselected consecutive epithelial ovarian cancer (EOC) patients from eastern China to screen for BRCA1/2 mutations using the next-generation sequencing approach. A total of 153 EOC patients were found to carry pathogenic germline mutations in BRCA1/2, accounting for an overall mutation incidence of 16.7% with the predominance in BRCA1 (13.1%) compared with BRCA2 (3.9%). We identified 53 novel pathogenic mutations, among which the c.283_286delCTTG and the c.4573C > T of BRCA1 were both found in two unrelated patients. More importantly, the most common mutation found in this study, c.5470_5477del8 was most likely to be Chinese population-related without an apparent founder origin. This hot-spot mutation was presumably associated with an increased risk of ovarian cancer. Taken together, germline BRCA1/2 mutations were common in Chinese EOC patients with distinct mutational spectrum compared to Western populations. Our study contributes to the current understanding of BRCA1/2 mutation prevalence worldwide. We recommend BRCA1/2 genetic testing to all Chinese women diagnosed with EOC to identify HBOC families, to provide genetic counseling and clinical management for at-risk relatives. Mutation carriers may also benefit from PARP-targeted therapies. © 2017 UICC.

Patient Safety Incidents and Nursing Workload.

PubMed

Carlesi, Katya Cuadros; Padilha, Kátia Grillo; Toffoletto, Maria Cecília; Henriquez-Roldán, Carlos; Juan, Monica Andrea Canales

2017-04-06

to identify the relationship between the workload of the nursing team and the occurrence of patient safety incidents linked to nursing care in a public hospital in Chile. quantitative, analytical, cross-sectional research through review of medical records. The estimation of workload in Intensive Care Units (ICUs) was performed using the Therapeutic Interventions Scoring System (TISS-28) and for the other services, we used the nurse/patient and nursing assistant/patient ratios. Descriptive univariate and multivariate analysis were performed. For the multivariate analysis we used principal component analysis and Pearson correlation. 879 post-discharge clinical records and the workload of 85 nurses and 157 nursing assistants were analyzed. The overall incident rate was 71.1%. It was found a high positive correlation between variables workload (r = 0.9611 to r = 0.9919) and rate of falls (r = 0.8770). The medication error rates, mechanical containment incidents and self-removal of invasive devices were not correlated with the workload. the workload was high in all units except the intermediate care unit. Only the rate of falls was associated with the workload. identificar a relação entre a carga de trabalho da equipe de enfermagem e a ocorrência de incidentes de segurança dos pacientes ligados aos cuidados de enfermagem de um hospital público no Chile. pesquisa transversal analítica quantitativa através de revisão de prontuários médicos. A estimativa da carga de trabalho em Unidade de Terapia Intensiva (UTI) foi realizada utilizando o Índice de Intervenções Terapêuticas-TISS-28 e para os outros serviços, foram utilizados os cocientes enfermeira/paciente e auxiliar de enfermagem/ paciente. Foram feitas análises univariada descritiva e multivariada. Para a análise multivariada utilizou-se análise de componentes principais e correlação de Pearson. foram analisados 879 prontuáriosclínicos de pós-alta e a carga de trabalho de 85 enfermeiros e 157 auxiliares de enfermagem. A taxa global de incidentes foi de 71,1%. Foi encontrada uma alta correlação positiva entre as variáveis de carga de trabalho (r = 0,9611 para r = 0,9919) e a taxa de quedas (r = 0,8770). As taxas de erro de medicação, incidentes de contenção mecânica e auto remoção de dispositivos invasivos não foram correlacionadas com a carga de trabalho. a carga de trabalho foi elevada em todas as unidades, exceto na unidade de cuidados intermédios. Apenas a taxa de quedas foi associada com a carga de trabalho. identificar la relación entre la carga laboral del equipo de enfermería y la ocurrencia de incidentes de seguridad del paciente relacionados con los cuidados de enfermería en un hospital público de Chile. investigación cuantitativa, analítica, transversal, realizada por revisión de fichas clínicas. La estimación de carga laboral en las Unidades de Cuidados Intensivos (UCI) se realizó utilizando el Índice de Intervenciones Terapéuticas (TISS-28) y, para el resto de los servicios, por la relación enfermera/paciente y auxiliar/paciente. Se realizó análisis descriptivo univariado y multivariado. Para el análisis multivariado se utilizó análisis de componentes principales y el test de correlación de Pearson. se revisaron 879 fichas clínicas posteriores al alta y la carga laboral de 85 enfermeras y 157 auxiliares de enfermería. La tasa global de incidentes fue 71,1%. Se encontró correlación positiva alta entre las variables de carga laboral (r = 0,9611 a r = 0,9919) y tasa de caídas (r = 0,8770). Las tasas de error de medicación, incidente por contención mecánica y auto retiro de invasivos no se correlacionaron con la carga laboral. la carga laboral fue elevada en todas las unidades a excepción de la unidad de cuidados intermedios. Sólo la tasa de caídas se asoció a la carga laboral.

Older Workers in the Market for Part-Time Employment. Appendices to PP 396.

DTIC Science & Technology

1983-09-01

Ehrenberg, R.G., Fringe Benefits and Overtime Behavior. Lexington, 1971. Levis, H. G., "Interes del Employeador en las Horas de Tobajo del Empleado...34 "The Employer Interest in Employees’ Hours of Work," Cuadernos de Economia , 18 (1969), pp. 38-54, summarized in Rosen, Harvey, reference below. Owen...just tangential to the g(h) function. The next question is: Which factors shift the optimum combination of h and c? C-I D * .k=* ~ .... LA A U..~..’ 4 g

An unexpected effect of TNF-α on F508del-CFTR maturation and function

PubMed Central

Bitam, Sara; Urbach, Valérie; Sermet-Gaudelus, Isabelle; Hinzpeter, Alexandre; Edelman, Aleksander

2015-01-01

Cystic fibrosis (CF) is a multifactorial disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene ( CFTR), which encodes a cAMP-dependent Cl - channel. The most frequent mutation, F508del, leads to the synthesis of a prematurely degraded, otherwise partially functional protein. CFTR is expressed in many epithelia, with major consequences in the airways of patients with CF, characterized by both fluid transport abnormalities and persistent inflammatory responses. The relationship between the acute phase of inflammation and the expression of wild type (WT) CFTR or F508del-CFTR is poorly understood. The aim of the present study was to investigate this effect. The results show that 10 min exposure to TNF-alpha (0.5-50ng/ml) of F508del-CFTR-transfected HeLa cells and human bronchial cells expressing F508del-CFTR in primary culture (HBE) leads to the maturation of F508del-CFTR and induces CFTR chloride currents. The enhanced CFTR expression and function upon TNFα is sustained, in HBE cells, for at least 24 h. The underlying mechanism of action involves a protein kinase C (PKC) signaling pathway, and occurs through insertion of vesicles containing F508del-CFTR to the plasma membrane, with TNFα behaving as a corrector molecule. In conclusion, a novel and unexpected action of TNFα has been discovered and points to the importance of systematic studies on the roles of inflammatory mediators in the maturation of abnormally folded proteins in general and in the context of CF in particular. PMID:26594334

A multiproxy reconstruction of the palaeoenvironment and palaeoclimate of the Late Pleistocene in northeastern Iberia: Cova dels Xaragalls, Vimbodí-Poblet, Paratge Natural de Poblet, Catalonia

USGS Publications Warehouse

López-García, Juan Manuel; Blain, Hugues-Alexandre; Bennàsar, Maria; Euba, Itxaso; Bañuls, Sandra; Bischoff, James; López-Ortega, Esther; Saladié, Palmira; Uzquiano, Paloma; Vallverdú, Josep

