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Sample records for hfe c282y homozygotes

  1. Serum hepcidin levels are innately low in HFE-related haemochromatosis but differ between C282Y-homozygotes with elevated and normal ferritin levels.

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    van Dijk, Boukje A C; Laarakkers, Coby M M; Klaver, Siem M; Jacobs, Esther M G; van Tits, Lambertus J H; Janssen, Mirian C H; Swinkels, Dorine W

    2008-09-01

    HFE C282Y-homozygosity has been associated with low hepcidin expression, leading to increased ferritin levels. However, serum hepcidin protein levels have not been documented in humans. In the current study, we compared serum hepcidin levels of newly diagnosed HFE C282Y-homozygotes with (N = 15) and without (N = 7) elevated serum ferritin levels to levels of 40 controls (20 heterozygotes and 20 wild types). In addition, hepcidin levels of four C282Y homozygotes were investigated during the course of all phlebotomy treatment phases. Serum hepcidin levels were lower in HFE C282Y-homozygotes (median; 25th-75th percentile: 1.88; 0.78-2.77 nmol/l) compared to controls (2.74; 1.45-5.39). Hepcidin/ferritin ratios were also lower in homozygotes. Homozygotes with an elevated serum ferritin had a higher serum hepcidin but a lower hepcidin/ferritin ratio than those with normal ferritin (2.28; 1.62-3.23 nmol/l hepcidin vs. 0.80; 0.60-1.29 and 3.63; 2.72-7.59 pmol hepcidin/microg ferritin vs. 13.2; 5.15-14.2). Serum hepcidin decreased during the depletion phase of phlebotomy and remained low during maintenance. This study showed that serum hepcidin is innately low in HFE-related haemochromatosis. Elevated ferritin levels were associated with increased hepcidin levels while erythropoiesis lead to lower hepcidin levels. During depletion, therefore, hepcidin levels are decreased, which may exacerbate intestinal iron absorption.

  2. GNPAT p.D519G is independently associated with markedly increased iron stores in HFE p.C282Y homozygotes.

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    Barton, James C; Chen, Wen-Pin; Emond, Mary J; Phatak, Pradyumna D; Subramaniam, V Nathan; Adams, Paul C; Gurrin, Lyle C; Anderson, Gregory J; Ramm, Grant A; Powell, Lawrie W; Allen, Katrina J; Phillips, John D; Parker, Charles J; McLaren, Gordon D; McLaren, Christine E

    2017-03-01

    GNPAT p.D519G positivity is significantly increased in HFE p.C282Y homozygotes with markedly increased iron stores. We sought to determine associations of p.D519G and iron-related variables with iron stores in p.C282Y homozygotes. We defined markedly increased iron stores as serum ferritin >2247pmol/L (>1000μg/L) and either hepatic iron >236μmol/g dry weight or iron >10g by induction phlebotomy (men and women). We defined normal or mildly elevated iron stores as serum ferritin stores with these variables: age; iron supplement use (dichotomous); whole blood units donated; erythrocyte units received as transfusion; daily alcohol consumption, g; and p.D519G positivity (heterozygosity or homozygosity). The mean age of 56 participants (94.6% men) was 55±10 (SD) y; 41 had markedly increased iron stores. Prevalences of swollen/tender 2nd/3rd metacarpophalangeal joints and elevated aspartate or alanine aminotransferase were significantly greater in participants with markedly increased iron stores. Only participants with markedly increased iron stores had cirrhosis. In multivariable analyses, p.D519G positivity was the only exposure variable significantly associated with markedly increased iron stores (odds ratio 9.9, 95% CI [1.6, 60.3], p=0.0126). GNPAT p.D519G is strongly associated with markedly increased iron stores in p.C282Y homozygotes after correction for age, iron-related variables, and alcohol consumption. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Hepatocellular carcinoma and the penetrance of HFE C282Y mutations: a cross sectional study

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    Lonsdale Ray

    2005-06-01

    Full Text Available Abstract Background Although most patients with hereditary haemochromatosis have HFE C282Y mutations, the lifetime risk to HFE C282Y homozygotes of developing fatal diseases such as hepatocellular carcinoma is uncertain. We have carried out a cross-sectional study to determine the proportion of diagnosed hepatocellular carcinoma patients who are homozygous for the HFE C282Y mutation; and to estimate the penetrance of this genotype with respect to hepatocellular carcinoma in East Anglia. Methods Tissue biopsies were analysed from 144 cases of hepatocellular carcinoma for HFE C282Y mutations; the data produced were compared with the frequency of HFE mutations in a large sample of the local population. Data were also retrieved from the East Anglian Cancer Intelligence Unit to determine the annual incidence of hepatocellular carcinoma; and from appropriate life tables. Results Eight out of 144 of the cases were homozygous for the HFE C282Y mutation, all 8 cases were male. 6 of these 8 cases had a previous diagnosis of hereditary haemochromatosis. Male HFE C282Y homozygotes were more likely to be diagnosed with hepatocellular carcinoma (odds ratio [OR] = 14, 95% confidence interval [CI] = 5–37. For this population, we estimate that the penetrance of the HFE C282Y homozygous genotype, with respect to hepatocellular carcinoma, was between 1.31 % and 2.1% for males and was zero for females. Conclusion In this population, we found that only a very small proportion of homozygotes for the HFE C282Y mutation developed hepatocellular carcinoma. However, individuals with this genotype have a significantly increased risk of this rare disease relative to those who do not carry the mutations.

  4. HFE C282Y homozygosity is associated with an increased risk of total hip replacement for osteoarthritis.

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    Wang, Yuanyuan; Gurrin, Lyle C; Wluka, Anita E; Bertalli, Nadine A; Osborne, Nicholas J; Delatycki, Martin B; Giles, Graham G; English, Dallas R; Hopper, John L; Simpson, Julie A; Graves, Stephen; Allen, Katrina J; Cicuttini, Flavia M

    2012-06-01

    The evidence for an association between mutations in the HFE (hemochromatosis) gene and the risk of hip or knee osteoarthritis is inconsistent. Total joint replacement is considered a surrogate measure for symptomatic end-stage osteoarthritis. We examined the relationship between HFE gene mutations and risk of total hip and knee replacement using a prospective cohort study. The Melbourne Collaborative Cohort Study recruited participants between 1990 and 1994. Participants born in Australia, New Zealand, the United Kingdom, or Ireland (n = 27,848) were genotyped for the HFE C282Y mutation. Total hip and knee replacements for osteoarthritis during 2001 to 2009 were ascertained from the Australian Orthopaedic Association National Joint Replacement Registry. Hazard ratios (HR)/odds ratios (OR) and confidence intervals (CI) were obtained from Cox regression or logistic regression. Compared with those with no C282Y mutation, C282Y homozygotes had an increased risk of single total hip replacement (HR 1.94, 95% CI 1.04-3.62) and bilateral total hip replacement (OR 5.86, 95% CI 2.36-14.57) for osteoarthritis, adjusting for age, sex, body mass index, and educational level. Only 3 C282Y homozygotes had single total knee replacement; the HR was 0.51 (95% CI 0.16-1.57). C282Y/H63D compound heterozygosity was not related to the risk of total hip or knee replacement. HFE C282Y homozygosity was associated with an increased risk of both single and bilateral total hip replacement for osteoarthritis. Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.

  5. The 16189 variant of mitochondrial DNA occurs more frequently in C282Y homozygotes with haemochromatosis than those without iron loading.

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    Livesey, K J; Wimhurst, V L C; Carter, K; Worwood, M; Cadet, E; Rochette, J; Roberts, A G; Pointon, J J; Merryweather-Clarke, A T; Bassett, M L; Jouanolle, A-M; Mosser, A; David, V; Poulton, J; Robson, K J H

    2004-01-01

    Patients with hereditary haemochromatosis (HH) are usually homozygous for the C282Y mutation in the HFE gene. They have variable expression of iron overload and present with a variety of complications, including liver disease, diabetes, arthropathy, fatigue, and cardiomyopathy. The mitochondrial 16189 variant is associated with diabetes, dilated cardiomyopathy, and low body fat at birth, and might contribute to genetic predisposition in further multifactorial disorders. The objective of this study was to determine the frequency of the 16189 variant in a range of patients with haemochromatosis, who had mutations in the HFE gene. Blood DNA was analysed for the presence of the 16189 variant in British, French, and Australian C282Y homozygotes and controls, with known iron status, and in birth cohorts. The frequency of the mitochondrial 16189 variant was found to be elevated in individuals with haemochromatosis who were homozygous for the C282Y allele, compared with population controls and with C282Y homozygotes who were asymptomatic (42/292 (14.4%); 102/1186 (8.6%) (p = 0.003); and 2/64 (3.1%) (p = 0.023), respectively). Iron loading in C282Y homozygotes with HH was exacerbated by the presence of the mitochondrial 16189 variant.

  6. The origin and spread of the HFE-C282Y haemochromatosis mutation.

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    Distante, S; Robson, K J H; Graham-Campbell, J; Arnaiz-Villena, A; Brissot, P; Worwood, Mark

    2004-09-01

    The mutation responsible for most cases of genetic haemochromatosis in Europe (HFE C282Y) appears to have been originated as a unique event on a chromosome carrying HLA-A3 and -B7. It is often described as a "Celtic mutation"--originating in a Celtic population in central Europe and spreading west and north by population movement. It has also been suggested that Viking migrations were largely responsible for the distribution of this mutation. Two, initial estimates of the age of the mutation are compatible with either of these suggestions. Here we examine the evidence about HFE C282Y frequencies, extended haplotypes involving HLA-A and -B alleles, the validity of calculations of mutation age, selective advantage and current views on the relative importance of "demic-diffusion" (population migration) and "adoption-diffusion" (cultural change) in the neolithic transition in Europe and since then. We conclude that the HFE C282Y mutation occurred in mainland Europe before 4,000 BC.

  7. Common variable immunodeficiency and IgG subclass deficiency in central Alabama hemochromatosis probands homozygous for HFE C282Y.

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    Barton, James C; Bertoli, Luigi F; Acton, Ronald T

    2003-01-01

    Eight hemochromatosis probands with HFE C282Y homozygosity had frequent, severe, or unusual infections and common variable immunodeficiency (CVID) or immunoglobulin (Ig) G subclass deficiency (IgGSD). Thus, we performed serum Ig isotyping and other characterization of 43 additional unselected probands, 5 human leukocyte antigen (HLA)-identical siblings, and 240 consecutive CVID or IgGSD index patients. C282Y allele frequencies were estimated in 58 CVID or IgGSD index patients without hemochromatosis phenotypes and in 341 controls. HLA-A and -B haplotypes and frequencies were determined in all 51 probands, 186 CVID or IgGSD index patients without hemochromatosis phenotypes, and 751 controls. Thirteen unselected probands (30%) had CVID or IgGSD. Among all 21 hemochromatosis probands with CVID (n = 4) or IgGSD (n = 17), Ig subclass deficiency patterns were IgG(1) (n = 5), IgG(1) and IgG(3) (n = 6), IgG(3) (n = 9), and IgG(1), IgG(3), and IgG(4) (n = 1). IgG(2) or IgA deficiency was not detected; one proband had IgM deficiency. Mean values of total IgG, IgG(1), and IgG(3) were significantly lower in probands with CVID or IgGSD. Mean values of age, transferrin saturation, and ferritin at diagnosis and phlebotomy units required to induce iron depletion were similar in probands with or without CVID or IgGSD; phlebotomy had no apparent effect on IgG levels. C282Y frequencies were similar in CVID or IgGSD index cases without hemochromatosis phenotypes and in controls. There was concordance of Ig and hemochromatosis phenotypes in probands and respective HLA-identical siblings. Eight of 240 CVID or IgGSD index patients had hemochromatosis phenotypes and C282Y homozygosity (3 vs 0.7% and 0.2% controls; P IgG abnormalities characteristic of CVID or IgGSD are common in hemochromatosis probands, and that the prevalence of hemochromatosis is increased in CVID and IgGSD index cases. These observations could be explained by the increased frequencies of HLA-A*03-B*07 in C282Y

  8. Expression of hereditary hemochromatosis C282Y HFE protein in HEK293 cells activates specific endoplasmic reticulum stress responses

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    Norris Suzanne

    2007-07-01

    Full Text Available Abstract Background Hereditary Hemochromatosis (HH is a genetic disease associated with iron overload, in which individuals homozygous for the mutant C282Y HFE associated allele are at risk for the development of a range of disorders particularly liver disease. Conformational diseases are a class of disorders associated with the expression of misfolded protein. HFE C282Y is a mutant protein that does not fold correctly and consequently is retained in the Endoplasmic Reticulum (ER. In this context, we sought to identify ER stress signals associated with mutant C282Y HFE protein expression, which may have a role in the molecular pathogenesis of HH. Results Vector constructs of Wild type HFE and Mutant C282Y HFE were made and transfected into HEK293 cell lines. We have shown that expression of C282Y HFE protein triggers both an unfolded protein response (UPR, as revealed by the increased GRP78, ATF6 and CHOP expression, and an ER overload response (EOR, as indicated by NF-κB activation. Furthermore, C282Y HFE protein induced apoptotic responses associated with activation of ER stress. Inhibition studies demonstrated that tauroursodeoxycholic acid, an endogenous bile acid, downregulates these events. Finally, we found that the co-existence of both C282Y HFE and Z alpha 1-antitrypsin protein (the protein associated with the liver disease of Z alpha 1-antitrypsin deficiency expression on ER stress responses acted as potential disease modifiers with respect to each other. Conclusion Our novel observations suggest that both the ER overload response (EOR and the unfolded protein response (UPR are activated by mutant C282Y HFE protein.

  9. Serum iron parameters, HFE C282Y genotype, and cognitive performance in older adults: results from the FACIT study

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    Schiepers, Olga; Van Boxtel, Martin; De Groot, Renate; Jolles, Jelle; De Kort, Wim; Swinkels, Dorine; Kok, Frans; Verhoef, Petra; Durga, Jane

    2010-01-01

    Schiepers, O. J., Van Boxtel, M. P. J., De Groot, R. H. M., Jolles, J., De Kort, W. L., Swinkels, D. W., et al. (2010). Serum iron parameters, HFE C282Y genotype, and cognitive performance in older adults: results from the FACIT study. The Journals of gerontology. Series A, Biological sciences and

  10. Porphyria cutanea tarda associated with HFE C282Y homozygosity, iron overload, and use of a contraceptive vaginal ring

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    James C. Barton

    2016-02-01

    Full Text Available Porphyria cutanea tarda (PCT is characterized by decreased uroporphyrinogen decarboxylase activity in hepatocytes, uroporphyrin I and heptacarboxyl porphyrin III accumulation, photosensitivity dermatitis, and increased storage iron. In women, estrogen therapy, including oral contraceptives, postmenopausal hormone replacement, and tamoxifen for breast cancer treatment, is a risk factor for PCT. We report the case of a woman who presented with PCT, HFE C282Y homozygosity, and hepatic iron overload and was using a contraceptive vaginal ring containing ethinyl estradiol, an estrogen. We discuss this case in the context of characteristics of other persons with PCT, including common HFE mutations, iron overload, and estrogen exposure.

  11. Ancestral association between HLA and HFE H63D and C282Y gene mutations from northwest Colombia

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    Libia M Rodriguez

    2015-03-01

    Full Text Available A significant association between HFE gene mutations and the HLA-A*03-B*07 and HLA-A*29-B*44 haplotypes has been reported in the Spanish population. It has been proposed that these mutations are probably connected with Celtic and North African ancestry, respectively. We aimed to find the possible ancestral association between HLA alleles and haplotypes associated with the HFE gene (C282Y and H63D mutations in 214 subjects from Antioquia, Colombia. These were 18 individuals with presumed hereditary hemochromatosis (“HH” and 196 controls. The HLA-B*07 allele was in linkage disequilibrium (LD with C282Y, while HLA-A*23, A*29, HLA-B*44, and B*49 were in LD with H63D. Altogether, our results show that, although the H63D mutation is more common in the Antioquia population, it is not associated with any particular HLA haplotype, whereas the C282Y mutation is associated with HLA-A*03-B*07, this supporting a northern Spaniard ancestry.

  12. HFE, SLC40A1, HAMP, HJV, TFR2, and FTL mutations detected by denaturing high-performance liquid chromatography after iron phenotyping and HFE C282Y and H63D genotyping in 785 HEIRS Study participants.