2012-01-01

The Cova dels Xaragalls is a small open karst system, located in the municipality of Vimbodí-Poblet (Tarragona, Catalonia, NE Spain). It is an important Holocene archaeological site that was inspected in the 1970s but from which little has been published. New excavations starting in 2008 have exposed a deep Late Pleistocene stratigraphical sequence. In this paper, we present for the first time palaeoenvironmental and palaeoclimatic reconstructions of this Late Pleistocene succession on the basis of both the small-vertebrate assemblages and the charcoals. Results from the small-vertebrate associations along the sequence indicate that the landscape had open-woodland habitats in the vicinity of the Cova del Xaragalls, with wet points in the surrounding area. Woodland habitats were dominant throughout the sequence, as evidenced by the abundance of the species Apodemus sylvaticus, but were better developed during warm periods (layers C5 and C8), whereas during cold periods (layers C4 and C3) the environment was slightly more humid in response to higher mean annual precipitation and the opening of the landscape. The charcoal analysis indicates that the woodland surrounding the cave was composed mainly of Pinus (more than 90% was identified as Pinus), but that during the cold period (C3–C4) it incorporated some Quercus ilex/coccifera and Angiosperm indet., probably linked with greater precipitation. Comparisons are made with other long palaeoenvironmental sequences from the northeastern Iberian Peninsula and with global marine isotopic curves, providing a scenario for the palaeoclimatic and palaeoenvironmental changes that occurred during the Late Pleistocene in the woodland areas surrounding the Cova dels Xaragalls.

Large Variations of Atmospheric 14C Associated With Dansgaard-Oeschger Cycles 10- 13

NASA Astrophysics Data System (ADS)

Weyhenmeyer, C. E.; Burns, S. J.; Fleitmann, D.; Mangini, A.; Matter, A.; Guilderson, T.; Reimer, P. J.

2006-12-01

A 1.7 m long stalagmite from Moomi Cave, Socotra Island in the Indian Ocean provides a continuous, high- resolution record of climate change between 53 and 41 kyr BP. In the northern high-latitude regions, this time period is characterized by several rapid climate change events, corresponding to Dansgaard-Oeschger (D/O) cycles 10-13. It has been suggested that these D/O cycles may be global events but high-resolution data from the low-latitude regions are scarce. As a result, the driving and feedback mechanisms of these rapid changes remain poorly understood. The presented stalagmite data of U/Th, stable isotopes (del 18O, del 13C) and radiocarbon (14C) provide unique information regarding the nature and timing of rapid climate changes in the tropics. A depth-age model for the Moomi Cave stalagmite was developed from 25 high-precision U/Th measurements, providing a solid chronology for this record. Oxygen isotope measurements of the stalagmite calcite reveal several large variations that are believed to reflect changes in the amount of precipitation, rather than temperature. A comparison to the Greenland Ice Core records shows a remarkable similarity to D/O cycles 10- 13 with warmer periods in the high-latitude regions being associated with increased precipitation in the tropics and vice versa. The stalagmite radiocarbon (14C) values from over 100 individual measurements reveal an almost identical cyclic pattern, tracing all four D/O cycles. Assuming no changes in the carbonate chemistry of the precipitating fluid, the radiocarbon values of the stalagmite calcite directly reflect changes in global atmospheric 14C concentrations. There are three possible explanations for these cyclic variations of 14C values: 1) changes in the carbonate chemistry of the drip water resulting in changes of the dead carbon fraction (DCF); 2) changes in the solar activity and/or Earth's magnetic field resulting in direct variations of atmospheric 14C concentrations; and 3) changes in the global ocean circulation resulting in varying amounts of 'dead' (14C-free) carbon being released into the atmosphere. We exclude the first scenario based on the fact that calcite del 13C values show very little variation throughout this record, thus excluding any significant changes in the carbonate chemistry and DCF. Based on model calculations and 10Be data from ice core records, we propose changes in the global ocean circulation as the primary mechanism for rapid changes in the atmospheric 14C reservoir.

A novel mutation in the MYO7A gene is associated with Usher syndrome type 1 in a Chinese family.

PubMed

He, Xiaoguang; Peng, Qi; Li, Siping; Zhu, Pengyuan; Wu, Chunqiu; Rao, Chunbao; Lin, Jingqi; Lu, Xiaomei

2017-08-01

We aimed to investigate the genetic causes of hearing loss in a Chinese proband with autosomal recessive congenital deafness. The targeted capture of 159 known deafness genes and next-generation sequencing were performed to study the genetic causes of hearing loss in the Chinese family. Sanger sequencing was employed to verify the variant mutations in members of this family. The proband harbored two mutations in the MYO7A gene in the form of compound heterozygosity. She was found to be heterozygous for a novel insertion mutation c.3847_3848 ins TCTG (p.N1285LfsX24) in exon 30 and for the known mutation c.2239_2240delAG (p.R747S fsX16)in exon 19. The novel mutation was absent in the 1000 Genomes Project. These variants were carried in the heterozygous state by the parents and were therefore co-segregated with the genetic disease. Clinical re-assessment, including detailed audiologic and ocular examinations, revealed congenital deafness and retinitis pigmentosa in the proband. Collectively, the combination of audiometric, ophthalmologic and genetic examinations successfully confirmed the phenotype of Usher syndrome type 1 (USH1). This study demonstrates that the novel mutation c.3847_3848insTCTG (p. N1285LfsX24) in compound heterozygosity with c.2239_2240delAG in the MYO7A gene is the main cause of USH1 in the proband. Our study expands the mutational spectrum of MYO7A and provides a foundation for further investigations elucidating the MYO7A-related mechanisms of USH1. Copyright © 2017 Elsevier B.V. All rights reserved.

Turbulence Model Comparisons for Shear Layers and Axisymmetric Jets.

DTIC Science & Technology

1979-10-01

Fishburne 1 1101 State Road, Bldg : Calspan Corporation Princeton, NJ 08540 Attn: Dr. Dnnald W. Boyer I Dr. Paul V. Marrone I Grumman /Bethpage Dr. Walter...H. Wurster 1 Grumman Aerospace, Inc. PO Box 400 Attn: Dr. Paul D. Del Guidice 1 Buffalo, NY 14221 Dr. Stanley Rudman 1 S. Oyster Bay Road Physics...Naval Air Systems Command PO Box 516 Mr. William Volz 1 St. Louis, MO 63166 Air 320-C, JP-l Washington, DC 20361 Northrop Corporation Electro-Mechanical

The Nursing Diagnosis of risk for pressure ulcer: content validation.

PubMed

Santos, Cássia Teixeira Dos; Almeida, Miriam de Abreu; Lucena, Amália de Fátima

2016-06-14

to validate the content of the new nursing diagnosis, termed risk for pressure ulcer. the content validation with a sample made up of 24 nurses who were specialists in skin care from six different hospitals in the South and Southeast of Brazil. Data collection took place electronically, through an instrument constructed using the SurveyMonkey program, containing a title, definition, and 19 risk factors for the nursing diagnosis. The data were analyzed using Fehring's method and descriptive statistics. The project was approved by a Research Ethics Committee. title, definition and seven risk factors were validated as "very important": physical immobilization, pressure, surface friction, shearing forces, skin moisture, alteration in sensation and malnutrition. Among the other risk factors, 11 were validated as "important": dehydration, obesity, anemia, decrease in serum albumin level, prematurity, aging, smoking, edema, impaired circulation, and decrease in oxygenation and in tissue perfusion. The risk factor of hyperthermia was discarded. the content validation of these components of the nursing diagnosis corroborated the importance of the same, being able to facilitate the nurse's clinical reasoning and guiding clinical practice in the preventive care for pressure ulcers. validar o conteúdo do novo diagnóstico de enfermagem, denominado risco de úlcera por pressão. trata-se de uma validação de conteúdo, com amostra composta por 24 enfermeiros especialistas no cuidado à pele, procedentes de seis diferentes hospitais do Sul e Sudeste brasileiro. A coleta de dados ocorreu por meio eletrônico, em instrumento construído pelo programa SurveyMonkey, que continha título, definição e 19 fatores de risco para o diagnóstico de enfermagem. Os dados foram analisados pelo método de Fehring e pela estatística descritiva. O projeto foi aprovado em Comitê de Ética em Pesquisa. título, definição e sete fatores de risco foram validados como "muito importante", sendo: imobilidade, pressão, fricção, cisalhamento, umidade, sensações prejudicadas e desnutrição. Dentre os demais fatores de risco, onze foram validados como "importante": desidratação, obesidade, anemia, baixo nível de albumina, prematuridade, envelhecimento, tabagismo, edema, circulação prejudicada, diminuição da oxigenação e da perfusão tissular. O fator de risco hipertermia foi descartado. a validação de conteúdo desses componentes do diagnóstico de enfermagem corroborou a importância dos mesmos, podendo facilitar o raciocínio clínico do enfermeiro, norteando a prática clínica no cuidado preventivo à úlcera por pressão. validar el contenido del nuevo diagnóstico de enfermería denominado riesgo de úlcera por presión. se trata de una validación de contenido, con muestra compuesta por 24 enfermeros especialistas en el cuidado de la piel, procedentes de seis diferentes hospitales del Sur y Sureste brasileño. La recolección de datos se realizó por medio electrónico, con un instrumento construido por el programa SurveyMonkey, que contenía: título, definición y 19 factores de riesgo para el diagnóstico de enfermería. Los datos fueron analizados por el método de Fehring y con la estadística descriptiva. El proyecto fue aprobado en el Comité de Ética en Investigación. título, definición y siete factores de riesgo fueron validados como "muy importante"; los factores fueron: inmovilidad, presión, fricción, cizallamiento, humedad, sensaciones perjudicadas y desnutrición. Entre los demás factores de riesgo, once fueron validados como "importante": deshidratación, obesidad, anemia, bajo nivel de albumina sérica, prematuridad, envejecimiento, tabaquismo, edema, circulación perjudicada, disminución de la oxigenación y perfusión tisular. El factor de riesgo hipertermia fue descartado. la validación de contenido, de esos componentes del diagnóstico de enfermería, confirmó la importancia de los mismos, lo que puede facilitar el raciocinio clínico del enfermero, orientando la práctica clínica en el cuidado preventivo de la úlcera por presión.

Novel PAX3 mutations causing Waardenburg syndrome type 1 in Tunisian patients.

PubMed

Trabelsi, Mediha; Nouira, Malek; Maazoul, Faouzi; Kraoua, Lilia; Meddeb, Rim; Ouertani, Ines; Chelly, Imen; Benoit, Valérie; Besbes, Ghazi; Mrad, Ridha

2017-12-01

Waardenburg syndrome (WS) is an auditory-pigmentary disease characterized by a clinical and genetic variability. WS is classified into four types depending on the presence or absence of additional symptoms: WS1, WS2, WS3 and WS4. Type 1 and 3 are mostly caused by PAX3 mutations, while type 2 and type 4 are genetically heterogeneous. The aims of this study are to confirm the diagnostic of WS1 by the sequencing of PAX3 gene and to evaluate the genotype phenotype correlation. A clinical classification was established for 14 patients WS, as proposed by the Waardenburg Consortium, and noted a predominance of type 1 and type 2 with 6 patients WS1, 7 patients WS2 and 1 patient WS3. A significant inter and intra-familial clinical heterogeneity was also observed. A sequencing of PAX3 gene in the 6 patients WS1 confirmed the diagnosis in 4 of them by revealing three novel mutations that modify two functional domains of the protein: the c.942delC; the c.933_936dupTTAC and the c.164delTCCGCCACA. These three variations are most likely responsible for the phenotype, however their pathogenic effects need to be confirmed by functional studies. The MLPA analysis of the 2 patients who were sequence negative for PAX3 gene revealed, in one of them, a heterozygous deletion of exons 5 to 9 confirming the WS1 diagnosis. Both clinical and molecular approaches led to the conclusion that there is a lack of genotype-phenotype correlation in WS1, an element that must be taken into account in genetic counseling. The absence of PAX3 mutation in one patient WS1 highlights the fact that the clinical classification is sometimes insufficient to distinguish WS1 from other types WS hence the interest of sequencing the other WS genes in this patient. Copyright © 2017 Elsevier B.V. All rights reserved.

Imaging the Laguna del Maule Volcanic Field, central Chile using magnetotellurics: Evidence for crustal melt regions laterally-offset from surface vents and lava flows

NASA Astrophysics Data System (ADS)

Cordell, Darcy; Unsworth, Martyn J.; Díaz, Daniel

2018-04-01

Magnetotelluric (MT) data were collected at the Laguna del Maule volcanic field (LdMVF), located in central Chile (36°S, 70.5°W), which has been experiencing unprecedented upward ground deformation since 2007. These data were used to create the first detailed three-dimensional electrical resistivity model of the LdMVF and surrounding area. The resulting model was spatially complex with several major conductive features imaged at different depths and locations around Laguna del Maule (LdM). A near-surface conductor (C1; 0.5 Ωm) approximately 100 m beneath the lake is interpreted as a conductive smectite clay cap related to a shallow hydrothermal reservoir. At 4 km depth, a strong conductor (C3; 0.3 Ωm) is located beneath the western edge of LdM. The proximity of C3 to the recent Pleistocene-to-Holocene vents in the northwest LdMVF and nearby hot springs suggests that C3 is a hydrous (>5 wt% H2O), rhyolitic partial melt with melt fraction >35% and a free-water hydrothermal component. C3 dips towards, and is connected to, a deeper conductor (C4; 1 Ωm). C4 is located to the north of LdM at >8 km depth below surface and is interpreted as a long-lived, rhyolitic-to-andesitic magma reservoir with melt fractions less than 35%. It is hypothesized that the deeper magma reservoir (C4) is providing melt and hydrothermal fluids to the shallower magma reservoir (C3). A large conductor directly beneath the LdMVF is not imaged with MT suggesting that any mush volume beneath LdM must be anhydrous (<2 wt% H2O), low temperature and low melt fraction (<25%) in order to go undetected. The presence of large conductors to the north has important implications for magma dynamics as it suggests that material may have a significant lateral component (>10 km) as it moves from the deep magma reservoir (C4) to create small, ephemeral volumes of eruptible melt (C3). It is hypothesized that there may be a north-south contrast in physical processes affecting the growth of melt-rich zones since major conductors are imaged in the northern LdMVF while no major conductors are detected beneath the southern vents. The analysis and interpretation of features directly beneath the lake is complicated by the surface conductor C1 which attenuates low-frequency signals. The attenuation from C1 does not affect C3 or C4. At 1 km depth directly beneath LdM, a weak conductor (C2; <10 Ωm) is imaged but is not required by the data. Forward modeling tests show that a relatively large (30 km3), high melt fraction (>50%), silicic reservoir with 5 wt% H2O at 2 to 5 km depth beneath the inflation center is not supported by the MT data. However, a smaller (10 km3) eruptible volume could go undetected even with relatively high melt fraction (>50%). The location of large melt regions to the north has important implications for long-term volcanic hazards at LdMVF as well as other volcanoes as it raises the possibility that the vent distribution is not always indicative of the location of deeper source regions of melt.

Detection of t(3;5) and NPM1/MLF1 rearrangement in an elderly patient with acute myeloid leukemia: clinical and laboratory study with review of the literature.