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    Barton, James C; Lafreniere, Susie A; Leiendecker-Foster, Catherine; Li, Honggui; Acton, Ronald T; Press, Richard D; Eckfeldt, John H

    2009-11-01

    We sought to identify mutations that could explain iron phenotype heterogeneity in adults with previous HFE genotyping to detect C282Y and H63D. HEIRS Study participants genotyped for C282Y and H63D were designated as high transferrin saturation (TS) and/or serum ferritin (SF) (high TS/SF), low TS/SF, or controls. We grouped 191 C282Y homozygotes as high TS/SF, low TS/SF, or controls, and 594 other participants by race/ethnicity as high TS/SF or controls. Using denaturing high-performance liquid chromatography (DHPLC), we screened 20 regions of HFE, SLC40A1, HAMP, HJV, TFR2, and FTL in each participant. DHPLC analyses were successful in 99.3% of 791 participants and detected 117 different mutations. In C282Y homozygotes, 4.0% of high TS/SF participants had SLC40A1 Q248H, HAMP -72C>T, or HAMP R59G heterozygosity (0% Controls; P = 0.1200). In whites, 4.1% with high TS/SF and 1.3% of controls had HFE S65C or E168Q (P = 0.3049). HJV c.-6C>G and FTL L55L frequencies were greater in whites with high TS/SF than controls (0.0811 vs. 0.0200, P = 0.0144; 0.5743 vs. 0.4400, P = 0.0204, respectively). One Hispanic with high TS/SF (1.3%) had HAMP G71D heterozygosity. In blacks, SLC40A1 Q248H frequencies did not differ significantly between high TS/SF and control participants. Among Asians, 2.8% with high TS/SF were HFE V295A heterozygotes. Mutations other than HFE C282Y and H63D reported to be pathogenic were infrequently detected in high TS/SF participants. Genetic regions in linkage disequilibrium with HJV c.-6C>G and FTL L55L could partly explain high TS/SF phenotypes in whites. Am. J. Hematol., 2009. Published 2009 Wiley-Liss, Inc.

  13. Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation.

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    Mattman, Andre; Huntsman, David; Lockitch, Gillian; Langlois, Sylvie; Buskard, Noel; Ralston, Diana; Butterfield, Yaron; Rodrigues, Pedro; Jones, Steven; Porto, Graça; Marra, Marco; De Sousa, Maria; Vatcher, Greg

    2002-08-01

    Hereditary hemochromatosis (HH) is classically associated with a Cys282Tyr (C282Y) mutation of the HFE gene. Non-C282Y HH is a heterogeneous group accounting for 15% of HH in Northern Europe. Pathogenic mutations of the transferrin receptor 2 (TfR2) gene have been identified in 4 Italian pedigrees with the latter syndrome. The goal of this study was to perform a mutational analysis of the TfR2 and HFE genes in a cohort of non-C282Y iron overload patients of mixed ethnic backgrounds. Several sequence variants were identified within the TfR2 gene, including a homozygous missense change in exon 17, c2069 A-->C, which changes a glutamine to a proline residue at position 690. This putative mutation was found in a severely affected Portuguese man and 2 family members with the same genotype. In summary, pathologic TfR2 mutations are present outside of Italy, accounting for a small proportion of non-C282Y HH.

  14. Association Studies of HFE C282Y and H63D Variants with Oral Cancer Risk and Iron Homeostasis Among Whites and Blacks

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    Nathan R. Jones

    2015-12-01

    Full Text Available Background: Polymorphisms in the hemochromatosis (HFE gene are associated with excessive iron absorption from the diet, and pro-oxidant effects of iron accumulation are thought to be a risk factor for several types of cancer. Methods: The C282Y (rs1800562 and H63D (rs1799945 polymorphisms were genotyped in 301 oral cancer cases and 437 controls and analyzed in relation to oral cancer risk, and serum iron biomarker levels from a subset of 130 subjects. Results: Individuals with the C282Y allele had lower total iron binding capacity (TIBC (321.2 ± 37.2 µg/dL vs. 397.7 ± 89.0 µg/dL, p = 0.007 and higher percent transferrin saturation (22.0 ± 8.7 vs. 35.6 ± 22.9, p = 0.023 than wild type individuals. Iron and ferritin levels approached significantly higher levels for the C282Y allele (p = 0.0632 and p = 0.0588, respectively. Conclusions: Iron biomarker levels were elevated by the C282Y allele, but neither (rs1800562 nor (rs1799945 was associated with oral cancer risk in blacks and whites.

  15. Transferrin receptor 2 (TfR2) and HFE mutational analysis in non‐C282Y iron overload: identification of a novel TfR2 mutation

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    Mattman, A.; Huntsman, D; Lockitch, G; Langlois, S.; Buskard, N; RALSTON, D.; BUTTERFIELD, Y.; Rodrigues, P; Jones, S.; Porto, G; Marra, M.; Sousa, M; VATCHER, G.

    2002-01-01

    Blood. 2002 Aug 1;100(3):1075-7. Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation. Mattman A, Huntsman D, Lockitch G, Langlois S, Buskard N, Ralston D, Butterfield Y, Rodrigues P, Jones S, Porto G, Marra M, De Sousa M, Vatcher G. SourceGenes, Elements, and Metabolism Program, Children and Women's Hospital of British Columbia, Vancouver, British Columbia, Canada. Abstract Hereditary hemochromatosis (HH...

  16. Mutations in HAMP and HJV genes and their impact on expression of clinical hemochromatosis in a cohort of 100 Spanish patients homozygous for the C282Y mutation of HFE gene.

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    Altès, Albert; Bach, Vanessa; Ruiz, Angels; Esteve, Anna; Felez, Jordi; Remacha, Angel F; Sardà, M Pilar; Baiget, Montserrat

    2009-10-01

    Most hereditary hemochromatosis (HH) patients are homozygous for the C282Y mutation of the HFE gene. Nevertheless, penetrance of the disease is very variable. In some patients, penetrance can be mediated by concomitant mutations in other iron master genes. We evaluated the clinical impact of hepcidin (HAMP) and hemojuvelin mutations in a cohort of 100 Spanish patients homozygous for the C282Y mutation of the HFE gene. HAMP and hemojuvelin mutations were evaluated in all patients by bidirectional direct cycle sequencing. Phenotype-genotype interactions were evaluated. A heterozygous mutation of the HAMP gene (G71D) was found in only one out of 100 cases. Following, we performed a study of several members of that family, and we observed several members had a digenic inheritance of the C282Y mutation of the HFE gene and the G71D mutation of the HAMP gene. This mutation in the HAMP gene did not modify the phenotype of the individuals who were homozygous for the C282Y mutation. One other patient presented a new polymorphism in the hemojuvelin gene, without consequences in iron load or clinical course of the disease. In conclusion, HAMP and hemojuvelin mutations are rare among Spanish HH patients, and their impact in this population is not significant.

  17. Frequency of the HFE C282Y and H63D mutations in Danish patients with clinical haemochromatosis initially diagnosed by phenotypic methods

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    Milman, Nils; Koefoed, Pernille; Pedersen, Palle

    2003-01-01

    diagnosis of clinical idiopathic haemochromatosis was made before blood samples were taken for HFE genotyping. The total series consisted of 58 patients (40 men and 18 women) with a median age of 60 yrs (range 18-74). HFE genotyping was performed by the polymerase chain reaction (PCR) technique. RESULTS...... idiopathic haemochromatosis diagnosed by phenotypic methods (serum transferrin saturation, serum ferritin, liver biopsy and mobilisable body iron stores). In 32 unrelated patients, frozen blood samples were available for genetic analysis. In a subsequent series of 26 unrelated Danish patients, a phenotypic...... appears to be the prevailing cause of clinically overt genetic haemochromatosis. This finding has implications both for the evaluation of patients with iron overload disorders and for the strategy in future population screening surveys....

  18. Prevalence of H63D, S65C and C282Y hereditary hemochromatosis gene mutations in Slovenian population by an improved high-throughput genotyping assay

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    Rupreht Ruth

    2007-11-01

    Full Text Available Abstract Background Hereditary hemochromatosis (HH is a common genetic disease characterized by excessive iron overload that leads to multi-organ failure. Although the most prevalent genotype in HH is homozygosity for C282Y mutation of the HFE gene, two additional mutations, H63D and S65C, appear to be associated with a milder form of HH. The aim of this study was to develop a high-throughput assay for HFE mutations screening based on TaqMan technology and to determine the frequencies of HFE mutations in the Slovenian population. Methods Altogether, 1282 randomly selected blood donors from different Slovenian regions and 21 HH patients were analyzed for the presence of HFE mutations by an in-house developed real-time PCR assay based on TaqMan technology using shorter non-interfering fluorescent single nucleotide polymorphism (SNP-specific MGB probes. The assay was validated by RFLP analysis and DNA sequencing. Results The genotyping assay of the H63D, S65C and C282Y mutations in the HFE gene, based on TaqMan technology proved to be fast, reliable, with a high-throughput capability and 100% concordant with genotypes obtained by RFLP and DNA sequencing. The observed frequency of C282Y homozygotes in the group of HH patients was only 48%, others were of the heterogeneous HFE genotype. Among 1282 blood donors tested, the observed H63D, S65C and C282Y allele frequency were 12.8% (95% confidence interval (CI 11.5 – 14.2%, 1.8% (95% CI 1.4 – 2.5% and 3.6% (95% CI 3.0 – 4.5%, respectively. Approximately 33% of the tested subjects had at least one of the three HH mutations, and 1% of them were C282Y homozygotes or compound heterozygotes C282Y/H63D or C282Y/S65C, presenting an increased risk for iron overload disease. A significant variation in H63D allele frequency was observed for one of the Slovenian regions. Conclusion The improved real-time PCR assay for H63D, S65C and C282Y mutations detection is accurate, fast, cost-efficient and ready for

  19. Prevalence of H63D, S65C and C282Y hereditary hemochromatosis gene mutations in Slovenian population by an improved high-throughput genotyping assay.

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    Cukjati, Marko; Vaupotic, Tomaz; Rupreht, Ruth; Curin-Serbec, Vladka

    2007-11-23

    Hereditary hemochromatosis (HH) is a common genetic disease characterized by excessive iron overload that leads to multi-organ failure. Although the most prevalent genotype in HH is homozygosity for C282Y mutation of the HFE gene, two additional mutations, H63D and S65C, appear to be associated with a milder form of HH. The aim of this study was to develop a high-throughput assay for HFE mutations screening based on TaqMan technology and to determine the frequencies of HFE mutations in the Slovenian population. Altogether, 1282 randomly selected blood donors from different Slovenian regions and 21 HH patients were analyzed for the presence of HFE mutations by an in-house developed real-time PCR assay based on TaqMan technology using shorter non-interfering fluorescent single nucleotide polymorphism (SNP)-specific MGB probes. The assay was validated by RFLP analysis and DNA sequencing. The genotyping assay of the H63D, S65C and C282Y mutations in the HFE gene, based on TaqMan technology proved to be fast, reliable, with a high-throughput capability and 100% concordant with genotypes obtained by RFLP and DNA sequencing. The observed frequency of C282Y homozygotes in the group of HH patients was only 48%, others were of the heterogeneous HFE genotype. Among 1282 blood donors tested, the observed H63D, S65C and C282Y allele frequency were 12.8% (95% confidence interval (CI) 11.5-14.2%), 1.8% (95% CI 1.4-2.5%) and 3.6% (95% CI 3.0-4.5%), respectively. Approximately 33% of the tested subjects had at least one of the three HH mutations, and 1% of them were C282Y homozygotes or compound heterozygotes C282Y/H63D or C282Y/S65C, presenting an increased risk for iron overload disease. A significant variation in H63D allele frequency was observed for one of the Slovenian regions. The improved real-time PCR assay for H63D, S65C and C282Y mutations detection is accurate, fast, cost-efficient and ready for routine screening and diagnostic procedures. The genotype frequencies in

  20. Effects of highly conserved major histocompatibility complex (MHC extended haplotypes on iron and low CD8+ T lymphocyte phenotypes in HFE C282Y homozygous hemochromatosis patients from three geographically distant areas.

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    Mónica Costa

    Full Text Available Hereditary Hemochromatosis (HH is a recessively inherited disorder of iron overload occurring commonly in subjects homozygous for the C282Y mutation in HFE gene localized on chromosome 6p21.3 in linkage disequilibrium with the human leukocyte antigen (HLA-A locus. Although its genetic homogeneity, the phenotypic expression is variable suggesting the presence of modifying factors. One such genetic factor, a SNP microhaplotype named A-A-T, was recently found to be associated with a more severe phenotype and also with low CD8(+T-lymphocyte numbers. The present study aimed to test whether the predictive value of the A-A-T microhaplotype remained in other population settings. In this study of 304 HH patients from 3 geographically distant populations (Porto, Portugal 65; Alabama, USA 57; Nord-Trøndelag, Norway 182, the extended haplotypes involving A-A-T were studied in 608 chromosomes and the CD8(+ T-lymphocyte numbers were determined in all subjects. Patients from Porto had a more severe phenotype than those from other settings. Patients with A-A-T seemed on average to have greater iron stores (p = 0.021, but significant differences were not confirmed in the 3 separate populations. Low CD8(+ T-lymphocytes were associated with HLA-A*03-A-A-T in Porto and Alabama patients but not in the greater series from Nord-Trøndelag. Although A-A-T may signal a more severe iron phenotype, this study was unable to prove such an association in all population settings, precluding its use as a universal predictive marker of iron overload in HH. Interestingly, the association between A-A-T and CD8(+ T-lymphocytes, which was confirmed in Porto and Alabama patients, was not observed in Nord-Trøndelag patients, showing that common HLA haplotypes like A*01-B*08 or A*03-B*07 segregating with HFE/C282Y in the three populations may carry different messages. These findings further strengthen the relevance of HH as a good disease model to search for novel candidate loci

  1. HFE-Related Hemochromatosis: The Haptoglobin 2-2 Type Has a Significant but Limited Influence on Phenotypic Expression of the Predominant p.C282Y Homozygous Genotype

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    Gérald Le Gac

    2009-01-01

    In this study we investigated influence of Hp2-2 and of potential confounders on the iron indices of 351 p.C282Y homozygous patients. We conclude that there is a cause-and-effect relationship between the Hp2-2 genotype and increased iron indices in p.C282Y homozygous patients. The Hp2-2 effect is, however, limited and only apparent in males.

  2. A time course of hepcidin response to iron challenge in patients with HFE and TFR2 hemochromatosis.

    Science.gov (United States)

    Girelli, Domenico; Trombini, Paola; Busti, Fabiana; Campostrini, Natascia; Sandri, Marco; Pelucchi, Sara; Westerman, Mark; Ganz, Tomas; Nemeth, Elizabeta; Piperno, Alberto; Camaschella, Clara

    2011-04-01

    Inadequate hepcidin production leads to iron overload in nearly all types of hemochromatosis. We explored the acute response of hepcidin to iron challenge in 25 patients with HFE-hemochromatosis, in two with TFR2-hemochromatosis and in 13 controls. Sixteen patients (10 C282Y/C282Y homozygotes, 6 C282Y/H63D compound heterozygotes) had increased iron stores, while nine (6 C282Y/C282Y homozygotes, 3 C282Y/H63D compound heterozygotes) were studied after phlebotomy-induced normalization of iron stores. We analyzed serum iron, transferrin saturation, and serum hepcidin by both enzyme-linked immunosorbent assay and mass-spectrometry at baseline, and 4, 8, 12 and 24 hours after a single 65-mg dose of oral iron. Serum iron and transferrin saturation significantly increased at 4 hours and returned to baseline values at 8-12 hours in all groups, except in the iron-normalized patients who showed the highest and longest increase of both parameters. The level of hepcidin increased significantly at 4 hours and returned to baseline at 24 hours in controls and in the C282Y/H63D compound heterozygotes at diagnosis. The hepcidin response was smaller in C282Y-homozygotes than in controls, barely detectable in the patients with iron-depleted HFE-hemochromatosis and absent in those with TFR2-hemochromatosis. Conclusions Our results are consistent with a scenario in which TFR2 plays a prominent and HFE a contributory role in the hepcidin response to a dose of oral iron. In iron-normalized patients with HFE hemochromatosis, both the low baseline hepcidin level and the weak response to iron contribute to hyperabsorption of iron.