PubMed

Lim, Gayoung; Choi, Jong Rak; Kim, Min Jin; Kim, So Young; Lee, Hee Joo; Suh, Jin-Tae; Yoon, Hwi-Joong; Lee, Juhie; Lee, Sanggyu; Lee, Woo-In; Park, Tae Sung

2010-06-01

We present a novel case of acute myeloid leukemia with an NPM1/MLF1 rearrangement in a 78-year-old Korean woman. The bone marrow chromosome study showed a complex karyotype: 46,XX,t(2;13) (q13;q32),der(3)t(3;5)(q25.1;q34),der(5)del(5)(?q31q34)t(3;5),inv(9)(p11q13)c,del(20)(q11.2)[13]/49,idem,+5,+8,+der(13)t(2;13)[7]. Multiplex gene rearrangement testing, cloning, and sequencing analyses revealed an NPM1/MLF1 fusion rearrangement between exon 6 of NPM1 (ENSG00000181163) and exon 2 of MLF1 (ENSG00000178053). Although t(3;5)(q25.1;q34) or the NPM1/MLF1 rearrangement has been reported mostly as a sole karyotypic abnormality in younger patients, it should also be considered in elderly patients with complex chromosomal abnormalities in acute myeloid leukemia or myelodysplastic syndrome. Copyright 2010 Elsevier Inc. All rights reserved.

Molecular genetics analysis of hereditary breast and ovarian cancer patients in India

PubMed Central

Soumittra, Nagasamy; Meenakumari, Balaiah; Parija, Tithi; Sridevi, Veluswami; Nancy, Karunakaran N; Swaminathan, Rajaraman; Rajalekshmy, Kamalalayam R; Majhi, Urmila; Rajkumar, Thangarajan

2009-01-01

Background Hereditary cancers account for 5–10% of cancers. In this study BRCA1, BRCA2 and CHEK2*(1100delC) were analyzed for mutations in 91 HBOC/HBC/HOC families and early onset breast and early onset ovarian cancer cases. Methods PCR-DHPLC was used for mutation screening followed by DNA sequencing for identification and confirmation of mutations. Kaplan-Meier survival probabilities were computed for five-year survival data on Breast and Ovarian cancer cases separately, and differences were tested using the Log-rank test. Results Fifteen (16%) pathogenic mutations (12 in BRCA1 and 3 in BRCA2), of which six were novel BRCA1 mutations were identified. None of the cases showed CHEK2*1100delC mutation. Many reported polymorphisms in the exonic and intronic regions of BRCA1 and BRCA2 were also seen. The mutation status and the polymorphisms were analyzed for association with the clinico-pathological features like age, stage, grade, histology, disease status, survival (overall and disease free) and with prognostic molecular markers (ER, PR, c-erbB2 and p53). Conclusion The stage of the disease at diagnosis was the only statistically significant (p < 0.0035) prognostic parameter. The mutation frequency and the polymorphisms were similar to reports on other ethnic populations. The lack of association between the clinico-pathological variables, mutation status and the disease status is likely to be due to the small numbers. PMID:19656415

Verification Test of Jet Industries Electra-Van 1000P,

DTIC Science & Technology

1980-10-01

Assistant Secretary for Conservation and Solar Ene ion of Electric Unclassified and Hybrid Vehicles 15 I Ia. DEL S FCATIOt OWNGRADING 16. DISTRIBUTION...Propulsion Batteries Charger 24. AUSTRACT (C m ern.. Fev neeey aid Idenify by block nmtbe) - The Je 4nfduis&ieElectra-Van IOOOP is a Chrysler Corp. pickup...Electric EV -1 SCR Controller (Figure 5). The propulsion motor is a General Electric d.c. motor, 37-hp, series-wound, rated at 2039 r/min. The 1000P has a

CHEK2*1100DELC Variant and Breast Cancer Risk

DTIC Science & Technology

2006-10-01

AD_________________ Award Number: DAMD17-03-1-0774 TITLE: CHEK2 *1100DELC Variant and Breast...01-10-2006 2. REPORT TYPE Final 3. DATES COVERED (From - To) 15 Sep 03 – 14 Sep 06 4. TITLE AND SUBTITLE CHEK2 *1100DELC...SUPPLEMENTARY NOTES 14. ABSTRACT: We propose to examine the association between the CHEK2 *1100delC gene variant and breast cancer among BRCA1/2

A Little CFTR Goes a Long Way: CFTR-Dependent Sweat Secretion from G551D and R117H-5T Cystic Fibrosis Subjects Taking Ivacaftor

PubMed Central

Char, Jessica E.; Wolfe, Marlene H.; Cho, Hyung-ju; Park, Il-Ho; Jeong, Jin Hyeok; Frisbee, Eric; Dunn, Colleen; Davies, Zoe; Milla, Carlos; Moss, Richard B.; Thomas, Ewart A. C.; Wine, Jeffrey J.

2014-01-01

To determine if oral dosing with the CFTR-potentiator ivacaftor (VX-770, Kalydeco) improves CFTR-dependent sweating in CF subjects carrying G551D or R117H-5T mutations, we optically measured sweat secretion from 32–143 individually identified glands in each of 8 CF subjects; 6 F508del/G551D, one G551D/R117H-5T, and one I507del/R117H-5T. Two subjects were tested only (−) ivacaftor, 3 only (+) ivacaftor and 3 (+/−) ivacaftor (1–5 tests per condition). The total number of gland measurements was 852 (−) ivacaftor and 906 (+) ivacaftor. A healthy control was tested 4 times (51 glands). For each gland we measured both CFTR-independent (M-sweat) and CFTR-dependent (C-sweat); C-sweat was stimulated with a β-adrenergic cocktail that elevated [cAMP]i while blocking muscarinic receptors. Absent ivacaftor, almost all CF glands produced M-sweat on all tests, but only 1/593 glands produced C-sweat (10 tests, 5 subjects). By contrast, 6/6 subjects (113/342 glands) produced C-sweat in the (+) ivacaftor condition, but with large inter-subject differences; 3–74% of glands responded with C/M sweat ratios 0.04%–2.57% of the average WT ratio of 0.265. Sweat volume losses cause proportionally larger underestimates of CFTR function at lower sweat rates. The losses were reduced by measuring C/M ratios in 12 glands from each subject that had the highest M-sweat rates. Remaining losses were estimated from single channel data and used to correct the C/M ratios, giving estimates of CFTR function (+) ivacaftor  = 1.6%–7.7% of the WT average. These estimates are in accord with single channel data and transcript analysis, and suggest that significant clinical benefit can be produced by low levels of CFTR function. PMID:24520399

Novel GNE mutations in Italian families with autosomal recessive hereditary inclusion-body myopathy.

PubMed

Broccolini, Aldobrando; Ricci, Enzo; Cassandrini, Denise; Gliubizzi, Carla; Bruno, Claudio; Tonoli, Emmanuel; Silvestri, Gabriella; Pescatori, Mario; Rodolico, Carmelo; Sinicropi, Stefano; Servidei, Serenella; Zara, Federico; Minetti, Carlo; Tonali, Pietro A; Mirabella, Massimiliano

2004-06-01

The most common form of autosomal recessive (AR) hereditary inclusion-body myopathy (HIBM), originally described in Persian-Jewish families, is characterized by onset in early adult life with weakness and atrophy of distal lower limb muscles, which progress proximally and relatively spare the quadriceps. AR HIBM is associated with mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene (GNE) on chromosome 9p12-13. In the present study we have identified seven novel GNE mutations in patients from five unrelated Italian families with clinical and pathologic features indicative of AR HIBM. Four were missense mutations (c.1556A>G [p.N519S], c.79C>T [p.P27S], c.1798G>A [p.A600T] and c.616G>A [p.G206S]), two consisted in a single-base deletion (c.616delG [p.G206fsX4] and c.1130delT [p.I377fsX16]) and one in an intronic single-base insertion (c.1070+2dupT). These latter findings further extend the type of GNE mutations associated with HIBM. Furthermore, in one patient we also identified the c.737G>A [p.R246Q] missense mutation that corresponds to the one previously reported in a family from the Bahamas. Interestingly, in two of our families distinct mutations affected nucleotide c.616 in exon 3 (c.616delG and c.616G>A). The possibility of specific portions of the gene being more prone to mutations remains to be elucidated. Copyright 2004 Wiley-Liss, Inc.

Prevalence of 2314delG mutation in Spanish patients with Usher syndrome type II (USH2).

PubMed

Beneyto, M M; Cuevas, J M; Millán, J M; Espinós, C; Mateu, E; González-Cabo, P; Baiget, M; Doménech, M; Bernal, S; Ayuso, C; García-Sandoval, B; Trujillo, M J; Borrego, S; Antiñolo, G; Carballo, M; Nájera, C

2000-06-01

The Usher syndrome (USH) is a group of autosomal recessive diseases characterized by congenital sensorineural hearing loss and retinitis pigmentosa. Three clinically distinct forms of Usher syndrome have so far been recognized and can be distinguished from one another by assessing auditory and vestibular function. Usher syndrome type II (USH2) patients have congenital moderate-to-severe nonprogressive hearing loss, retinitis pigmentosa, and normal vestibular function. Genetic linkage studies have revealed genetic heterogeneity among the three types of USH, with the majority of USH2 families showing linkage to the USH2A locus in 1q41. The USH2A gene (MIM 276901) has been identified: three mutations, 2314delG, 2913delG, and 4353-54delC, were initially reported in USH2A patients, the most frequent of which is the 2314delG mutation. It has been reported that this mutation can give rise to typical and atypical USH2 phenotypes. USH2 cases represent 62% of all USH cases in the Spanish population, and 95% of these cases have provided evidence of linkage to the USH2A locus. In the present study, the three reported mutations were analyzed in 59 Spanish families with a diagnosis of USH type II. The 2314delG was the only mutation identified in our population: it was detected in 25% of families and 16% of USH2 chromosomes analyzed. This study attempts to estimate the prevalence of this common mutation in a homogeneous Spanish population.

Abundancias químicas de las estrellas CP del grupo HgMn μ Leporis y 53 Tauri. II. Boro, Berilio, Carbono, Magnesio, Aluminio y Silicio

NASA Astrophysics Data System (ADS)

López García, Z.; Malaroda, S. M.; Faraggiana, R.

Se determinan las abundancias químicas de los elementos más livianos presentes en dos estrellas CP del grupo HgMn, μ Lep y 53 Tau, utilizando espectros IUE de alta resolución y técnicas de cálculo de espectros sintéticos. Para el cálculo de las líneas se utiliza la lista mas completa de datos atómicos disponible y el programa SYNTHE. Para el cálculo de la abundancia de un elemento se comparan, para cada imagen, los perfiles observados del mayor número de líneas presentes con los perfiles calculados obtenidos por variación de las abundancias iniciales, reteniendo la abundancia para la cual el acuerdo entre las líneas observadas y calculadas es considerado visualmente el mejor. Los resultados obtenidos son comparados con los estimados por la teoría de la difusión.

Astronomía Gamma desde El Leoncito

NASA Astrophysics Data System (ADS)

Rovero, A. C.; Colombo, E.; Sahade, J.; Weekes, T. C.

La astronomía gamma, en el extremo de energías detectadas hasta el presente, se encuentra en desarrollo en muchas partes del mundo y proporciona resultados sorprendentes a medida que la tecnología avanza en el desarrollo de nuevos detectores. La técnica Cherenkov Atmosférica es la utilizada para la detección, mediante telescopios en tierra, del efecto secundario causado por la radiación gamma de muy altas energías (E ≈ TeV). Por medio de telescopios o arreglos de detectores y utilizando la técnica mencionada, se han podido detectar algunas fuentes puntuales de mucha importancia astrofísica como la Nebulosa del Cangrejo y la galaxia de núcleo activo Markarian 421. El sistema instalado en San Juan, en cooperación con el grupo de Radiación Gamma del Observatorio Whipple, está constituído por tres colectores de 1.5m que registran pulsos de luz generados por las cascadas de partículas producidas por rayos cósmicos de todo tipo al entrar en la atmósfera terrestre. El sistema opera por barrido en ascención recta de la fuente observada que, para esta etapa del experimento, es el Centro Galáctico. Esta fuente extensa es conocida como emisor gamma de energías inferiores al TeV y ha sido observada anteriormente en este rango de energía desde el hemisferio norte pero con elevaciones bajas, situación no óptima para este tipo de técnica. Se presentan los primeros resultados del análisis de los datos obtenidos observando la región del Centro Galáctico, luego de dos años de observaciones, así como una descripción de la técnica Cherenkov Atmosférica y del equipo utilizado en la experiencia.

[Detection and prenatal diagnosis for RS1 gene mutations in two Chinese families with X-linked juvenile retinoschisis].

PubMed

Chu, Yan; Fang, Dong; Hou, Qiao-fang; Wang, Li-ya; Guo, Xi-rang; Wang, Ying-tai; Liao, Shi-xiu

2013-04-01

To identify potential mutations of retinoschisis 1 (RS1) gene responsible for X-linked retinoschisis (XLRS) in two Chinese families. The 6 exons and flanking intronic regions were analyzed with PCR and direct sequencing. Two RS1 mutations were identified in the two families, which included 1 frameshift mutation (c.573delG, p.Pro192fs) and 1 missense mutation (c.626G>A, p.Arg209His). Two RS1 mutations have been identified, among which Pro192fs mutation is discovered for the first time in Chinese population. Above results may enrich our understanding of the clinical manifestations of XLRS and facilitated early diagnosis and genetic counseling for the disease.

Low-Mass Dark Matter Search with the DarkSide-50 Experiment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Agnes, P.; et al.

We present the results of a search for dark matter WIMPs in the mass range below 20 GeV/c^2 using a target of low-radioactivity argon. The data were obtained using the DarkSide-50 apparatus at Laboratori Nazionali del Gran Sasso (LNGS). The analysis is based on the ionization signal, for which the DarkSide-50 time projection chamber is fully efficient at 0.1 keVee. The observed rate in the detector at 0.5 keVee is about 1.5 events/keVee/kg/day and is almost entirely accounted for by known background sources. We obtain a 90% C.L. exclusion limit above 1.8 GeV/c^2 for the spin-independent cross section of darkmore » matter WIMPs on nucleons, extending the exclusion region for dark matter below previous limits in the range 1.8-6 GeV/c^2.« less

Associations between NRAMP1 Polymorphisms and Susceptibility to Ulcerative Colitis/Crohn's Disease: A Meta-Analysis.