  3. Prevalence of the C282Y mutation for haemochromatosis on the Island of Majorca.

    Science.gov (United States)

    Guix, P; Picornell, A; Parera, M; Tomás, C; Muncunill, J; Castro, J A; Rossell, J; Vaquer, P; Ramon, M M; Obrador, A

    2000-08-01

    The C282Y mutation of the HFE gene has been reported to be present in most of the patients with hereditary haemochromatosis (HH) of Northern European ancestry. HH affects approximately 1/300 individuals, but it is not evenly distributed in the different European countries. In the present study, polymerase chain reaction (PCR) and restriction-enzyme digestion were used to analyse the frequency of the most important mutation in haemochromatosis (C282Y) in subjects from Majorca (Balearic Islands, Spain) and patients with haemochromatosis. The results were compared with other studies from Spain and Europe. A total of 420 Majorcan chromosomes were analysed and the C282Y mutation was observed at a frequency of 2.62%+/-0.8 (11 heterozygotes: eight men and three women). In the group of hereditary haemochromatosis probands, 13 out of 14 were homozygous for the C282Y mutation. In the distribution of the C282Y mutation, a north-west to south-east cline was detected, supporting the Celtic origin of this mutation.

  4. HFE mutations in the elderly.

    Science.gov (United States)

    Willis, Gavin; Wimperis, Jennie Z; Smith, Katy; Fellows, Ian W; Jennings, Barbara A

    2003-01-01

    Most individuals diagnosed with hereditary hemochromatosis have mutations in both copies of the HFE gene, with such mutations being common in populations of north European origin. The number of individuals currently diagnosed and treated for hemochromatosis is small relative to the number carrying two HFE mutations. Studies searching for undiagnosed hemochromatosis cases among disease cohorts have generally failed to find the number of cases that would be expected if disease were the commonest outcome for individuals with two C282Y HFE mutations. Our aim was to test the hypothesis that individuals with two HFE mutations would be under-represented in an elderly population because many would have died from disease caused by hemochromatosis before they reached old age. This is a cross-sectional study of elderly patients referred for full blood counts at the Norfolk and Norwich University Hospital. We screened blood samples from 1,000 elderly men (aged 85 and over) and women (aged 89 and over) for the C282Y, H63D, and S65C mutations of the HFE gene. We also analyzed any recent laboratory data relevant to signs of hemochromatosis. None of the ten possible genotypes was significantly under- or over-represented compared to the expected frequency calculated from the Hardy-Weinberg equation. Four C282Y homozygotes were found. There were few significant differences in the laboratory findings between the genotypes. Our data suggest that most people with HFE mutations survive to old age and do not suffer from signs of iron overload and hemochromatosis.

  5. Analysis of HFE and TFR2 mutations in selected blood donors with biochemical parameters of iron overload.

    Science.gov (United States)

    De Gobbi, Marco; Daraio, Filomena; Oberkanins, Christian; Moritz, Anne; Kury, Fritz; Fiorelli, Gemino; Camaschella, Clara

    2003-04-01

    Hereditary hemochromatosis is a recessive condition characterized by iron accumulation in several organs, followed by organ damage and failure. The disorder is prevalently due to C282Y and H63D mutations in the HFE gene, but additional HFE and TFR2 mutations have been reported. Early iron overload may be assessed by biochemical parameters such as increased transferrin saturation and serum ferritin. Taking advantage of the collection of 178 DNA samples selected for increased transferrin saturation (>50% in males and >45% in females) from a previous large scale screening of Italian blood donors, we simultaneously assessed the presence of 14 hemochromatosis-associated molecular defects (11 of HFE and 3 of TFR2) by a reverse hybridization-based strip assay. In the series studied the overall C282Y allele frequency was 9% and that of the H63D and S65C was 22.2% and 1.4%, respectively. One rare HFE allele (E168Q), but no TFR2 mutation was detected. When checked at a second examination, transferrin saturation was significantly higher in C282Y homozygotes, H63D/ C282Y compound heterozygotes and H63D homozygotes as compared to wild-type subjects (pTFR2 mutations was identified in this series confirming the preliminary indication of their rare occurrence. Subjects with hemochromatosis-associated genotypes show a persistently higher mean transferrin saturation than do those with wild type genotypes.

  6. Incidence of cardiac arrhythmias in asymptomatic hereditary hemochromatosis subjects with C282Y homozygosity.

    Science.gov (United States)

    Shizukuda, Yukitaka; Tripodi, Dorothy J; Zalos, Gloria; Bolan, Charles D; Yau, Yu-Ying; Leitman, Susan F; Waclawiw, Myron A; Rosing, Douglas R

    2012-03-15

    It is not well known whether systemic iron overload per se in hereditary hemochromatosis (HH) is associated with cardiac arrhythmias before other signs and symptoms of cardiovascular disease occur. In the present study, we examined the incidence of cardiac arrhythmia in cardiac asymptomatic subjects with HH (New York Heart Association functional class I) and compared it to that in age- and gender-matched normal volunteers. The 42 subjects with HH and the 19 normal control subjects were recruited through the National Heart, Lung, and Blood Institute-sponsored "Heart Study of Hemochromatosis." They completed 48-hour Holter electrocardiography ambulatory monitoring at the baseline evaluation. The subjects with HH were classified as newly diagnosed (group A) and chronically treated (group B) subjects. All subjects with HH had C282Y homozygosity, and the normal volunteers lacked any HFE gene mutations known to cause HH. Although statistically insignificant, the incidence of ventricular and supraventricular ectopy tended to be greater in the combined HH groups than in the controls. Supraventricular ectopy was more frequently noted in group B compared to in the controls (ectopy rate per hour 11.1 ± 29.9 vs 1.5 ± 3.5, p cardiac arrhythmias was not significantly reduced after 6 months of intensive iron removal therapy in the group A subjects. No life-threatening arrhythmias were observed in our subjects with HH. In conclusion, our data suggest that the incidence of cardiac arrhythmias is, at most, marginally increased in asymptomatic subjects with HH. A larger clinical study is warranted to further clarify our observation. Published by Elsevier Inc.

  7. Clinical characteristics and analysis of HFE gene variants (C282Y ...

    African Journals Online (AJOL)

    Age-related macular degeneration (AMD) is a complex genetic disorder with multiple etiologies. Multiple genes as well as environmental effects are thought to play a role in causing AMD. Recent evidence pointed that elevated iron overload, resulting from hereditary defects of iron homeostasis, is associated with retinal ...

  8. Coincident natural selection of CCR532 and C282Y in Europe: to ...

    Indian Academy of Sciences (India)

    Keywords. CCR532; C282Y; natural selection; Black Death; plague. Author Affiliations. Marjan Gharagozloo1 Abbas Ghaderi1. Department of Immunology, Shiraz University of Medical Sciences, P.O. Box 71345 1798, Shiraz, Iran. Dates. Manuscript received: 30 November 2004; Manuscript revised: 9 February 2005 ...

  9. Time-course analysis of serum hepcidin, iron and cytokines in a C282Y homozygous patient with Schnitzler's syndrome treated with IL-1 receptor antagonist.

    Science.gov (United States)

    van Deuren, Marcel; Kroot, Joyce J C; Swinkels, Dorine W

    2009-09-01

    It is currently unknown if the increase of the hepatic iron regulatory hormone hepcidin during inflammation in man depends on an intact HFE-protein. Here we describe the temporal relationship of serum hepcidin, serum iron and cytokines in a patient with HFE-related (C282Y homozygous) hereditary hemochromatosis who was treated for an auto-inflammatory condition, i.e. variant Schnitzler's syndrome, with the potent anti-inflammatory cytokine inter-leukin-1 receptor antagonist (IL-1ra, anakinra). The patient had bouts of fever with peaking serum IL-6 concentrations followed by peaking serum hepcidin levels, while serum iron was low. Upon treatment, these peaks disappeared and hepcidin levels became non-detectable, consistent with HFE deficiency. In conclusion, this in vivo human model: i) supports the importance of an HFE-independent IL-6-hepcidin axis in the development of hypoferremia and anemia of inflammation; and ii) suggests that chronic inflammation protects patients with HFE-related hereditary hemochromatosis from iron accumulation.

  10. Time-course analysis of serum hepcidin, iron and cytokines in a C282Y homozygous patient with Schnitzler’s syndrome treated with IL-1 receptor antagonist

    Science.gov (United States)

    van Deuren, Marcel; Kroot, Joyce J. C.; Swinkels, Dorine W.

    2009-01-01

    It is currently unknown if the increase of the hepatic iron regulatory hormone hepcidin during inflammation in man depends on an intact HFE-protein. Here we describe the temporal relationship of serum hepcidin, serum iron and cytokines in a patient with HFE-related (C282Y homozygous) hereditary hemochromatosis who was treated for an auto-inflammatory condition, i.e. variant Schnitzler’s syndrome, with the potent anti-inflammatory cytokine inter-leukin-1 receptor antagonist (IL-1ra, anakinra). The patient had bouts of fever with peaking serum IL-6 concentrations followed by peaking serum hepcidin levels, while serum iron was low. Upon treatment, these peaks disappeared and hepcidin levels became non-detectable, consistent with HFE deficiency. In conclusion, this in vivo human model: i) supports the importance of an HFE-independent IL-6-hepcidin axis in the development of hypoferremia and anemia of inflammation; and ii) suggests that chronic inflammation protects patients with HFE-related hereditary hemochromatosis from iron accumulation. PMID:19608676

  11. Prevalence of common HFE and SERPINA1 mutations in patients with hepatocellular carcinoma in a Moroccan population.

    Science.gov (United States)

    Ezzikouri, Sayeh; El Feydi, Abdellah Essaid; El Kihal, Latifa; Afifi, Rajae; Benazzouz, Mustapha; Hassar, Mohammed; Chafik, Abdelaziz; Pineau, Pascal; Benjelloun, Soumaya

    2008-02-01

    Hereditary hemochromatosis and SERPINA1 mutation were reported to affect liver functions. Our objective was to estimate the prevalence of HFE and SERPINA1 (formerly known as alpha1-antitrypsin, AAT) mutations and assess their influence on hepatocellular carcinoma development. This study included 222 controls and 96 cases with hepatocellular carcinoma. PCR-RFLP was used to characterize S and Z alleles in SERPINA1, as well as C282Y/H63D alleles of HFE. In healthy subjects and hepatocellular carcinoma patients as well, no homozygotes for the C282Y mutation were found. In controls, heterozygosity and homozygosity for the H63D mutation were 27 and 0.9%, respectively. Among patients, homozygosity for the H63D mutation was 3.1%, whereas heterozygosity for C282Y and H63D was 2.1 and 35.4%, respectively. Interestingly, albeit it does not reach significance (p=0.062), H63D was more prevalent in hepatocellular carcinoma patients than in controls (38.5 vs. 27.9%, respectively). The association was stronger when considering only male patients with hepatocellular carcinoma (47.1 vs. 23.6, p=0.001). Allele frequencies of S and Z in controls were 0.45% (95% CI=0.2-1.07) and 0.22% (95% CI=0.2-0.6), respectively, and 1 for S and 0% for Z in HCC. No significant difference was found between cases and controls. We provide a novel appraisal of HFE and SERPINA1 mutations prevalence in the Moroccan population. Results are consistent with the worldwide spread of the H63D and S mutation and the north European restriction of the C282Y and Z. Our results show that H63D carriage is increased among hepatocellular carcinoma patients, suggesting that it may confer an increased susceptibility to hepatocellular carcinoma even in a heterozygous state. On the contrary, HFE C282Y and SERPINA1 mutations do not contribute to hepatocellular carcinoma development.

  12. Was the C282Y mutation an Irish Gaelic mutation that the Vikings helped disseminate?

    DEFF Research Database (Denmark)

    Olsson, Karl Sigvard; Konar, Jan; Dufva, Inge Hoegh

    2011-01-01

    The HLA-related hemochromatosis mutation C282Y is thought to have originated in Ireland in a person with HLA-A3-B14 and was spread by Vikings. Irish people with two HLA-A3 alleles had a high risk of hemochromatosis. In this study, from west Sweden, we wanted to test these hypotheses.......The HLA-related hemochromatosis mutation C282Y is thought to have originated in Ireland in a person with HLA-A3-B14 and was spread by Vikings. Irish people with two HLA-A3 alleles had a high risk of hemochromatosis. In this study, from west Sweden, we wanted to test these hypotheses....

  13. Effect of Hereditary Hemochromatosis Gene H63D and C282Y Mutations on Iron Overload in Sickle Cell Disease Patients

    Directory of Open Access Journals (Sweden)

    Yunus Kasım Terzi

    2016-12-01

    Full Text Available Objective: Hemochromatosis is an autosomal recessive disease that is one of the most important reasons for iron overload. Sickle cell disease is a hemoglobinopathy that occurs as a result of a homozygous mutation in the hemoglobin gene. Erythrocyte transfusion is frequently used in the treatment of this disease. Iron overload as a result of transfusion is important in the mortality and morbidity of sickle cell anemia patients as well as in other hemoglobinopathies. In this study, the effect of hemochromatosis gene (HFE p.H63D and p.C282Y mutations on transfusion-related cardiac and liver iron overload in sickle cell disease patients who carry homozygous hemoglobin S mutation has been investigated. Materials and Methods: This is a prospective single-center crosssectional study in patients with homozygous hemoglobin S mutation between the years 2008 and 2013. The patients were divided into two groups. The first group (group A, n=31 was receiving chelation therapy and the second group (group B, n=13 was not. Direct and indirect iron loads were analyzed by magnetic resonance imaging and biochemically, respectively. HFE gene mutations were analyzed by polymerase chain reaction-restriction fragment length polymorphism method. Statistical analyses were performed by independent samples t-test. Results: p.H63D mutation was detected in 10 (32.3% patients in group A and in only 1 patient (7.7% in group B. When the 2 groups were compared for iron overload, iron deposition in the liver was significantly higher in group B (p=0.046. In addition, in group A, iron deposition was significantly higher in HFE mutation carriers compared to patients without the mutation (p=0.05. Conclusion: Results of this study showed that HFE gene mutations are important in iron deposition in the liver in patients with sickle cell disease.

  14. The evolutionary adaptation of the C282Y mutation to culture and climate during the European Neolithic.

    Science.gov (United States)

    Heath, Kathleen M; Axton, Jacob H; McCullough, John M; Harris, Nathan

    2016-05-01

    The C282Y allele is the major cause of hemochromatosis as a result of excessive iron absorption. The mutation arose in continental Europe no earlier than 6,000 years ago, coinciding with the arrival of the Neolithic agricultural revolution. Here we hypothesize that this new Neolithic diet, which originated in the sunny warm and dry climates of the Middle East, was carried by migrating farmers into the chilly and damp environments of Europe where iron is a critical micronutrient for effective thermoregulation. We argue that the C282Y allele was an adaptation to this novel environment. To address our hypothesis, we compiled C282Y allele frequencies, known Neolithic sites in Europe and climatic data on temperature and rainfall for statistical analysis. Our findings indicate that the geographic cline for C282Y frequency in Europe increases as average temperatures decrease below 16°C, a critical threshold for thermoregulation, with rainy days intensifying the trend. The results indicate that the deleterious C282Y allele, responsible for most cases of hemochromatosis, may have evolved as a selective advantage to culture and climate during the European Neolithic. © 2016 The Authors American Journal of Physical Anthropology Published by Wiley Periodicals, Inc.

  15. HFE-Associated Hereditary Haemochromatosis

    OpenAIRE

    Eijkelkamp, Emmeke J; Yapp, Thomas R; Powell, Lawrie W

    2000-01-01

    Hereditary hemochromatosis is a common inherited disorder of the iron metabolism. Screening studies indicate that it has a prevalence of one in 200 to 400, depending on the population studied, and a carrier rate of about one in seven to one in 10. Feder et al identified the hereditary hemochromatosis gene (HFE) in 1996 and two candidate mutations; the C282Y mutation has been shown to be responsible for the majority of the hereditary hemochromatosis cases worldwide. The gene discovery has led ...