PubMed

Sun, Manyi; Zhang, Li; Shi, Songli

2016-01-01

Multiple environmental and genetic factors contribute to the risks of ulcerative colitis (UC) and Crohn's disease (CD). Several allelic variants have been identified in natural resistance associated macrophage protein 1 (NRAMP1) gene; however, their association with UC/CD remains conflicting. The purpose of this study was to evaluate whether NRAMP1 polymorphisms are associated with the susceptibility to UC/CD. A meta-analysis on the association between the NRAMP1 polymorphisms and susceptibility to UC/CD was performed. Relevant studies were retrieved from the databases. After eligible data were extracted, Mantel-Haenszel statistics and random/fixed effects model were applied to calculate the pooled odds radio (OR) and 95% confidence interval (95% CI). Seven articles containing 536 UC cases, 997 CD cases, and 1361 controls were collected. No significant association between allele 2 frequency of NRAMP1 and susceptibility to UC/CD was detected in overall population (all p > 0.05). However, increased UC/CD risk for allele 3 was observed in Caucasian population (OR = 1.27, 95% CI = 1.08~1.50, p = 0.04), whereas decreased UC/CD risk was detected in non-Caucasian population (OR = 0.72, 95% CI = 0.60~0.87, p < 0.001), under "allele 3 vs. other alleles" model. Moreover, a significant increase in CD risk for T carrier frequency of -237 C/T (OR = 0.44, 95% CI, 0.26~0.75, p = 0.003) was detected, but not 274 C/T and 1729+55del4 (TGTG) +/del. The polymorphism of -237 C/T is related to the risk of CD; and the association of allele 3 with UC/CD risk differs in Caucasian and non-Caucasian population, which might be the potential biomarkers for clinical diagnosis of UC/CD.

Military Standard Generators Prototype Modifications. Volume 3. 60 kW DoD Generator Set

DTIC Science & Technology

1988-03-31

14 JAN ., 17 :35: ’w. 6843 GEN S DS-00 273 . .. •- -,- - 32. 351 3 DE,-.. F Z EX ,-UST 2 895. 93 DEL;. F C REL!:7T 3 988.34 DEC-. F C 4 EXH-4AUST 4...33. 351 DEG. F C 20 GEN. FRAME TOP 11. 64 DEG. F C 2:1 GEN. FRAME BTTM 82. 15± DEG. F C 21 GEN. FRAME BTTM 113. i6 DEG. F C 2,. GEN. EXCITER 32. 992...DEG. F C 21 GEli . FRAME BTTM ±88.15 DEG. F S2 -EN. EXCITER 12. 49 DEG. F C 22 S-EN. EXCITER 185. 5 DEG. F 27 G2N. ’OLT. REG. 95. 459 DEG. F C 23 GEN

Novel mutations in MYO7A and USH2A in Usher syndrome.

PubMed

Maubaret, Cécilia; Griffoin, Jean-Michel; Arnaud, Bernard; Hamel, Christian

2005-03-01

Usher syndrome is an autosomal recessive disease associating retinitis pigmentosa and neurosensory deafness. Three clinical types (USH1, USH2, USH3) and 11 mutated genes or loci have been described. Mutations in MYO7A and USH2A are responsible for about 40% and 60% of Usher syndromes type 1 and 2, respectively. These genes were screened in a series of patients suffering from Usher syndrome. We performed SSCP screening of MYO7A in 12 unrelated patients suffering from Usher syndrome type 1 (USH1) and USH2A in 28 unrelated patients affected by Usher syndrome type 2 (USH2). Six mutations in MYO7A were found in five patients, including two novel mutations c.397C > G (His133Asp) and 1244-2A > G (Glu459Stop), accounting for 42% of our USH1 patients. Twelve mutations in USH2A were found in 11 patients, including four new mutations c.850delGA, c.1841-2A > G, c.3129insT, and c.3920C > G (Ser1307Stop), accounting for 39% of our USH2 patients

Microwave Observations and Modeling of O2 (1-delta(sub g)) and O3 Diurnal Variation in the Mesosphere

NASA Technical Reports Server (NTRS)

Sandor, Brad J.; Clancy, R. Todd; Rusch, David W.; Randall, Cora E.; Eckman, Richard S.; Siskind, David S.; Muhleman, Duane O.

1997-01-01

The first microwave measurements of an electronically excited molecular species in the Earth's atmosphere are presented. Local thermodynamic equilibrium (LTE) rotational line emission from mesospheric O2(1-del(sub g)) was observed at a frequency of 255.01794 GHz (lambda is approx. 1.2 mm), employing the National Radio Astronomy Observatory (NRAO) millimeter facility at Kitt Peak, Arizona (32 N, 111 W). The pressure broadened line shapes of the O2(1-del(sub g)) spectra, which were obtained in January and April 1992 and in January and November 1993, are inverted to retrieve O2(1-del(sub g)) mixing profiles over the 50-70 km altitude region. The observed daytime abundances exceed ozone abundances in the lower mesosphere, which are separately retrieved with coincident O3 spectral line (249.7886 GHz) observations. The January and November 1993 observations are binned into 20-60 min time intervals to study O2(1-del(sub g)) diurnal behavior. Derived abundances of O2(1-del(sub g)) between 50 and 70 km for the four observation dates are 9%, 31%, 3%, and 26%, respectively, each +/- 10% higher than predicted, based on the simple photochemistry of lower mesospheric O2(1-del(sub g)). Modeled variation of [O2(1-del(sub g))] with time of day agrees with observed variation in that the observed difference between model and data abundances is constant throughout the daylight hours of each observation date. Model underprediction Of [02(lAg)] is consistent with similar model underprediction of mesospheric [O3]. A perturbation to the photochemical model that forces decreased ozone chemical loss brings brings both model [O3] and [O2(1-del(sub g))] into agreement with the observations. O2(1-del(sub g)) abundances derived from these 1.2 mm observations agree with [O2(1-del(sub g))] values derived from comparable SME observations of the 1.27 micrometers emission, with assumption of a 3880 sec O2(1-del(sub g)) radiative lifetime. The 6800 sec O2(1-del(sub g)) radiative lifetime proposed by Mlynczak and Nesbitt is ruled out by the similar comparison.

An USH2A founder mutation is the major cause of Usher syndrome type 2 in Canadians of French origin and confirms common roots of Quebecois and Acadians

PubMed Central

Ebermann, Inga; Koenekoop, Robert K; Lopez, Irma; Bou-Khzam, Lara; Pigeon, Renée; Bolz, Hanno J

2009-01-01

Congenital hearing loss affects approximately one child in 1000. About 10% of the deaf population have Usher syndrome (USH). In USH, hearing loss is complicated by retinal degeneration with onset in the first (USH1) or second (USH2) decade. In most populations, diagnostic testing is hampered by a multitude of mutations in nine genes. We have recently shown that in French Canadians from Quebec, USH1 largely results from a single USH1C founder mutation, c.216G>A (‘Acadian allele'). The genetic basis of USH2 in Canadians of French descent, however, has remained elusive. Here, we have investigated nine USH2 families from Quebec and New Brunswick (the former Acadia) by haplotype analyses of the USH2A locus and sequencing of the three known USH2 genes. Seven USH2A mutations were identified in eight patients. One of them, c.4338_4339delCT, accounts for 10 out of 18 disease alleles (55.6%). This mutation has previously been reported in an Acadian USH2 family, and it was found in homozygous state in the three Acadians of our sample. As in the case of c.216G>A (USH1C), a common haplotype is associated with c.4338_4339delCT. With a limited number of molecular tests, it will now be possible in these populations to estimate whether children with congenital hearing impairment of different degrees will develop retinal disease – with important clinical and therapeutic implications. USH2 is the second example that reveals a significant genetic overlap between Quebecois and Acadians: in contrast to current understanding, other genetic disorders present in both populations are likely based on common founder mutations as well. PMID:18665195

Two siblings with congenital central hypothyroidism caused by a novel mutation in the IGSF1 gene.

PubMed

Oguma, Makiko; Kobayashi, Mizuki; Yamazaki, Masayo; Yokoyama, Koji; Morikawa, Shuntaro; Yamaguchi, Takeshi; Yamagata, Takanori; Tajima, Toshihiro

2018-01-01

Genetic defects in the immunoglobulin superfamily member 1(IGSF1) protein are the cause of congenital central hypothyroidism (C-CH). Here we report two Japanese siblings with C-CH due to a novel IGSF1 mutation. The youngest brother showed a failure to thrive, hypothermia, and neonatal icterus six days after birth. Further endocrine evaluations led to the diagnosis of C-CH. In addition, PRL deficiency was later detected. In contrast, the elder brother did not show symptoms of severe hypothyroidism during the neonatal period, but he had been followed up by doctors due to psychomotor developmental delays since the age of 1 yr. At the age of 3 yr, he had low thyroxine and PRL levels and was also diagnosed with C-CH. Because of the C-CH and PRL deficiency, an IGSF1 deficiency was suspected. Sequence analysis of the IGSF1 gene identified a novel hemizygous mutation of p.Trp1173GlyfsTer8 (NM_001170961.1:c.3517del) in both siblings. In conclusion, the phenotypic severity of C-CH is different, even in siblings. Importantly, an IGSF1 deficiency may result in severe hypothyroidism during the neonatal period.

77 FR 54948 - Unblocking of Specially Designated Nationals and Blocked Persons Pursuant to Executive Order 12978

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-06

...., Bogota, Colombia; c/ o INVERSIONES AGROINDUSTRIALES DEL OCCIDENTE LTDA., Bogota, Colombia; c/o CANADUZ S... COLOMBO-ANDINAS LTDA., Bogota, Colombia; c/o INVERSIONES Y CONSTRUCCIONES ABC S.A., Cali, Colombia; c/ o...

Development of High Angle of Attack Control Laws for an Unstable, Non- Minimum Phase Aircraft Using Variations of the Quantitative Feedback Technique

DTIC Science & Technology

1991-12-01

1del dif can LLL!Li XS :4 Figure H.4. Pff ( 1 ,I) Final Compensation Block Diagram (a 60) 1 - 1 -2 A, :Craf- -2^ Gain Coal AL-tuator 1 dif fl.9 7.3 Ui Gain...i1ll1lJll, ll,IIIIJ9litl IIJJII t1 1 2 24 0 7 2 Form Approved REPORT DOCUMENTATION PAGE 0MB No 0704-0188 puoitc rwomrnq curden or t..t ciie-icr :it...ferson oavn H g.ai. suite 12C4 ... rngton. , . zj202-1302, ind to t’e Q)tf.,e )t Maraentet a dgt P werivork Redcon Poje 1 k704O’ 88). hshrgton .C 20503 1

ELANE mutant-specific activation of different UPR pathways in congenital neutropenia.

PubMed

Nustede, Rainer; Klimiankou, Maksim; Klimenkova, Olga; Kuznetsova, Inna; Zeidler, Cornelia; Welte, Karl; Skokowa, Julia

2016-01-01

A number of studies have demonstrated induction of the unfolded protein response (UPR) in patients with severe congenital neutropenia (CN) harbouring mutations of ELANE, encoding neutrophil elastase. Why UPR is not activated in patients with cyclic neutropenia (CyN) carrying the same ELANE mutations is unclear. We evaluated the effects of ELANE mutants on UPR induction in myeloid cells from CN and CyN patients, and analysed whether additional CN-specific defects contribute to the differences in UPR induction between CN and CyN patients harbouring identical ELANE mutations. We investigated CN-specific p.C71R and p.V174_C181del (NP_001963.1) and CN/CyN-shared p.S126L (NP_001963.1) ELANE mutants. We found that transduction of haematopoietic cells with p.C71R, but not with p.V174_C181del or p.S126L ELANE mutants induced expression of ATF6, and the ATF6 target genes PPP1R15A, DDIT3 and HSPA5. Recently, we found that levels of secretory leucocyte protease inhibitor (SLPI), a natural ELANE inhibitor, are diminished in myeloid cells from CN patients, but not CyN patients. Combined knockdown of SLPI by shRNA and transduction of ELANE p.S126L in myeloid cells led to elevated levels of ATF6, PPP1R15A and HSPA5 RNA, suggesting that normal levels of SLPI in CyN patients might protect them from the UPR induced by mutant ELANE. In summary, different ELANE mutants have different effects on UPR activation, and SLPI regulates the extent of ELANE-triggered UPR. © 2015 John Wiley & Sons Ltd.

High Incidence of ACE/PAI-1 in Association to a Spectrum of Other Polymorphic Cardiovascular Genes Involving PBMCs Proinflammatory Cytokines in Hypertensive Hypercholesterolemic Patients: Reversibility with a Combination of ACE Inhibitor and Statin

PubMed Central

Mouawad, Charbel; Haddad, Katia; Hamoui, Samar; Azar, Albert; Fajloun, Ziad; Makdissy, Nehman

2015-01-01

Cardiovascular diseases (CVDs) are significantly high in the Lebanese population with the two most predominant forms being atherosclerosis and venous thrombosis. The purpose of our study was to assess the association of a spectrum of CVD related genes and combined state of hypertension hypercholesterolemia (HH) in unrelated Lebanese. Twelve polymorphisms were studied by multiplex PCR and reverse hybridization of DNA from 171 healthy individuals and 144 HH subjects. Two genes were significantly associated with HH: ACE (OR: 9.20, P<0.0001) and PAI-1 (OR: 2.29, P = 0.007), respectively with the occurrence of the risky alleles “Del” and “4G”. The frequencies of the Del and 4G alleles were found to be 0.98 and 0.90 in the HH group versus 0.84 and 0.79 in the healthy group, respectively. Serum ACE activity and PAI-I increased significantly with Del/Del and 4G/5G genotypes. The co-expression of Del/4G(+/+) was detected in 113 out of 171 (66.0%) controls and 125 out of 144 (86.8%) HH subjects. Del/4G(-/-) was detected in only 6 (3.5%) controls and undetected in the HH group. Three venous thrombosis related genes [FV(Leiden), MTHFR(A1298C) and FXIII(V34L)] were significantly related to the prominence of the co-expression of Del/4G(+/+). A range of 2 to 8 combined polymorphisms co-expressed per subject where 5 mutations were the most detected. In Del/4G(+/+) subjects, peripheral blood mononuclear cells (PBMCs) produced significant elevated levels of IFN-γ and TNF-α contrary to IL-10, and no variations occurred for IL-4. ACE inhibitor (ramipril) in combination with statin (atorvastatin) and not alone reversed significantly the situation. This first report from Lebanon sheds light on an additional genetic predisposition of a complex spectrum of genes involved in CVD and suggests that the most requested gene FVL by physicians may not be sufficient to diagnose eventual future problems that can occur in the cardiovascular system. Subjects expressing the double mutations (Del/4G) are at high risk for the onset of CVDs. PMID:25973747

Molecular Analysis of DMP1 Mutants Causing Autosomal Recessive Hypophosphatemic Rickets

PubMed Central

Farrow, Emily G.; Davis, Siobhan I.; Ward, Leanne M.; Summers, Lelia J.; Bubbear, Judith S.; Keen, Richard; Stamp, Trevor C.B.; Baker, Laurence R. I.; Bonewald, Lynda F.; White, Kenneth E.