  16. Autoimmune Conditions in 235 Hemochromatosis Probands with HFE C282Y Homozygosity and Their First-Degree Relatives

    Directory of Open Access Journals (Sweden)

    James C. Barton

    2015-01-01

    Full Text Available We performed a retrospective study of autoimmune conditions (ACs in 235 hemochromatosis probands at diagnosis by analyzing age, sex, ACs, history of first-degree family members with ACs (FH, diabetes, heavy ethanol consumption, elevated serum ALT/AST, nonalcoholic fatty liver disease, viral hepatitis, cirrhosis, iron removed to achieve iron depletion (QFe, and positivity for human leukocyte antigen (HLA haplotypes A∗01, B∗08; A∗02, B∗44; A∗03, B∗07; A∗03, B∗14; and A∗29, B∗44. There were 138 men (58.7%. Median followup was 19.6 y. One or more of 19 ACs were diagnosed in each of 35 probands (14.9%. Prevalences of Hashimoto’s thyroiditis, rheumatoid arthritis, and ankylosing spondylitis were 8.1% (95% CI: [5.1, 12.5], 1.7% [0.6, 4.6], and 0.0085 [0.0015, 0.0337], respectively. Eighteen probands (7.7% had a FH. Eight probands with ACs had 9 family members with ACs. In a logistic regression, ACs were less likely in men (odds ratio (OR 0.3 [0.1, 0.6] and more likely in probands with a FH (OR 4.1 [1.4, 11.8]. Overall ACs risk was not significantly associated with QFe or HLA haplotypes. Estimated survival of probands with and without ACs did not differ significantly. We conclude that ACs are common in hemochromatosis probands, especially women and probands with a FH.

  17. Homozygosity For The C282Y Substitution In The HFE Gene: The Incomplete Penetrance And Variable Expressivity

    Directory of Open Access Journals (Sweden)

    Dilum Ekanayake

    2015-01-01

    Full Text Available The syndrome of hepatic cirrhosis diabetes and skin pigmentation (‘Bronze diabetes’ has been well documented, including its propensity to lead to hepatocellular cancer. However, this picture of advanced disease is much less common nowadays with increased awareness and early diagnosis. However, in addition to this, it has been increasingly recognised that in contrast to other diseases inherited as autosomal recessive traits, subjects carrying the genetic predisposition infrequently develop overt disease. This is due only in part to physiological and pathological blood loss, and further relevant genetic mutations have been anticipated. Indeed, an international consortium has recently identified that the genetic variant ( GNPAT has been identified as predisposing to iron overload related disease. Further mutations can be anticipated and will assist in early diagnosis and treatment as well as identifying subjects predisposed to significant iron overload.

  18. Changing aspects of HFE-related hereditary haemochromatosis and endeavours to early diagnosis

    NARCIS (Netherlands)

    Jacobs, E. M. G.; Verbeek, A. L. M.; Kreeftenberg, H. G.; van Deursen, C. Th. B. M.; Marx, J. J. M.; Stalenhoef, A. F. H.; Swinkels, D. W.; de Vries, R. A.

    2007-01-01

    HFE-related hereditary haernochromatosis (HH) is an iron overload disease attributed to the highly prevalent homozygosity for the C282Y mutation in the HFE gene. The pathophysiology of this error in iron metabolism is not completely elucidated yet, although deficiency of the iron regulatory hormone

  19. Changing aspects of HFE-related hereditary haemochromatosis and endeavours to early diagnosis.

    NARCIS (Netherlands)

    Jacobs, E.M.G.; Verbeek, A.L.M.; Kreeftenberg, H.G.; Deursen, C.T. van; Marx, J.J.M.; Stalenhoef, A.F.H.; Swinkels, D.W.; Vries, R.A. de

    2007-01-01

    HFE-related hereditary haemochromatosis (HH) is an iron overload disease attributed to the highly prevalent homozygosity for the C282Y mutation in the HFE gene. The pathophysiology of this error in iron metabolism is not completely elucidated yet, although deficiency of the iron regulatory hormone

  20. HFE Genotyping in Patients with Elevated Serum Iron Indices and Liver Diseases

    Directory of Open Access Journals (Sweden)

    Andreia Silva Evangelista

    2015-01-01

    Full Text Available Iron abnormalities in chronic liver disease may be the result of genetic diseases or secondary factors. The present study aimed to identify subjects with HFE-HH in order to describe the frequency of clinical manifestations, identify risk factors for iron elevation, and compare the iron profile of HFE-HH to other genotypes in liver disease patients. A total of 108 individuals with hepatic disease, transferrin saturation (TS > 45%, and serum ferritin (SF > 350 ng/mL were tested for HFE mutations. Two groups were characterized: C282Y/C282Y or C282Y/H63D genotypes (n=16 were the HFE hereditary hemochromatosis (HFE-HH group; and C282Y and H63D single heterozygotes, the H63D/H63D genotype, and wild-type were considered group 2 (n=92. Nonalcoholic liver disease, alcoholism, and chronic hepatitis C were detected more frequently in group 2, whereas arthropathy, hepatocarcinoma, diabetes, and osteoporosis rates were significantly higher in the HFE-HH group. TS > 82%, SF > 2685 ng/mL, and serum iron > 178 μg/dL were the cutoffs for diagnosis of HFE-HH in patients with liver disease. Thus, in non-Caucasian populations with chronic liver disease, HFE-HH diagnosis is more predictable in those with iron levels higher than those proposed in current guidelines for the general population.

  1. Study of the effect of HFE gene mutations on iron overload in ...

    African Journals Online (AJOL)

    Background: HFE gene mutations have been shown to be responsible for hereditary hemochromatosis. Their effect on iron load in β-thalassemia patients and carriers remains controversial. Objectives: We aimed to determine the prevalence of HFE gene mutations (C282Y and H63D) in β-thalassemia patients and carriers ...

  2. Study of the effect of HFE gene mutations on iron overload in ...

    African Journals Online (AJOL)

    Manal Michel Wilson

    2015-03-04

    Mar 4, 2015 ... Abstract Background: HFE gene mutations have been shown to be responsible for hereditary hemochromatosis. Their effect on iron load in b-thalassemia patients and carriers remains contro- versial. Objectives: We aimed to determine the prevalence of HFE gene mutations (C282Y and H63D) in.

  3. HFE gene mutations and iron metabolism in Wilson's disease.

    Science.gov (United States)

    Erhardt, Andreas; Hoffmann, Arne; Hefter, Harald; Häussinger, Dieter

    2002-12-01

    There is increasing evidence for an interaction between iron and copper metabolism. Iron indices (ferritin, transferrin saturation [TS], serum iron), liver parameters, the prevalence and significance of C282Y and H63D HFE mutations were studied in 40 unrelated, Caucasian patients with Wilson's disease and 295 healthy controls. Due to specific treatment Wilson's disease was well controlled in all but one patient. The allele frequencies for the C282Y (11.3% vs. 6.2%) and the H63D (18.8% vs. 16.4%) mutation did not differ between patients with Wilson's disease and healthy controls. One patient with C282Y homozygous HH and Wilson's disease was identified showing progressive liver disease despite reasonable venesection and copper chelation therapy. No differences in iron indices and liver values were seen between HFE heterozygous and HFE wildtype patients with Wilson's disease. Higher serum ferritin levels were noticed in patients with Wilson's disease compared to healthy controls (149 +/- 26 microg/l vs. 87 +/- 8 microg/l; P Wilson's disease in order to detect iron overload. HFE mutations other than C282Y homozygosity seem to have no impact on iron indices and liver parameters as long as Wilson's disease is controlled.

  4. La mutacion H63D del gen HFE se asocia con un riesgo aumentado de carcinoma hepatocelular The H63D mutation of the HFE gene is related to the risk of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    P. Ropero

    2007-07-01

    HFE gene were identified in leucocyte genomic DNA using a polymerase chain reaction (PCR and specific restriction enzymes. Results (cases/controls: 1. Genotype distribution: a C282Y mutation: homozygotes 1/0, heterozygotes 12/23, wild type 183/158 (p = 0.07, non significant; b H63D mutation: homozygotes 9/5, heterozygotes 85/52, wild type 102/124 (0dds ratio 2.00, 95% C.I. 1.29-3.12, p = 0.002. Four cases and 6 controls were carriers of heterozygous mixed genotypes. 2. Allele frequencies: a C282Y mutation: wild type allele 378/339, mutated allele 14/23 (p = 0.11, non significant; b H63D mutation: wild type allele 289/300, mutated allele 103/62 (0dds ratio 1.72, 95% C.I. 1.19-2.50, p = 0.004. Age at diagnosis, gender and etiology of the underlying liver disease do not influence these findings. Conclusion: the C282Y mutation in the HFE gene is not related to the risk of HCC in non-hemochromatosis patients. The H63D mutation is associated with a higher risk of HCC in cirrhotic patients irrespective of their underlying liver disease.

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

    Directory of Open Access Journals (Sweden)

    Paulo Lisboa Bittencourt

    2009-01-01

    Full Text Available BACKGROUND: 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. AIMS: To evaluate the role of HFE, TfR2 and SCL40A1 mutations in Brazilian subjects with HH. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

  6. HFE gene mutations and iron status of Brazilian blood donors

    Directory of Open Access Journals (Sweden)

    P.C.J.L. Santos

    2010-01-01

    Full Text Available Mutations of the HFE and TFR2 genes have been associated with iron overload. HFE and TFR2 mutations were assessed in blood donors, and the relationship with iron status was evaluated. Subjects (N = 542 were recruited at the Hemocentro da Santa Casa de São Paulo, São Paulo, Brazil. Iron status was not influenced by HFE mutations in women and was independent of blood donation frequency. In contrast, men carrying the HFE 282CY genotype had lower total iron-binding capacity (TIBC than HFE 282CC genotype carriers. Men who donated blood for the first time and were carriers of the HFE 282CY genotype had higher transferrin saturation values and lower TIBC concentrations than those with the homozygous wild genotype for the HFE C282Y mutation. Moreover, in this group of blood donors, carriers of HFE 63DD plus 63HD genotypes had higher serum ferritin values than those with the homozygous wild genotype for HFE H63D mutation. Multiple linear regression analysis showed that HFE 282CY leads to a 17.21% increase (P = 0.018 and a 83.65% decrease (P = 0.007 in transferrin saturation and TIBC, respectively. In addition, serum ferritin is influenced by age (3.91%, P = 0.001 and the HFE 63HD plus DD genotype (55.84%, P = 0.021. In conclusion, the HFE 282Y and 65C alleles were rare, while the HFE 63D allele was frequent in Brazilian blood donors. The HFE C282Y and H63D mutations were associated with alterations in iron status in blood donors in a gender-dependent manner.

  7. Hemochromatosis (HFE gene mutations in Brazilian chronic hemodialysis patients

    Directory of Open Access Journals (Sweden)

    F.V. Perícole

    2005-09-01

    Full Text Available Patients with chronic renal insufficiency (CRI have reduced hemoglobin levels, mostly as a result of decreased kidney production of erythropoietin, but the relation between renal insufficiency and the magnitude of hemoglobin reduction has not been well defined. Hereditary hemochromatosis is an inherited disorder of iron metabolism. The importance of the association of hemochromatosis with treatment for anemia among patients with CRI has not been well described. We analyzed the frequency of the C282Y and H63D mutations in the HFE gene in 201 Brazilian individuals with CRI undergoing hemodialysis. The analysis of the effects of HFE mutations on iron metabolism and anemia with biochemical parameters was possible in 118 patients of this study (hemoglobin, hematocrit, ferritin levels, transferrin saturation, and serum iron. A C282Y heterozygous mutation was found in 7/201 (3.4% and H63D homozygous and heterozygous mutation were found in 2/201 (1.0% and 46/201 (22.9%, respectively. The allelic frequencies of the HFE mutations (0.017 for C282Y mutation and 0.124 for H63D mutation did not differ between patients with CRI and healthy controls. Regarding the biochemical parameters, no differences were observed between HFE heterozygous and mutation-negative patients, although ferritin levels were not higher among patients with the H63D mutation (P = 0.08. From what we observed in our study, C282Y/H63D HFE gene mutations are not related to degrees of anemia or iron stores in CRI patients receiving intravenous iron supplementation (P > 0.10. Nevertheless, the present data suggest that the H63D mutation may have an important function as a modulating factor of iron overload in these patients.

  8. high prevalence of the cys282tyr hfe mutation facilitates an improved ...

    African Journals Online (AJOL)

    screened for two common haemochromatosis (HFE) gene mutations. The local frequencies of mutations C282Y and. H63D were determined and the DNA results correlated with biochemical parameters. Setting. Patients were referred from private practitioners, health workers and pathologists for a molecular diagnosis of.

  9. The 16189 variant of mitochondrial DNA occurs more frequently in C282Y homozygotes with haemochromatosis than those without iron loading

    National Research Council Canada - National Science Library

    Livesey, K J; Wimhurst, V L C; Carter, K; Worwood, M; Cadet, E; Rochette, J; Roberts, A G; Pointon, J J; Merryweather-Clarke, A T; Bassett, M L; Jouanolle, A-M; Mosser, A; David, V; Poulton, J; Robson, K J H

    2004-01-01

    .... The mitochondrial 16189 variant is associated with diabetes, dilated cardiomyopathy, and low body fat at birth, and might contribute to genetic predisposition in further multifactorial disorders...

  10. Precipitating factors of porphyria cutanea tarda in Brazil with emphasis on hemochromatosis gene (HFE) mutations. Study of 60 patients

    OpenAIRE

    Vieira, Fatima Mendonça Jorge; Nakhle, Maria Cristina; ABRANTES-LEMOS, Clarice Pires; Cançado,Eduardo Luiz Rachid; Reis,Vitor Manoel Silva dos

    2013-01-01

    BACKGROUND: Porphyria cutanea tarda is the most common form of porphyria, characterized by the decreased activity of the uroporphyrinogen decarboxylase enzyme. Several reports associated HFE gene mutations of hereditary hemochromatosis with porphyria cutanea tarda worldwide, although up to date only one study has been conducted in Brazil. OBJECTIVES: Investigation of porphyria cutanea tarda association with C282Y and H63D mutations in the HFE gene. Identification of precipitating factors...

  11. Study of the HFE gene common polymorphisms in French patients with sporadic amyotrophic lateral sclerosis.

    Science.gov (United States)

    Praline, Julien; Blasco, Hélène; Vourc'h, Patrick; Rat, Valérian; Gendrot, Chantal; Camu, William; Andres, Christian R

    2012-06-15

    Our objective was to investigate whether the C282Y (p.Cys 282 Tyr) and H63D (p. His 63 Asp) HFE polymorphisms were associated with sporadic amyotrophic lateral sclerosis (SALS) in the French population. We searched for a relation of HFE polymorphisms with the clinical characteristics of the disease. The HFE polymorphisms were studied in 824 patients with SALS and 583 controls. We compared the frequency of the polymorphisms between SALS and controls groups by univariate and multivariate statistics, taking into account gender, site, age-at-onset and survival. We did not observe significant difference in the frequency of H63D polymorphism between SALS and control group. We observed a significant difference for C282Y between patients and controls with a low frequency of the Y allele in patients (3.2%) compared to our control group (5.9%). Disease duration, distribution of gender, site-of-onset, age-at-onset did not differ between groups taking into account genotypes of each polymorphism. Our results in this large cohort of ALS patients indicate that H63D polymorphism is not associated with SALS in the French population. This conclusion does not exclude a weak effect of the HFE gene polymorphisms in certain ALS populations, or an effect of other rare HFE gene variants. Copyright © 2012 Elsevier B.V. All rights reserved.

  12. HFE gene polymorphisms and the risk for autism in Egyptian children and impact on the effect of oxidative stress.

    Science.gov (United States)

    Gebril, Ola H; Meguid, Nagwa A

    2011-01-01

    Autism is among the commonest neurodevelopmental childhood disorders worldwide; its aetiology is still unknown. Iron metabolism alteration in the central nervous system is recently implicated as a risk factor for several neurodegenerative disorders. Haemochromatosis HFE gene polymorphisms (p.H63D and p.C282Y) have shown significant association with several neurological diseases. Some evidences show altered iron related proteins in serum of autistic children. The aim of this work is to conduct a preliminary pilot study for the association of HFE polymorphisms and autism. All cases were referred from the clinic of special needs, National Research Centre, Cairo. Clinical diagnosis was based on the criteria for autistic disorder as defined in the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision (DSM-IV-TR). Whole genome DNA was extracted; p.H63D and p.C282Y genotyping was studied using specific sequence amplification followed by restriction enzyme digestion on a sample of autism patients (25 cases) and twenty controls. The p.H63D is more abundant than the C282Y among both autism and control samples. No significant association of p.H63D nor p.C282Y polymorphism and autism was revealed. We here report on the first pilot study of the possible genetic association between autism and HFE gene polymorphisms among Egyptians. Although our results do not prove the role of HFE polymorphisms as risk factors for autism, yet this does not exclude the role of iron in this prevalent disorder. Further extended studies are recommended to include other iron metabolism genes.