2009-01-01

We previously demonstrated that the mutations Met1Val (M1V) and the deletion of nucleotides 1484-1490 (1484-1490del) in Dentin matrix protein-1 (DMP1) cause the novel disorder autosomal recessive hypophosphatemic rickets (ARHR), which is associated with elevated Fibroblast growth factor-23 (FGF23). To further understand the role of DMP1 in ARHR, we undertook molecular genetic and in vitro expression studies. First, we examined a kindred with a severe hypophosphatemic rickets phenotype and recessive inheritance. Analyses of this family demonstrated that the affected members had elevated serum FGF23 and carried a large, biallelic deletion that removed the majority of DMP1. At a minimum, this deletion encompassed 49 kb between DMP1 exon 3 and an intergenic region 5′ to the next telomeric gene, integrin-binding sialoprotein (IBSP). We next performed immunofluorescent studies in cells to understand the effects of the known ARHR mutations on DMP1 cellular processing. These analyses showed that the M1V DMP1 mutant was not sorted to the trans-Golgi network (TGN) and secretory pathway, but filled the entire cytoplasm. In contrast, the 1484-1490del mutant localized to the TGN and was secreted, similar to wild type DMP1. The 1484-1490del mutation replaces the DMP1 18 C-terminal amino acids with 33 non-native residues. Truncation of wild type DMP1 by these native 18 residues followed by Western blot and confocal microscopic analyses demonstrated a wild type expression pattern when compared with the 1484-1490del mutant, indicating that the last 18 residues are not critical for cellular trafficking, but that the 33 additional residues arising from the 1484-1490del mutation likely compromise DMP1 processing. The relationship between DMP1 and FGF23 is unclear. To test endogenous DMP1 response to serum metabolites that also regulate FGF23, UMR-106 cells were treated with 1,25(OH)2 vitamin D (1×10−7M) and showed a 12-fold increase in DMP1 mRNA and protein at 24 hr. In summary, we have identified a novel DMP1 deletion as the cause of ARHR, as well as demonstrated that the ARHR mutations alter DMP1 cellular processing, and that DMP1 can be regulated by vitamin D. Taken together, this work expands our understanding of the genetic and molecular mechanisms associated with DMP1 alterations causing ARHR. PMID:19007919

A protocol for storage and long-distance shipment of Mediterranean fruit fly (Diptera: Tephritidae) eggs. 1. Effect of temperature, embryo age , and storage time on survival and quality

DOE Office of Scientific and Technical Information (OSTI.GOV)

Caceres, C.; Wornoayporn, V.; Islam, S.M.

The operational use of Mediterranean fruit fly (medfly) Ceratitis capitata (Wiedemann), genetic sexing strains in Sterile Insect Technique applications can be maximized by developing methods for effective shipment of eggs. This would enable a central production facility to maintain the relevant mother stocks and large colonies to supply eggs to satellite centers that would mass produce only males for irradiation and release. In order to achieve this, the survival of medfly embryos of different ages was assessed after storage at 5, 10, 15, 20, and 25 deg. C in water for different periods of time. Survival was affected by allmore » 3 variables, i.e., embryo age, water temperature, and length of storage. Storage of embryos at any temperature for 120 h resulted in almost no survival. Controlling the age of the embryo at the time of the temperature treatment is crucial for the success of this procedure. Embryos collected between 0 to 12 h after oviposition and pre-incubated at 25 deg. C for 12 h provide a suitable 72 h window for shipment when maintained between 10 to 15 deg. C. Under these conditions, no significant reductions in survival during all the developmental stages were observed. (author) [Spanish] El uso operacional de cepas de la mosca del mediterraneo Ceratitis capitata (Wiedemann) en las cuales es posible separar los sexos a traves de mecanismos geneticos para su utilizacion en la Tecnica del Insecto Esteril (TIE), puede ser maximizado con el desarrollo de metodos efectivos para el envio y transporte de huevos. Esto permite que un laboratorio de produccion centralizada mantenga las respectivas colonias responsables por la produccion de huevos para este abastecer laboratorios satelites responsables por la produccion masiva de solamente machos para subsiguiente irradiacion y liberacion. Para ser posible esta alternativa fue evaluada la supervivencia de embriones de diferentes edades despues de su almacenamiento en agua a 5, 10, 15, 20 y 25 deg. C por diferentes periodos de tiempo. La supervivencia fue afectada por las 3 variables evaluadas, la edad del embrion, la temperatura del agua y el periodo de almacenamiento. El almacenamiento de los embriones a cualquier temperatura por 120 horas dio como resultado la casi no supervivencia. Una edad controlada de los embriones a tratar es crucial para el exito de este protocolo. Embriones colectados entre 0 a 12 horas despues de la oviposicion y su previa incubacion a 25 deg. C por 12 horas brinda un margen de hasta de 72 horas de duracion del almacenamiento y transporte, siempre y cuando estos se mantengan en una temperatura de entre 10 a 15{sup o}C. En estas condiciones, fue registrada una reduccion no significante de la supervivencia de los diferentes estados de desarrollo. (author)« less

An evening at "La Clinica del Pueblo".

PubMed

Shefsky, M L

1986-01-01

This article describes a typical evening at the Clinica del Pueblo in the Hispanic neighborhood of Adams-Morgan in Washington, D.c. The Clinical del Pueblo began operating in 1983 in response to the urgen medical needs of Central American refugees arriving in the Washington D.c. area. The refugees bring with them severe trauma, fear, and health problems caused by the civil was and exacerbated by inadequate or non-existant health services. Approximately 80,000 Salvadoran refugees live in the area. They do not receive adequate health care for 3 reasons. 1) Because the US goverment is unwilling to recognize them as true refugees, they live with the constant threat of deportatin back to the violence from which they have fled. 2) Refugees lack the ability to pay for private care. 3) Langauage and culture create frightening barriers to health care for the refugees. For those who do seek care, these barriers can lead to the inadequate or incomplete diagnoses and poor compliance and follow-up. Plenty International and the Central American Refugee Center responded to these problems by organizing a free clinic to provide not only medical care but also a training course for volunteers. The director of the clinic organizes the course, the classes are taught by a variety of people including the clinic's volunteer physicians, nurses, and public health educators as well as graduates of previus training courses and people from the wider community. The services of the clinic reach only a small portion of the population in need. However, the fact that free medical services are now available to some Central American refugees make the Clinica del Pueblo an important program.

Polygenic Profile and Exercise-Induced Muscle Damage by a Competitive Half-Ironman.

PubMed

Del Coso, Juan; Salinero, Juan J; Lara, Beatriz; Gallo-Salazar, César; Areces, Francisco; Herrero, David; Puente, Carlos

2017-11-14

Del Coso, J, Salinero, JJ, Lara, B, Gallo-Salazar, C, Areces, F, Herrero, D, and Puente, C. Polygenic profile and exercise-induced muscle damage by a competitive half-ironman. J Strength Cond Res XX(X): 000-000, 2017-To date, it is still unknown why some individuals develop higher levels of muscle damage than other individuals, despite participating in exercise with comparable levels of physical intensity. The aim of this investigation was to analyze 7 single-nucleotide polymorphisms (SNPs) that are candidates to explain individual variations in the level of muscle damage attained during a half-ironman competition. Using the model of Williams and Folland (2, 1, and 0 points for optimal, intermediate, and suboptimal genotype), we determined the total genotype score from the accumulated combination of 7 SNPs (ACE = 287bp Ins/Del; ACTN3 = p.R577X; creatine kinase, muscle type = NcoI; insulin-like growth factor 2 = C13790G; interleukin-6 = 174G>C; myosin light chain kinase = C37885A; and tumor necrosis factor-α = 308G>A) in 22 experienced triathletes. Before and after the race, a sample of venous blood was obtained to measure serum markers of muscle damage. Two groups of triathletes were established according to their postcompetition serum CK concentration: low CK responders (n = 10; 377 ± 86 U·L) vs. high CK responders (n = 12; 709 ± 136 U·L). At the end of the race, low CK responders had lower serum myoglobin concentrations (384 ± 243 vs. 597 ± 293 ng·ml, p = 0.04). Although the groups were similar in age, anthropometric characteristics, and training habits, total genotype score was higher in low CK responders than in high CK responders (7.7 ± 1.1 vs. 5.5 ± 1.1 point, p < 0.01). A favorable polygenic profile can contribute to reducing the level of muscle damage developed during endurance exercise.