  13. Influence of HFE variants and cellular iron on monocyte chemoattractant protein-1

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    Simmons Zachary

    2009-02-01

    Full Text Available Abstract Background Polymorphisms in the MHC class 1-like gene known as HFE have been proposed as genetic modifiers of neurodegenerative diseases that include neuroinflammation as part of the disease process. Variants of HFE are relatively common in the general population and are most commonly associated with iron overload, but can promote subclinical cellular iron loading even in the absence of clinically identified disease. The effects of the variants as well as the resulting cellular iron dyshomeostasis potentially impact a number of disease-associated pathways. We tested the hypothesis that the two most common HFE variants, H63D and C282Y, would affect cellular secretion of cytokines and trophic factors. Methods We screened a panel of cytokines and trophic factors using a multiplexed immunoassay in human neuroblastoma SH-SY5Y cells expressing different variants of HFE. The influence of cellular iron secretion on the potent chemokine monocyte chemoattractant protein-1 (MCP-1 was assessed using ferric ammonium citrate and the iron chelator, desferroxamine. Additionally, an antioxidant, Trolox, and an anti-inflammatory, minocycline, were tested for their effects on MCP-1 secretion in the presence of HFE variants. Results Expression of the HFE variants altered the labile iron pool in SH-SY5Y cells. Of the panel of cytokines and trophic factors analyzed, only the release of MCP-1 was affected by the HFE variants. We further examined the relationship between iron and MCP-1 and found MCP-1 secretion tightly associated with intracellular iron status. A potential direct effect of HFE is considered because, despite having similar levels of intracellular iron, the association between HFE genotype and MCP-1 expression was different for the H63D and C282Y HFE variants. Moreover, HFE genotype was a factor in the effect of minocycline, a multifaceted antibiotic used in treating a number of neurologic conditions associated with inflammation, on MCP-1

  14. АЛЛЕЛИ 282Y И H63D ГЕНА HFE И ПРЕДРАСПОЛОЖЕННОСТЬ К СИНДРОМУ ХРОНИЧЕСКОЙ ПЕРЕГРУЗКИ ЖЕЛЕЗОМ И НАРУШЕНИЮ ПОРФИРИНОВОГО ОБМЕНА ПРИ НЕАЛКОГОЛЬНОЙ ЖИРОВОЙ БОЛЕЗНИ ПЕЧЕНИ

    Directory of Open Access Journals (Sweden)

    А. Б. Кривошеев

    2012-01-01

    Full Text Available Testing for carriers of mutations C282Y and H63D HFE gene in 57 patients with nonalcoholic fatty liver disease was completed. Abnormalities in the metabolism of porphyrins were detected in 39 (68.4% patients, mutations C282Y and H63D were detected in 16 (28.1% patients, of whom 12 patients with metabolic disorders of porphyrins and symptoms of the syndrome of chronic iron overload. In 41 (71.9% patients without the mutations found disorders metabolism of porphyrins were in 27 (65.8% patients. They had no symptoms of the syndrome of chronic iron overload. Detection of C282Y and H63D mutations in the gene HFE in conjunction with disorders of porphyrin metabolism in association with the syndrome of chronic iron overload, but the probability will consider these patients as candidates for inclusion in the higher risk of formation of liver fibrosis.

  15. The effect of the hemochromatosis (HFE genotype on lead load and iron metabolism among lead smelter workers.

    Directory of Open Access Journals (Sweden)

    Guangqin Fan

    Full Text Available Both an excess of toxic lead (Pb and an essential iron disorder have been implicated in many diseases and public health problems. Iron metabolism genes, such as the hemochromatosis (HFE gene, have been reported to be modifiers for lead absorption and storage. However, the HFE gene studies among the Asian population with occupationally high lead exposure are lacking.To explore the modifying effects of the HFE genotype (wild-type, H63D variant and C282Y variant on the Pb load and iron metabolism among Asian Pb-workers with high occupational exposure.Seven hundred and seventy-one employees from a lead smelter manufacturing company were tested to determine their Pb intoxication parameters, iron metabolic indexes and identify the HFE genotype. Descriptive and multivariate analyses were conducted.Forty-five H63D variant carriers and no C282Y variant carrier were found among the 771 subjects. Compared with subjects with the wild-type genotype, H63D variant carriers had higher blood lead levels, even after controlling for factors such as age, sex, marriage, education, smoking and lead exposure levels. Multivariate analyses also showed that the H63D genotype modifies the associations between the blood lead levels and the body iron burden/transferrin.No C282Y variant was found in this Asian population. The H63D genotype modified the association between the lead and iron metabolism such that increased blood lead is associated with a higher body iron content or a lower transferrin in the H63D variant. It is indicated that H63D variant carriers may be a potentially highly vulnerable sub-population if they are exposed to high lead levels occupationally.

  16. Precipitating factors of porphyria cutanea tarda in Brazil with emphasis on hemochromatosis gene (HFE) mutations. Study of 60 patients.

    Science.gov (United States)

    Vieira, Fatima Mendonça Jorge; Nakhle, Maria Cristina; Abrantes-Lemos, Clarice Pires; Cançado, Eduardo Luiz Rachid; Reis, Vitor Manoel Silva dos

    2013-01-01

    Porphyria cutanea tarda is the most common form of porphyria, characterized by the decreased activity of the uroporphyrinogen decarboxylase enzyme. Several reports associated HFE gene mutations of hereditary hemochromatosis with porphyria cutanea tarda worldwide, although up to date only one study has been conducted in Brazil. Investigation of porphyria cutanea tarda association with C282Y and H63D mutations in the HFE gene. Identification of precipitating factors (hepatitis C, HIV, alcoholism and estrogen) and their link with HFE mutations. An ambispective study of 60 patients with PCT was conducted during the period from 2003 to 2012. Serological tests for hepatitis C and HIV were performed and histories of alcohol abuse and estrogen intake were investigated. HFE mutations were identified with real-time PCR. Porphyria cutanea tarda predominated in males and alcohol abuse was the main precipitating factor. Estrogen intake was the sole precipitating factor present in 25% of female patients. Hepatitis C was present in 41.7%. All HIV-positive patients (15.3%) had a history of alcohol abuse. Allele frequency for HFE mutations, i.e., C282Y (p = 0.0001) and H63D (p = 0.0004), were significantly higher in porphyria cutanea tarda patients, compared to control group. HFE mutations had no association with the other precipitating factors. Alcohol abuse, hepatitis C and estrogen intake are prevalent precipitating factors in our porphyria cutanea tarda population; however, hemochromatosis in itself can also contribute to the outbreak of porphyria cutanea tarda, which makes the research for HFE mutations necessary in these patients.

  17. The role of tmprss6 and hfe variants in iron deficiency anemia in celiac disease.

    Science.gov (United States)

    De Falco, Luigia; Tortora, Raffaella; Imperatore, Nicola; Bruno, Mariasole; Capasso, Mario; Girelli, Domenico; Castagna, Annalisa; Caporaso, Nicola; Iolascon, Achille; Rispo, Antonio

    2017-12-01

    We investigated the role of HFE C282Y, H63D and TMPRSS6 A736V variants in the pathogenesis of iron deficiency anemia (IDA) in celiac disease (CD) patients, at diagnosis and after 1-year of gluten free diet (GFD). Demographic and clinical features were prospectively recorded for all CD patients between 2013 and 2017. C282Y, H63D and A736V variants were evaluated for CD patients and controls. Finally, 505 consecutive CD patients and 539 age-matched control subjects were enrolled. At diagnosis, 229 CD subjects had IDA (45.3%), with a subgroup of anemic patients (45.4%) presented persistent IDA at follow-up. C282Y allele frequency was significantly increased in CD compared with controls (1.1% vs 0.2%, P=0.001), whereas H63D and A736V allele frequencies were similar among patients and controls (P=0.92 and 0.84, respectively). At diagnosis, C282Y variant in anemic CD patients was significantly increased compared to non-anemic group (2% and 0.5%, P=0.04). At follow-up, A736V was significantly increased in IDA persistent than in IDA not persistent (57.7% vs 35.2%, P<0.0001). CD patients with H63D mutation showed higher Hb, MCV, serum iron and ferritin levels than subjects without HFE mutations. Decreased hepcidin values were observed in anemic compared to non-anemic subjects at follow-up (1.22±1.14 vs 2.08±2.15, P<0.001). This study suggests a protective role of HFE in IDA CD patients and confirms the role of TMPRSS6 in predicting oral iron response modulating hepcidin action on iron absorption. Iron supplementation therapeutic management in CD could depend on TMPRSS6 genotype that could predict persistent IDA despite iron supplementation and GFD. This article is protected by copyright. All rights reserved. © 2017 Wiley Periodicals, Inc.

  18. HFE H63D polymorphism as a modifier of the effect of cumulative lead exposure on pulse pressure: the Normative Aging Study.

    Science.gov (United States)

    Zhang, Aimin; Park, Sung Kyun; Wright, Robert O; Weisskopf, Marc G; Mukherjee, Bhramar; Nie, Huiling; Sparrow, David; Hu, Howard

    2010-09-01

    Cumulative lead exposure is associated with a widened pulse pressure (PP; the -difference between systolic and diastolic blood pressure), a marker of arterial stiffness and a predictor of cardiovascular disease. Polymorphisms in the hemochromatosis gene (HFE) have been shown to modify the impact of cumulative lead exposure on measures of adult cognition and cardiac function. We examined whether the HFE mutations modify the impact of lead on PP in -community-dwelling older men. We examined 619 participants with a total of 1,148 observations of PP from a substudy of bone lead levels (a measure of cumulative exposure, measured by in vivo K-shell X-ray fluorescence) and health in the Normative Aging Study between 1991 and 2001. Linear mixed-effects regression models with random intercepts were constructed. Of the 619 subjects, 138 and 72 carried the HFE H63D and C282Y variants, respectively. After adjusting for age; education; alcohol intake; smoking; daily intakes of calcium, sodium, and potassium; total calories; family history of hypertension; diabetes; height; heart rate; high-density lipoprotein (HDL); total cholesterol:HDL ratio; and waist circumference, baseline bone lead levels were associated with steeper increases in PP in men with at least one H63D allele (p-interaction = 0.03 for tibia and 0.02 for patella) compared with men with only the wild types or C282Y variant. The HFE H63D polymorphism, but not the C282Y mutation, appears to enhance susceptibility to the deleterious impact of cumulative lead on PP, possibly via prooxidative or pro-inflammatory mechanisms.

  19. Preliminary investigation of bottlenose dolphins (Tursiops truncatus) for hfe gene-related hemochromatosis.

    Science.gov (United States)

    Phillips, Brianne E; Venn-Watson, Stephanie; Archer, Linda L; Nollens, Hendrik H; Wellehan, James F X

    2014-10-01

    Hemochromatosis (iron storage disease) has been reported in diverse mammals including bottlenose dolphins (Tursiops truncatus). The primary cause of excessive iron storage in humans is hereditary hemochromatosis. Most human hereditary hemochromatosis cases (up to 90%) are caused by a point mutation in the hfe gene, resulting in a C282Y substitution leading to iron accumulation. To evaluate the possibility of a hereditary hemochromatosis-like genetic predisposition in dolphins, we sequenced the bottlenose dolphin hfe gene, using reverse transcriptase-PCR and hfe primers designed from the dolphin genome, from liver of affected and healthy control dolphins. Sample size included two case animals and five control animals. Although isotype diversity was evident, no coding differences were identified in the hfe gene between any of the animals examined. Because our sample size was small, we cannot exclude the possibility that hemochromatosis in dolphins is due to a coding mutation in the hfe gene. Other potential causes of hemochromatosis, including mutations in different genes, diet, primary liver disease, and insulin resistance, should be evaluated.

  20. Mutations in HFE causing hemochromatosis are associated with primary hypertriglyceridemia.

    Science.gov (United States)

    Solanas-Barca, María; Mateo-Gallego, Rocío; Calmarza, Pilar; Jarauta, Estíbaliz; Bea, Ana M; Cenarro, Ana; Civeira, Fernando

    2009-11-01

    Most cases of primary hypertriglyceridemia (HTG) are caused by the interaction of unknown polygenes and environmental factors. Elevated iron storage is associated with metabolic syndrome, diabetes, and obesity, and all of them are associated with HTG. The aim of the study was to analyze whether HFE mutations causing hereditary hemochromatosis (HH) are associated with primary HTG. Genetic predisposition to HH was analyzed in a case-control study. The study was conducted at University Hospital Lipid Clinic. We studied two groups: 1) the HTG group, composed of 208 patients; and 2) the control group, composed of 215 normolipemic subjects and 161 familial hypercholesterolemia patients. Two HFE mutations (C282Y and H63D) were analyzed. We measured HH genetic predisposition difference between groups. HH genetic predisposition was 5.9 and 4.4 times higher in the HTG group than in the normolipemic (P = 0.02) and FH (P = 0.05) subjects, respectively. There were 35 cases (16.8%) of iron overload in the primary HTG group, 14 (6.5%) and nine (5.6%) in the normolipidemic and FH groups, respectively. A higher HH genetic predisposition and a different prevalence of iron overload in subjects with HH genetic predisposition among groups contributed to this higher prevalence. None of the four cases with the HFE genotype associated with high risk of HH in the control groups presented iron overload; however, in eight of 11 subjects (72.7%) with primary HTG and HH genetic predisposition, the iron overload was present. Mutations in HFE gene, favoring iron overload and causing HH, could play an important role in the development of several phenotypes of primary HTG.

  1. Severity of iron overload of proband determines serum ferritin levels in families with HFE-related hemochromatosis: the HEmochromatosis FAmily Study.

    Science.gov (United States)

    Jacobs, Esther M G; Hendriks, Jan C M; van Deursen, Cees Th B M; Kreeftenberg, Herman G; de Vries, Richard A; Marx, Joannes J M; Stalenhoef, Anton F H; Verbeek, André L M; Swinkels, Dorine W

    2009-01-01

    In families of patients with clinically detected hereditary hemochromatosis (HH) early screening has been suggested to prevent morbidity and mortality. Here, we aim to identify determinants for iron overload in first-degree family members of C282Y homozygous probands with clinically detected HH. Data on HFE-genotype, iron parameters, demographics, lifestyle factors and health, were collected from 224 Dutch C282Y homozygous patients with clinically diagnosed HH and 735 of their first-degree family members (FDFM), all participating in the HEmochromatosis FAmily Study (HEFAS). The best predictive multivariable model forecasted 45% of variation of the serum ferritin levels. In this model severity of iron overload in the proband significantly predicted serum ferritin levels in FDFM. Other significant determinants in this model consisted of C282Y homozygosity, compound heterozygosity, age at testing for serum ferritin and supplemental iron intake, whereas a low body mass index showed a protective effect. This study provides a model to assess the risk of development of iron overload for relatives of probands with HH. These results might be instrumental in the development of an optimal strategy for future family screening programs.

  2. Lack of evidence for the pathogenic role of iron and HFE gene mutations in Brazilian patients with nonalcoholic steatohepatitis

    Directory of Open Access Journals (Sweden)

    M.M. Deguti

    2003-06-01

    Full Text Available The hypothesis of the role of iron overload associated with HFE gene mutations in the pathogenesis of nonalcoholic steatohepatitis (NASH has been raised in recent years. In the present study, biochemical and histopathological evidence of iron overload and HFE mutations was investigated in NASH patients. Thirty-two NASH patients, 19 females (59%, average 49.2 years, 72% Caucasians, 12% Mulattoes and 12% Asians, were submitted to serum aminotransferase and iron profile determinations. Liver biopsies were analyzed for necroinflammatory activity, architectural damage and iron deposition. In 31 of the patients, C282Y and H63D mutations were tested by PCR-RFLP. Alanine aminotransferase levels were increased in 30 patients, 2.42 ± 1.12 times the upper normal limit on average. Serum iron concentration, transferrin saturation and ferritin averages were 99.4 ± 31.3 g/dl, 33.1 ± 12.7% and 219.8 ± 163.8 µg/dl, respectively, corresponding to normal values in 93.5, 68.7 and 78.1% of the patients. Hepatic siderosis was observed in three patients and was not associated with architectural damage (P = 0.53 or with necroinflammatory activity (P = 0.27. The allelic frequencies (N = 31 found were 1.6 and 14.1% for C282Y and H63D, respectively, which were compatible with those described for the local population. In conclusion, no evidence of an association of hepatic iron overload and HFE mutations with NASH was found. Brazilian NASH patients comprise a heterogeneous group with many associated conditions such as hyperinsulinism, environmental hepatotoxin exposure and drugs, but not hepatic iron overload, and their disease susceptibility could be related to genetic and environmental features other than HFE mutations.

  3. Best practice guidelines for the molecular genetic diagnosis of Type 1 (HFE-related hereditary haemochromatosis

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    Barton David E

    2006-11-01

    Full Text Available Abstract Background Hereditary haemochromatosis (HH is a recessively-inherited disorder of iron over-absorption prevalent in Caucasian populations. Affected individuals for Type 1 HH are usually either homozygous for a cysteine to tyrosine amino acid substitution at position 282 (C282Y of the HFE gene, or compound heterozygotes for C282Y and for a histidine to aspartic acid change at position 63 (H63D. Molecular genetic testing for these two mutations has become widespread in recent years. With diverse testing methods and reporting practices in use, there was a clear need for agreed guidelines for haemochromatosis genetic testing. The UK Clinical Molecular Genetics Society has elaborated a consensus process for the development of disease-specific best practice guidelines for genetic testing. Methods A survey of current practice in the molecular diagnosis of haemochromatosis was conducted. Based on the results of this survey, draft guidelines were prepared using the template developed by UK Clinical Molecular Genetics Society. A workshop was held to develop the draft into a consensus document. The consensus document was then posted on the Clinical Molecular Genetics Society website for broader consultation and amendment. Results Consensus or near-consensus was achieved on all points in the draft guidelines. The consensus and consultation processes worked well, and outstanding issues were documented in an appendix to the guidelines. Conclusion An agreed set of best practice guidelines were developed for diagnostic, predictive and carrier testing for hereditary haemochromatosis and for reporting the results of such testing.

  4. Analysis of HFE and TFR2 gene mutations in patients with acute leukemia.

    Science.gov (United States)

    Veneri, Dino; Franchini, Massimo; Krampera, Mauro; de Matteis, Giovanna; Solero, Pietro; Pizzolo, Giovanni

    2005-06-01

    There are increasing evidences regarding the association between iron overload and extra-hepatic malignancies. We studied the prevalence of 12 hereditary hemochromatosis (HH) gene mutations (C282Y, V53M, V59M, H63D, H63H, S56C, Q127H, E168Q, E168X, W169X and Q283P in the HFE gene and Y250X in the TFR2 gene) and its correlation with the iron status in 82 adult patients with acute leukemia (AL); 48 patients (58.5%) were affected by acute myeloid leukemia (AML) and 34 patients (41.5%) by acute lymphoblastic leukemia (ALL); 27 patients (32.9%) had at least one HH gene mutation (6 heterozygous for C282Y, 6 homozygous for H63D, 13 heterozygous for H63D and 2 heterozygous for S56C). Mean serum ferritin levels at diagnosis were increased (822.5+/-811.4 microg/L). However, there was no difference between patients positive or negative for the HH gene mutations. Similarly, we did not observe any statistically significant difference as far as iron status between AML and ALL patients. Our study does not support the evidence of an association between hemochromatosis gene mutations and iron overload in AL patients.

  5. Porfiria cutánea tarda: asociación con mutaciones HFE, hepatitis virales, alcohol y otros factores de riesgo en Guipúzcoa, País Vasco Porphyria cutanea tarda: An analysis of HFE gene mutations, hepatitis viruses, alcohol intake, and other risk factors in 54 patients from Guipúzcoa, Basque Country, Spain

    OpenAIRE

    A. Castiella; Zapata, E.; M. D. de Juan; F. Múgica; Barrio, J.; P. Otazua; J. A. Arriola; A. Cosme; E. Elosegui; Fernández, J.; L. Zubiaurre; L. F. Alzate; Utrilla, E.

    2008-01-01

    Objetivo: estudiar la frecuencia de las mutaciones en el gen HFE (C282Y, H63D, S65C) en un grupo de 54 pacientes con porfiria cutánea tarda (PCT) y en un grupo de controles sanos (donantes de sangre) en Guipúzcoa. También analizar su relación con los virus de la hepatitis B y C (VHB, VHC), alcohol y otros factores de riesgo reconocidos. Métodos: el análisis de las mutaciones se hizo mediante PCR. Se compararon las frecuencias alélicas y genotípicas. Se determinaron la probabilidad y el test d...

  6. Non-HFE hemochromatosis

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    Paulo Caleb Júnior de Lima Santos

    2012-01-01

    Full Text Available Hereditary hemochromatosis (HH is an autosomal recessive disorder classically related to HFE mutations. However, since 1996, it is known that HFE mutations explain about 80% of HH cases, with the remaining around 20% denominated non-HFE hemochromatosis. Nowadays, four main genes are implicated in the pathophysiology of clinical syndromes classified as non-HFE hemochromatosis: hemojuvelin (HJV, type 2Ajuvenile HH, hepcidin (HAMP, type 2B juvenile HH, transferrin receptor 2 (TFR2, type 3 HH and ferroportin (SLC40A1, type 4 HH. The aim of this review is to explore molecular, clinical and management aspects of non-HFE hemochromatosis.

  7. Natural selection on HFE in Asian populations contributes to enhanced non-heme iron absorption.

    Science.gov (United States)

    Ye, Kaixiong; Cao, Chang; Lin, Xu; O'Brien, Kimberly O; Gu, Zhenglong

    2015-06-10

    HFE, a major regulator of iron (Fe) homeostasis, has been suggested to be under positive selection in both European and Asian populations. While the genetic variant under selection in Europeans (a non-synonymous mutation, C282Y) has been relatively well-studied, the adaptive variant in Asians and its functional consequences are still unknown. Identifying the adaptive HFE variants in Asians will not only elucidate the evolutionary history and the genetic basis of population difference in Fe status, but also assist the future practice of genome-informed dietary recommendation. Using data from the International HapMap Project, we confirmed the signatures of positive selection on HFE in Asian populations and identified a candidate adaptive haplotype that is common in Asians (52.35-54.71%) but rare in Europeans (5.98%) and Africans (4.35%). The T allele at tag SNP rs9366637 (C/T) captured 95.8% of this Asian-common haplotype. A significantly reduced HFE expression was observed in individuals carrying T/T at rs9366637 compared to C/C and C/T, indicating a possible role of gene regulation in adaptation. We recruited 57 women of Asian descent and measured Fe absorption using stable isotopes in those homozygous at rs9366637. We observed a 22% higher absorption in women homozygous for the Asian-common haplotype (T/T) compared to the control genotype (C/C). Additionally, compared with a group of age-matched Caucasian women, Asian women exhibited significantly elevated Fe absorption. Our results indicate parallel adaptation of HFE gene in Europeans and Asians with different genetic variants. Moreover, natural selection on HFE may have contributed to elevated Fe absorption in Asians. This study regarding population differences in Fe homeostasis has significant medical impact as high Fe level has been linked to an increased disease risk of metabolic syndromes.

  8. The mitochondrial nt 16189 polymorphism and hereditary hemochromatosis.

    Science.gov (United States)

    Beutler, Ernest; Beutler, Lisa; Lee, Pauline L; Barton, James C

    2004-01-01

    It has been claimed that a noncoding mitochondrial polymorphism at nt 16189 is correlated with the penetrance of the homozygous state for the C282Y mutation of the HFE gene. We have genotyped homozygotes for the C282Y mutation and find no relationship between the ferritin levels and the inheritance of the mitochondrial polymorphism. Indeed, the small difference found is in the opposite direction of that reported previously.

  9. HFE MUTATIONS AND IRON OVERLOAD IN PATIENTS WITH ALCOHOLIC LIVER DISEASE

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    Luis COSTA-MATOS

    2013-03-01

    Full Text Available Context Alcoholic liver disease (ALD is generally associated with iron overload, which may contribute to its pathogenesis, through increased oxidative stress and cellular damage. There are conflicting reports in literature about hemochromatosis (HFE gene mutations and the severity of liver disease in alcoholic patients. Objectives To compare the prevalence of mutations in the hemochromatosis (HFE gene between patients with ALD and healthy controls; to assess the relation of HFE mutations with liver iron stores and liver disease severity. Methods Liver biopsy specimens were obtained from 63 ALD patients (during routine treatment and 52 healthy controls (during elective cholecystectomy. All individuals underwent routine liver function tests and HFE genotyping (to detect wild-type sequences and C282Y, H63D, S65C, E168Q, E168X, V59M, H63H, P160delC, Q127H, Q283P, V53M and W164X mutations. Associations between HFE mutations and risk of excessive liver iron stores, abnormal serum ferritin, liver fibrosis, or necroinflammatory activity were assessed by multivariate logistic regression analysis. Results ALD patients had significantly higher serum ferritin and transferrin saturation than controls (both P<0.05, but the distribution of HFE mutations was similar between the two groups. For ALD patients, the odds ratio for having at least one HFE mutation and excessive liver iron stores was 17.23 (95% confidence interval (CI: 2.09-142.34, P = 0.008. However, the presence of at least one HFE mutation was not associated with an increased risk of liver fibrosis or necroinflammatory activity. Active alcohol ingestion showed the strongest association to increased serum ferritin (OR = 8.87, 95% CI: 2.11-34.78, P = 0.003. Conclusions ALD patients do not present with a differential profile of HFE mutations from healthy controls. In ALD patients, however, the presence of at least one HFE mutation increases the risk of having excessive liver iron stores but has no

  10. Mutations in the HFE, TFR2, and SLC40A1 genes in patients with hemochromatosis.

    Science.gov (United States)

    Del-Castillo-Rueda, Alejandro; Moreno-Carralero, María-Isabel; Cuadrado-Grande, Nuria; Alvarez-Sala-Walther, Luis-Antonio; Enríquez-de-Salamanca, Rafael; Méndez, Manuel; Morán-Jiménez, María-Josefa

    2012-10-15

    Hereditary hemochromatosis causes iron overload and is associated with a variety of genetic and phenotypic conditions. Early diagnosis is important so that effective treatment can be administered and the risk of tissue damage avoided. Most patients are homozygous for the c.845G>A (p.C282Y) mutation in the HFE gene; however, rare forms of genetic iron overload must be diagnosed using a specific genetic analysis. We studied the genotype of 5 patients who had hyperferritinemia and an iron overload phenotype, but not classic mutations in the HFE gene. Two patients were undergoing phlebotomy and had no iron overload, 1 with metabolic syndrome and no phlebotomy had mild iron overload, and 2 patients had severe iron overload despite phlebotomy. The patients' first-degree relatives also underwent the analysis. We found 5 not previously published mutations: c.-408_-406delCAA in HFE, c.1118G>A (p.G373D), c.1473G>A (p.E491E) and c.2085G>C (p.S695S) in TFR2; and c.-428_-427GG>TT in SLC40A1. Moreover, we found 3 previously published mutations: c.221C>T (p.R71X) in HFE; c.1127C>A (p.A376D) in TFR2; and c.539T>C (p.I180T) in SLC40A1. Four patients were double heterozygous or compound heterozygous for the mutations mentioned above, and the patient with metabolic syndrome was heterozygous for a mutation in the TFR2 gene. Our findings show that hereditary hemochromatosis is clinically and genetically heterogeneous and that acquired factors may modify or determine the phenotype. Copyright © 2012. Published by Elsevier B.V.

  11. Four variants in transferrin and HFE genes as potential markers of iron deficiency anaemia risk: an association study in menstruating women

    Directory of Open Access Journals (Sweden)

    Arroyo-Pardo Eduardo

    2011-10-01

    Full Text Available Abstract Background Iron deficiency anaemia is a worldwide health problem in which environmental, physiologic and genetic factors play important roles. The associations between iron status biomarkers and single nucleotide polymorphisms (SNPs known to be related to iron metabolism were studied in menstruating women. Methods A group of 270 Caucasian menstruating women, a population group at risk of iron deficiency anaemia, participated in the study. Haematological and biochemical parameters were analysed and 10 selected SNPs were genotyped by minisequencing assay. The associations between genetic and biochemical data were analysed by Bayesian Model Averaging (BMA test and decision trees. Dietary intake of a representative subgroup of these volunteers (n = 141 was assessed, and the relationship between nutrients and iron biomarkers was also determined by linear regression. Results Four variants, two in the transferrin gene (rs3811647, rs1799852 and two in the HFE gene (C282Y, H63D, explain 35% of the genetic variation or heritability of serum transferrin in menstruating women. The minor allele of rs3811647 was associated with higher serum transferrin levels and lower transferrin saturation, while the minor alleles of rs1799852 and the C282Y and H63D mutations of HFE were associated with lower serum transferrin levels. No association between nutrient intake and iron biomarkers was found. Conclusions In contrast to dietary intake, these four SNPs are strongly associated with serum transferrin. Carriers of the minor allele of rs3811647 present a reduction in iron transport to tissues, which might indicate higher iron deficiency anaemia risk, although the simultaneous presence of the minor allele of rs1799852 and HFE mutations appear to have compensatory effects. Therefore, it is suggested that these genetic variants might potentially be used as markers of iron deficiency anaemia risk.

  12. Porfiria cutánea tarda: asociación con mutaciones HFE, hepatitis virales, alcohol y otros factores de riesgo en Guipúzcoa, País Vasco Porphyria cutanea tarda: An analysis of HFE gene mutations, hepatitis viruses, alcohol intake, and other risk factors in 54 patients from Guipúzcoa, Basque Country, Spain

    Directory of Open Access Journals (Sweden)

    A. Castiella

    2008-12-01

    Full Text Available Objetivo: estudiar la frecuencia de las mutaciones en el gen HFE (C282Y, H63D, S65C en un grupo de 54 pacientes con porfiria cutánea tarda (PCT y en un grupo de controles sanos (donantes de sangre en Guipúzcoa. También analizar su relación con los virus de la hepatitis B y C (VHB, VHC, alcohol y otros factores de riesgo reconocidos. Métodos: el análisis de las mutaciones se hizo mediante PCR. Se compararon las frecuencias alélicas y genotípicas. Se determinaron la probabilidad y el test de Chi cuadrado. Resultados: no encontramos asociación entre C282Y y PCT (5,76 vs. 5% controles. Se observó una alta frecuencia alélica en la mutación H63D en PCT (34,25%, pero sin ser estadísticamente significativa (controles 29,31%, debido a la alta prevalencia de esta mutación en la población vasca. La mutación S65C fue menor en PCT que en controles. Encontramos una idéntica presencia de H63D en heterocigosis en ambos grupos (38,8 vs. 38,8%. La asociación con el VHC se objetivó en el 35,18% de los pacientes y la infección por VHB en el 7,4%. Un 55,55% de los pacientes tenía un hábito alcohólico de más de 60 g etanol día. Todos eran negativos para el virus de la inmunodeficiencia humana (VIH y 1 de las 5 mujeres con PCT tomaba estrógenos. Conclusión: las mutaciones C282Y y H63D no tienen un papel relevante en los pacientes con PCT en Guipúzcoa. Los factores externos (consumo importante de alcohol y VHC parecen jugar un papel fundamental en el desarrollo de la PCT en nuestra población.Aim: to study the frequency of HFE gene mutations (C282Y, H63D, S65C in a group of 54 sporadic PCT patients and in a group of healthy controls (blood donors from Guipúzcoa, Spain. We studied the association of PCT with HCV, HBV, alcohol abuse, and other established risk factors. Methods: the analysis of mutations was made by PCR. Allelic and genotypic frequencies were compared. Probability was determined and a Chi-squared test was performed. Results

  13. Molecular basis of HFE-hemochromatosis

    Directory of Open Access Journals (Sweden)

    Maja eVujic Spasic

    2014-03-01

    Full Text Available Iron-overload disorders owing to genetic misregulation of iron acquisition are referred to as hereditary hemochromatosis (HH. The most prevalent genetic iron overload disorder in Caucasians is caused by mutations in the HFE gene, an atypical MHC class I molecule. Recent studies classified HFE/Hfe-hemochromatosis as a liver disease with the primarily failure in the production of the liver iron hormone hepcidin in hepatocytes. Inadequate hepcidin expression signals for excessive iron absorption from the diet and iron deposition in tissues causing multiple organ damage and failure. This review focuses on the molecular actions of the HFE/Hfe and hepcidin in maintaining systemic iron homeostasis and approaches undertaken so far to combat iron overload in HFE/Hfe-HH. In the light of the recent investigations, novel roles of extra-hepatocytic Hfe are discussed raising a question to the relevance of the multipurpose functions of Hfe for the understanding of HH associated pathologies.

  14. EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH).

    Science.gov (United States)

    Porto, Graça; Brissot, Pierre; Swinkels, Dorine W; Zoller, Heinz; Kamarainen, Outi; Patton, Simon; Alonso, Isabel; Morris, Michael; Keeney, Steve

    2016-04-01

    Molecular genetic testing for hereditary hemochromatosis (HH) is recognized as a reference test to confirm the diagnosis of suspected HH or to predict its risk. The vast majority (typically >90%) of patients with clinically characterized HH are homozygous for the p.C282Y variant in the HFE gene, referred to as HFE-related HH. Since 1996, HFE genotyping was implemented in diagnostic algorithms for suspected HH, allowing its early diagnosis and prevention. However, the penetrance of disease in p.C282Y homozygotes is incomplete. Hence, homozygosity for p.C282Y is not sufficient to diagnose HH. Neither is p.C282Y homozygosity required for diagnosis as other rare forms of HH exist, generally referred to as non-HFE-related HH. These pose significant challenges when defining criteria for referral, testing protocols, interpretation of test results and reporting practices. We present best practice guidelines for the molecular genetic diagnosis of HH where recommendations are classified, as far as possible, according to the level and strength of evidence. For clarification, the guidelines' recommendations are preceded by a detailed description of the methodology and results obtained with a series of actions taken in order to achieve a wide expert consensus, namely: (i) a survey on the current practices followed by laboratories offering molecular diagnosis of HH; (ii) a systematic literature search focused on some identified controversial topics; (iii) an expert Best Practice Workshop convened to achieve consensus on the practical recommendations included in the guidelines.

  15. EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH)

    Science.gov (United States)

    Porto, Graça; Brissot, Pierre; Swinkels, Dorine W; Zoller, Heinz; Kamarainen, Outi; Patton, Simon; Alonso, Isabel; Morris, Michael; Keeney, Steve

    2016-01-01

    Molecular genetic testing for hereditary hemochromatosis (HH) is recognized as a reference test to confirm the diagnosis of suspected HH or to predict its risk. The vast majority (typically >90%) of patients with clinically characterized HH are homozygous for the p.C282Y variant in the HFE gene, referred to as HFE-related HH. Since 1996, HFE genotyping was implemented in diagnostic algorithms for suspected HH, allowing its early diagnosis and prevention. However, the penetrance of disease in p.C282Y homozygotes is incomplete. Hence, homozygosity for p.C282Y is not sufficient to diagnose HH. Neither is p.C282Y homozygosity required for diagnosis as other rare forms of HH exist, generally referred to as non-HFE-related HH. These pose significant challenges when defining criteria for referral, testing protocols, interpretation of test results and reporting practices. We present best practice guidelines for the molecular genetic diagnosis of HH where recommendations are classified, as far as possible, according to the level and strength of evidence. For clarification, the guidelines' recommendations are preceded by a detailed description of the methodology and results obtained with a series of actions taken in order to achieve a wide expert consensus, namely: (i) a survey on the current practices followed by laboratories offering molecular diagnosis of HH; (ii) a systematic literature search focused on some identified controversial topics; (iii) an expert Best Practice Workshop convened to achieve consensus on the practical recommendations included in the guidelines. PMID:26153218

  16. Dietary advice in HFE-hemochromatosis

    NARCIS (Netherlands)

    Doorn, van G.M.; Gosselink, I.M.G.

    2012-01-01

    This report aims to provide dietary advice which is based on what is known so far about the effect of a diet, particularly on iron overload in HFE-hemochromatosis. The reason that the recommendations in principle apply only to the group of individuals with HFE-gene mutations and are focused on the

  17. HFE and Spherical Cryostats MC Study

    Energy Technology Data Exchange (ETDEWEB)

    Brodsky, Jason P. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2016-09-26

    The copper vessel containing the nEXO TPC is surrounded by a buffer of HFE, a liquid refrigerant with very low levels of radioactive element contamination. The HFE is contained within the cryostat’s inner vessel, which is in turn inside the outer vessel. While some HFE may be necessary for stable cooling of nEXO, it is possible that using substantially more than necessary for thermal reasons will help reduce backgrounds originating in the cryostats. Using a larger amount of HFE is accomplished by making the cryostat vessels larger. By itself, increasing the cryostat size somewhat increases the background rate, as the thickness of the cryostat wall must increase at larger sizes. However, the additional space inside the cryostat will be filled with HFE which can absorb gamma rays headed for the TPC. As a result, increasing the HFE reduces the number of backgrounds reaching the TPC. The aim of this study was to determine the relationship between HFE thickness and background rate. Ultimately, this work should support choosing a cryostat and HFE size that satisfies nEXO’s background budget. I have attempted to account for every consequence of changing the cryostat size, although naturally this remains a work in progress until a final design is achieved. At the moment, the scope of the study includes only the spherical cryostat design. This study concludes that increasing cryostat size reduces backgrounds, reaching neglible backgrounds originating from the cryostat at the largest sizes. It also shows that backgrounds originating from the inherent radioactivity of the HFE plateau quickly, so may be considered essentially fixed at any quantity of HFE.

  18. HFE modulates transferrin receptor 2 levels in hepatoma cells via interactions that differ from transferrin receptor 1-HFE interactions.

    Science.gov (United States)

    Chen, Juxing; Chloupková, Maja; Gao, Junwei; Chapman-Arvedson, Tara L; Enns, Caroline A

    2007-12-21

    Mutations in the transmembrane glycoproteins transferrin receptor 2 (TfR2) and HFE are associated with hereditary hemochromatosis. Interactions between HFE and transferrin receptor 1 (TfR1) have been mapped to the alpha1- and alpha2-helices in HFE and to the helical domain of TfR1. Recently, TfR2 was also reported to interact with HFE in transfected mammalian cells. To test whether similar HFE residues are important for both TfR1 and TfR2 binding, a mutant form of HFE (W81AHFE) that has an approximately 5,000-fold lower affinity for TfR1 than HFE was employed. As expected, W81AHFE does not interact with TfR1. However, we found that the same mutation in HFE does not affect the TfR2/HFE interaction. This finding indicates that the TfR2/HFE and TfR1/HFE interactions are distinct. We further observed that, unlike TfR1/HFE, Tf does not compete with HFE for binding to TfR2 and that binding is independent of pH (pH 6-7.5). TfR2-TfR1 and HFE-HLA-B7 chimeras were generated to map the domains of the TfR2/HFE interaction. TfR1 and HLA-B7 were chosen because of their similar overall structures with TfR2 and HFE, respectively. We mapped the interacting domains to the putative stalk and protease-like domains of TfR2 located between residues 104 and 250 and to the alpha3 domain of HFE, both of which differ from the TfR1/HFE interacting domains. Furthermore, we found that HFE increases TfR2 levels in hepatic cells independent of holo-Tf.

  19. Haplotype analysis of the HFE gene among populations of Northern Eurasia, in patients with metabolic disorders or stomach cancer, and in long-lived people.

    Science.gov (United States)

    Mikhailova, S V; Babenko, V N; Ivanoshchuk, D E; Gubina, M A; Maksimov, V N; Solovjova, I G; Voevoda, M I

    2016-06-17

    Previously, it was shown that the HFE gene (associated with human hereditary hemochromatosis) has several haplotypes of intronic polymorphisms. Some haplotype frequencies are race specific and hence can be used in phylogenetic analysis. We assumed that analysis of Caucasoid patients-living now in Western Siberia and having diseases associated with dietary habits and metabolic rate-will allow us to understand the processes of possible selection during settling of the northern part of Asia. Haplotype analysis of Northern Eurasian native and recently settled ethnic groups was performed on polymorphisms rs1799945, rs1800730, rs1800562, rs2071303, rs1800708, rs1572982, rs2794719, rs807209, and rs2032451 of this gene. The CCA haplotype of the rs2071303, rs1800708, and rs1572982 was found to be associated with HLA-A2 (39 %) in Asian populations. Haplotype analysis for the rs1799945, rs1800730, rs1800562, rs2071303, rs1800708, and rs1572982 was performed on Russian patients with some metabolic disorders or stomach cancer and among long-lived people. Decreased frequencies of the TTA haplotype (T in rs2071303, T in rs1800708, and A in rs1572982) were observed in the groups of patients with diseases associated with overweight (fatty liver disease, type 2 diabetes mellitus, or metabolic syndrome + arterial hypertension) as compared with the control sample. We detected significant differences in this haplotype's frequency between the patients with type 2 diabetes mellitus and Russian adolescents, elderly citizens, and long-lived people (χ(2) P value = 0.003, 0.010, and 0.015, respectively). No significant differences in frequencies of the alleles with mutations in coding regions of the HFE gene (C282Y, H63D, and S65C) were detected between the analyzed patients (with stomach cancer, metabolic syndrome, fatty liver disease, or type 2 diabetes mellitus) and the control Caucasoid sample. Monophyletic origin of H63D (rs1799945) was confirmed in Caucasoids and Northern

  20. H63D mutation in HFE gene is common in Indians and is associated ...

    Indian Academy of Sciences (India)

    inated in a Celtic population in central Europe and spread west and north by population movement. There are ... mutation with the C282Y mutation is a known risk factor for iron overload (Pointon et al. 2000) The H63D ... gene causally associated with the disease may aid in resolv- ing its single or multiple origins within a ...

  1. A heterozygote–homozygote test of Hardy–Weinberg equilibrium

    OpenAIRE

    Zhou, Jin J; Lange, Kenneth; Papp, Jeanette C.; Sinsheimer, Janet S.

    2009-01-01

    The century-old Hardy–Weinberg law remains fundamental to population genetics. Typically Hardy–Weinberg equilibrium is tested in unrelated individuals using a χ2 goodness-of-fit test that compares expected and observed numbers of heterozygotes and homozygotes. In this report, we propose a likelihood ratio test for Hardy–Weinberg equilibrium that accommodates a mixture of pedigree and random sample data. The underlying statistical model depends on a parameter γ determining the ratio of heteroz...

  2. HFE gene mutations and Wilson's disease in Sardinia.

    Science.gov (United States)

    Sorbello, Orazio; Sini, Margherita; Civolani, Alberto; Demelia, Luigi

    2010-03-01

    Hypocaeruloplasminaemia can lead to tissue iron storage in Wilson's disease and the possibility of iron overload in long-term overtreated patients should be considered. The HFE gene encodes a protein that is intimately involved in intestinal iron absorption. The aim of this study was to determine the prevalence of the HFE gene mutation, its role in iron metabolism of Wilson's disease patients and the interplay of therapy in copper and iron homeostasis. The records of 32 patients with Wilson's disease were reviewed for iron and copper indices, HFE gene mutations and liver biopsy. Twenty-six patients were negative for HFE gene mutations and did not present significant alterations of iron metabolism. The HFE mutation was significantly associated with increased hepatic iron content (Pgene wild-type. The HFE gene mutations may be an addictional factor in iron overload in Wilson's disease. Our results showed that an adjustment of dosage of drugs could prevent further iron overload induced by overtreatment only in patients HFE wild-type. 2009. Published by Elsevier Ltd.

  3. Coincident natural selection of CCR5∆32 and C282Y in Europe: to ...

    Indian Academy of Sciences (India)

    Unknown

    CCR5 is a member of the G protein-coupled chemokine receptor superfamily which acts as one of the major co- receptors for HIV-1 infection. A 32-base pair deletion (∆32) in the CCR5 gene results in defective expression of the receptor on the cell surface and blocks entry of the virus. The inactive CCR5∆32 allele confers ...

  4. A heterozygote-homozygote test of Hardy-Weinberg equilibrium.

    Science.gov (United States)

    Zhou, Jin J; Lange, Kenneth; Papp, Jeanette C; Sinsheimer, Janet S

    2009-11-01

    The century-old Hardy-Weinberg law remains fundamental to population genetics. Typically Hardy-Weinberg equilibrium is tested in unrelated individuals using a chi(2) goodness-of-fit test that compares expected and observed numbers of heterozygotes and homozygotes. In this report, we propose a likelihood ratio test for Hardy-Weinberg equilibrium that accommodates a mixture of pedigree and random sample data. The underlying statistical model depends on a parameter gamma determining the ratio of heterozygous genotypes to homozygous genotypes among pedigree founders. As our heterozygous-homozygous test accommodates markers with dominant and recessive alleles, it can handle the phase ambiguities encountered in combining several linked single nucleotide polymorphisms into a single supermarker. No prior haplotyping is necessary. Our experience on real and simulated data suggests that the heterozygous-homozygous test has good type-one error and power.

  5. Prediction of the Spectroscopic Parameters of New Iron Compounds: Hydride of Iron Cyanide/Isocyanide, HFeCN/HFeNC

    Science.gov (United States)

    Redondo, Pilar; Barrientos, Carmen; Largo, Antonio

    2016-09-01

    Iron is the most abundant transition metal in space. Its abundance is similar to that of magnesium, and until today only, FeO and FeCN have been detected. However, magnesium-bearing compounds such as MgCN, MgNC, and HMgNC are found in IRC+10216. It seems that the hydrides of iron cyanide/isocyanide could be good candidates to be present in space. In the present work we carried out a characterization of the different minima on the quintet and triplet [C, Fe, H, N] potential energy surfaces, employing several theoretical approaches. The most stable isomers are predicted to be hydride of iron cyanide HFeCN, and isocyanide HFeNC, in their 5Δ states. Both isomers are found to be quasi-isoenergetics. The HFeNC isomer is predicted to lie about 0.5 kcal/mol below HFeCN. The barrier for the interconversion process is estimated to be around 6.0 kcal/mol, making this process unfeasible under low temperature conditions, such as those in the interstellar medium. Therefore, both HFeCN and HFeNC could be candidates for their detection. We report geometrical parameters, vibrational frequencies, and rotational constants that could help with their experimental characterization.

  6. A sustainable system of systems approach: a new HFE paradigm.

    Science.gov (United States)

    Thatcher, Andrew; Yeow, Paul H P

    2016-01-01

    Sustainability issues such as natural resource depletion, pollution and poor working conditions have no geographical boundaries in our interconnected world. To address these issues requires a paradigm shift within human factors and ergonomics (HFE), to think beyond a bounded, linear model understanding towards a broader systems framework. For this reason, we introduce a sustainable system of systems model that integrates the current hierarchical conceptualisation of possible interventions (i.e., micro-, meso- and macro-ergonomics) with important concepts from the sustainability literature, including the triple bottom line approach and the notion of time frames. Two practical examples from the HFE literature are presented to illustrate the model. The implications of this paradigm shift for HFE researchers and practitioners are discussed and include the long-term sustainability of the HFE community and comprehensive solutions to problems that consider the emergent issues that arise from this interconnected world. A sustainable world requires a broader systems thinking than that which currently exists in ergonomics. This study proposes a sustainable system of systems model that incorporates ideas from the ecological sciences, notably a nested hierarchy of systems and a hierarchical time dimension. The implications for sustainable design and the sustainability of the HFE community are considered.

  7. Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice.

    Science.gov (United States)

    Gao, Junwei; Chen, Juxing; De Domenico, Ivana; Koeller, David M; Harding, Cary O; Fleming, Robert E; Koeberl, Dwight D; Enns, Caroline A

    2010-04-22

    Hereditary hemochromatosis is caused by mutations in the hereditary hemochromatosis protein (HFE), transferrin-receptor 2 (TfR2), hemojuvelin, hepcidin, or ferroportin genes. Hepcidin is a key iron regulator, which is secreted by the liver, and decreases serum iron levels by causing the down-regulation of the iron transporter, ferroportin. Mutations in either HFE or TfR2 lower hepcidin levels, implying that both HFE and TfR2 are necessary for regulation of hepcidin expression. In this study, we used a recombinant adeno-associated virus, AAV2/8, for hepatocyte-specific expression of either Hfe or Tfr2 in mice. Expression of Hfe in Hfe-null mice both increased Hfe and hepcidin mRNA and lowered hepatic iron and Tf saturation. Expression of Tfr2 in Tfr2-deficient mice had a similar effect, whereas expression of Hfe in Tfr2-deficient mice or of Tfr2 in Hfe-null mice had no effect on liver or serum iron levels. Expression of Hfe in wild-type mice increased hepcidin mRNA and lowered iron levels. In contrast, expression of Tfr2 had no effect on wild-type mice. These findings suggest that Hfe is limiting in formation of the Hfe/Tfr2 complex that regulates hepcidin expression. In addition, these studies show that the use of recombinant AAV vector to deliver genes is a promising approach for studying physiologic consequences of protein complexes.

  8. Conducting multistage HFE validations-constructing Systems Usability Case

    Energy Technology Data Exchange (ETDEWEB)

    Laarni, Jari; Savioja, Paula; Norros, Leena; Linasuo, Marja; Karvonen, Hannu; Wahlstorm, Mikael [Human Factors in Complex Systems, Vuorimiehentie 3 (Finland); Salo Leena [Fortum, eilaniementie, Fortum (Finland)

    2014-08-15

    This paper describes how independent stepwise Human Factors Engineering (HFE) validations have been conducted in Fortum Lovisa power plant control room modernization project. We discuss the challenges of HFE verification and validation in a project which is realized in multiple phases, stretches over several years in time, and is in tight coupling with automation modernization. These challenges eventually lead to the need of developing a new approach to control HFE validation; conducting validations in a stepwise manner. In our sub-system validation approach a particular sub-system of the control room are always the main focus of testing but simultaneously we also analyse the overall operational concept and its possible development needs.

  9. Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

    Science.gov (United States)

    Benyamin, Beben; Esko, Tonu; Ried, Janina S; Radhakrishnan, Aparna; Vermeulen, Sita H; Traglia, Michela; Gögele, Martin; Anderson, Denise; Broer, Linda; Podmore, Clara; Luan, Jian’an; Kutalik, Zoltan; Sanna, Serena; van der Meer, Peter; Tanaka, Toshiko; Wang, Fudi; Westra, Harm-Jan; Franke, Lude; Mihailov, Evelin; Milani, Lili; Häldin, Jonas; Winkelmann, Juliane; Meitinger, Thomas; Thiery, Joachim; Peters, Annette; Waldenberger, Melanie; Rendon, Augusto; Jolley, Jennifer; Sambrook, Jennifer; Kiemeney, Lambertus A; Sweep, Fred C; Sala, Cinzia F; Schwienbacher, Christine; Pichler, Irene; Hui, Jennie; Demirkan, Ayse; Isaacs, Aaron; Amin, Najaf; Steri, Maristella; Waeber, Gérard; Verweij, Niek; Powell, Joseph E; Nyholt, Dale R; Heath, Andrew C; Madden, Pamela AF; Visscher, Peter M; Wright, Margaret J; Montgomery, Grant W; Martin, Nicholas G; Hernandez, Dena; Bandinelli, Stefania; van der Harst, Pim; Uda, Manuela; Vollenweider, Peter; Scott, Robert A; Langenberg, Claudia; Wareham, Nicholas J; van Duijn, Cornelia; Beilby, John; Pramstaller, Peter P; Hicks, Andrew A; Ouwehand, Willem H; Oexle, Konrad; Gieger, Christian; Metspalu, Andres; Camaschella, Clara; Toniolo, Daniela; Swinkels, Dorine W; Whitfield, John B

    2014-01-01

    Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here we analyse genetic association data on biochemical markers of iron status from eleven European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find eleven genome-wide-significant (p < 5 × 10−8) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease. PMID:25352340

  10. Population Screening for Hereditary Haemochromatosis in Australia: Construction and Validation of a State-Transition Cost-Effectiveness Model.

    Science.gov (United States)

    de Graaff, Barbara; Si, Lei; Neil, Amanda L; Yee, Kwang Chien; Sanderson, Kristy; Gurrin, Lyle C; Palmer, Andrew J

    2017-03-01

    HFE-associated haemochromatosis, the most common monogenic disorder amongst populations of northern European ancestry, is characterised by iron overload. Excess iron is stored in parenchymal tissues, leading to morbidity and mortality. Population screening programmes are likely to improve early diagnosis, thereby decreasing associated disease. Our aim was to develop and validate a health economics model of screening using utilities and costs from a haemochromatosis cohort. A state-transition model was developed with Markov states based on disease severity. Australian males (aged 30 years) and females (aged 45 years) of northern European ancestry were the target populations. The screening strategy was the status quo approach in Australia; the model was run over a lifetime horizon. Costs were estimated from the government perspective and reported in 2015 Australian dollars ($A); costs and quality-adjusted life-years (QALYs) were discounted at 5% annually. Model validity was assessed using goodness-of-fit analyses. Second-order Monte-Carlo simulation was used to account for uncertainty in multiple parameters. For validity, the model reproduced mortality, life expectancy (LE) and prevalence rates in line with published data. LE for C282Y homozygote males and females were 49.9 and 40.2 years, respectively, slightly lower than population rates. Mean (95% confidence interval) QALYS were 15.7 (7.7-23.7) for males and 14.4 (6.7-22.1) for females. Mean discounted lifetime costs for C282Y homozygotes were $A22,737 (3670-85,793) for males and $A13,840 (1335-67,377) for females. Sensitivity analyses revealed discount rates and prevalence had the greatest impacts on outcomes. We have developed a transparent, validated health economics model of C282Y homozygote haemochromatosis. The model will be useful to decision makers to identify cost-effective screening strategies.

  11. Intragenic haplotype analysis of common HFE mutations in the ...

    Indian Academy of Sciences (India)

    ... Public Lectures · Lecture Workshops · Refresher Courses · Symposia. Home; Journals; Journal of Genetics; Volume 94; Issue 2. Intragenic haplotype analysis of common HFE mutations in the Portuguese population. Sandra Toste Luís Relvas Catarina Pinto Celeste Bento Augusto Abade M. Letícia Ribeiro Licínio Manco.

  12. [Iron in the era of molecular biology].

    Science.gov (United States)

    Deugnier, Y; Moirand, R; Brissot, P; David, V

    1999-11-01

    Identification of the HFE gene and its C282Y and H63D mutations has improved the classification of iron overload disorders. Inherited hemochromatosis is due mainly, or perhaps only, to C282Y homozygosity, whereas nonhemochromatosis forms of iron overload are due to other HFE mutations and are usually responsible for mild overload precipitated by another factor such as cirrhosis or insulin-resistance. In practice, the diagnosis of inherited hemochromatosis rests on demonstration of homozygosity for the C282Y mutation; in this setting, the role of liver biopsy is to evaluate the prognosis by looking for fibrosis. In patients who are not homozygous for the C282Y mutation but have severe iron overload, causes other than hemochromatosis should be looked for before the extremely remote possibility of nonC282Y-related hemochromatosis is considered; here, liver biopsy remains of considerable diagnostic usefulness.

  13. Probable early-onset Alzheimer's disease in an apolipoprotein E2 homozygote.

    Science.gov (United States)

    Cole, Lauren; Belden, Christine; Jacobson, Sandra; Liebsack, Carolyn; Myers, Kent; Reninger, Cornelia; Berk, Camryn; Sabbagh, Marwan N

    2010-01-01

    To describe a case of early-onset Alzheimer's disease (AD) in an apolipoprotein (Apo) ε2/ε2 homozygote. Apo ε2/ε2 is the rarest of the ApoE genotypes, representing only 1.4% of the population. Cognitive decline in ApoE ε2 homozygotes has rarely been reported. We report a 58-year-old Apo ε2/ε2 female who meets clinical criteria for probable AD as confirmed by neuropsychological testing, positron emission/computed tomography scan, CSF analysis and genetic screening for known mutations. The clinical course is typical of AD, with progressive cognitive and functional decline. Clinically confirmed early-onset AD is atypical in ApoE2 homozygotes but can occur. Copyright © 2010 S. Karger AG, Basel.

  14. Highly sensitivity adhesion molecules detection in hereditary haemochromatosis patients reveals altered expression.

    LENUS (Irish Health Repository)

    Norris, S

    2012-02-01

    Several abnormalities in the immune status of patients with hereditary haemochromatosis (HH) have been reported, suggesting an imbalance in their immune function. This may include persistent production of, or exposure to, altered immune signalling contributing to the pathogenesis of this disorder. Adhesion molecules L-, E- and P-Selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) are some of the major regulators of the immune processes and altered levels of these proteins have been found in pathological states including cardiovascular diseases, arthritis and liver cancer. The aim of this study was to assess L-, E- and P-Selectin, ICAM-1 and VCAM-1 expression in patients with HH and correlate these results with HFE mutation status and iron indexes. A total of 139 subjects were diagnosed with HH (C282Y homozygotes = 87, C282Y\\/H63D = 26 heterozygotes, H63D homozygotes = 26), 27 healthy control subjects with no HFE mutation (N\\/N), 18 normal subjects heterozygous for the H63D mutation served as age-sex-matched controls. We observed a significant decrease in L-selectin (P = 0.0002) and increased E-selectin and ICAM-1 (P = 0.0006 and P = 0.0059) expression in HH patients compared with healthy controls. This study observes for the first time that an altered adhesion molecules profile occurs in patients with HH that is associated with specific HFE genetic component for iron overload, suggesting that differential expression of adhesion molecules may play a role in the pathogenesis of HH.

  15. Blunted hepcidin response to inflammation in the absence of Hfe and transferrin receptor 2.

    Science.gov (United States)

    Wallace, Daniel F; McDonald, Cameron J; Ostini, Lesa; Subramaniam, V Nathan

    2011-03-10

    The induction of the iron-regulatory peptide hepcidin by proinflammatory cytokines is thought to result in the withholding of iron from invading pathogens. Hfe and transferrin receptor 2 (Tfr2) are involved in the homeostatic regulation of hepcidin and their disruption causes hereditary hemochromatosis (HH). To determine whether either Hfe or Tfr2 is involved in the inflammatory pathway regulating hepcidin, we analyzed the effect of inflammation in 3 mouse models of HH. The inflammatory response and indicators of iron homeostasis were measured in wild-type, Hfe(-/-), Tfr2(-/-), and Hfe(-/-)/Tfr2(-/-) mice injected with lipopolysaccharide (LPS). The administration of LPS significantly reduced serum iron in wild-type and Hfe(-/-) mice, with smaller reductions in Tfr2(-/-) and Hfe(-/-)/Tfr2(-/-) mice. Low basal levels of hepcidin in the Hfe(-/-)/Tfr2(-/-) mice were increased in response to LPS, but remained significantly lower than in the other strains of mice. These results suggest that despite the absence of Hfe and Tfr2, hepcidin is responsive to inflammation; however, the low basal expression and subsequent low levels of circulating hepcidin are insufficient to reduce serum iron effectively. This suggests that in HH, the iron-withholding response to invading pathogens may be inadequate, and this is especially the case in the absence of both Hfe and Tfr2.

  16. Probable Early-Onset Alzheimer's Disease in an Apolipoprotein E2 Homozygote

    OpenAIRE

    Cole, Lauren; Belden, Christine; Jacobson, Sandra; Liebsack, Carolyn; Myers, Kent; Reninger, Cornelia; Berk, Camryn; Sabbagh, Marwan N.

    2010-01-01

    Objective: To describe a case of early-onset Alzheimer's disease (AD) in an apolipoprotein (Apo) epsilon 2/epsilon 2 homozygote. Background: Apo epsilon 2/epsilon 2 is the rarest of the ApoE genotypes, representing only 1.4% of the population. Cognitive decline in ApoE epsilon 2 homozygotes has rarely been reported. Case Report/Methods: We report a 58-year-old Apo epsilon 2/epsilon 2 female who meets clinical criteria for probable AD as confirmed by neuropsychological testing, positron emissi...

  17. Different outcome of six homozygotes for prothrombin A20210A gene variant

    Directory of Open Access Journals (Sweden)

    Angiolillo Antonella

    2008-07-01

    Full Text Available Abstract Prothrombin G20210A gene variant (FII G20210A is a risk factor for venous thrombotic disease while conflicting results have been reported for the risk of arterial thrombotic events. However, vascular episodes were absent in up to 40% of the 67 homozygotes for the G20210A described so far, which indicates that the clinical expression depends on additional risk/trigger factors. We describe six homozygotes for the G20210A variant, among which the first pair of siblings (cases n. 3 and 4 reported so far that displayed a strongly heterogeneous clinical outcome. Case 1, a female of 27 years, developed a full thrombosis of common femoral, superficial and popliteal veins. She assumed oral contraceptives in the last two years. Case n. 2, 34 years old, suffered of recurrent pregnancy loss in absence of any causative alteration. Cases n. 3 and n. 5 experienced arterial thrombotic disease, i.e., juvenile myocardial infarction (40 years old and stroke (48 years old, respectively, in absence of other risk factors. Finally, cases n. 4 and 6 identified as homozygotes for the FII G20210A variant being consanguineous of symptomatic subjects bearing the variant, did not experience any episode of venous nor arterial disease. Both of them have chronic liver disease with an impairement of the prothrombin time INR. Thus, homozygotes for the G20210A are at risk for arterial (in addition to venous thromobotic events; chronic liver disease might modulate this risk.

  18. Effect of Hfe Deficiency on Memory Capacity and Motor Coordination after Manganese Exposure by Drinking Water in Mice.

    Science.gov (United States)

    Alsulimani, Helal Hussain; Ye, Qi; Kim, Jonghan

    2015-12-01

    Excess manganese (Mn) is neurotoxic. Increased manganese stores in the brain are associated with a number of behavioral problems, including motor dysfunction, memory loss and psychiatric disorders. We previously showed that the transport and neurotoxicity of manganese after intranasal instillation of the metal are altered in Hfe-deficient mice, a mouse model of the iron overload disorder hereditary hemochromatosis (HH). However, it is not fully understood whether loss of Hfe function modifies Mn neurotoxicity after ingestion. To investigate the role of Hfe in oral Mn toxicity, we exposed Hfe-knockout (Hfe (-/-)) and their control wild-type (Hfe (+/+)) mice to MnCl2 in drinking water (5 mg/mL) for 5 weeks. Motor coordination and spatial memory capacity were determined by the rotarod test and the Barnes maze test, respectively. Brain and liver metal levels were analyzed by inductively coupled plasma mass spectrometry. Compared with the water-drinking group, mice drinking Mn significantly increased Mn concentrations in the liver and brain of both genotypes. Mn exposure decreased iron levels in the liver, but not in the brain. Neither Mn nor Hfe deficiency altered tissue concentrations of copper or zinc. The rotarod test showed that Mn exposure decreased motor skills in Hfe (+/+) mice, but not in Hfe (-/-) mice (p = 0.023). In the Barns maze test, latency to find the target hole was not altered in Mn-exposed Hfe (+/+) compared with water-drinking Hfe (+/+) mice. However, Mn-exposed Hfe (-/-) mice spent more time to find the target hole than Mn-drinking Hfe (+/+) mice (p = 0.028). These data indicate that loss of Hfe function impairs spatial memory upon Mn exposure in drinking water. Our results suggest that individuals with hemochromatosis could be more vulnerable to memory deficits induced by Mn ingestion from our environment. The pathophysiological role of HFE in manganese neurotoxicity should be carefully examined in patients with HFE-associated hemochromatosis and

  19. Transgenic HFE-dependent induction of hepcidin in mice does not require transferrin receptor-2.

    Science.gov (United States)

    Schmidt, Paul J; Fleming, Mark D

    2012-06-01

    Hereditary hemochomatosis (HH) is caused by mutations in several genes, including HFE and transferrin receptor-2 (TFR2). Loss of either protein decreases expression of the iron regulatory hormone hepcidin by the liver, leading to inappropriately high iron uptake from the diet, and resulting in systemic iron overload. In tissue culture, overexpressed HFE and TFR2 physically interact. Hepatocellular overexpression of Hfe in vivo increases hepcidin expression, despite an associated decrease in Tfr2. On this basis, we hypothesized that Tfr2 would not be required for Hfe-dependent up-regulation of hepcidin. We show that hepatocellular overexpression of Hfe in Tfr2(Y245X/Y245X) mice leads to hepcidin induction eventuating in iron deficiency and a hypochromic, microcytic anemia. Furthermore, coimmunoprecipitation studies using liver lysates did not provide evidence for physical interaction between Hfe and Tfr2 in vivo. In conclusion, we demonstrate that Tfr2 is not essential for Hfe-mediated induction of hepcidin expression, supporting the possibility that TFR2 may regulate iron metabolism in an HFE-independent manner. Copyright © 2012 Wiley Periodicals, Inc.

  20. Identification of novel mutations in HFE, HFE2, TfR2, and SLC40A1 genes in Chinese patients affected by hereditary hemochromatosis.

    Science.gov (United States)

    Wang, Yongwei; Du, Yali; Liu, Gang; Guo, Shanshan; Hou, Bo; Jiang, Xianyong; Han, Bing; Chang, Yanzhong; Nie, Guangjun

    2017-04-01

    Hereditary hemochromatosis (HH) is a group of inherited iron-overload disorders associated with pathogenic defects in the genes encoding hemochromatosis (HFE), hemojuvelin (HJV/HFE2), hepcidin (HAMP), transferrin receptor 2 (TfR2), and ferroportin (FPN1/SLC40A1) proteins, and the clinical features are well described. However, there have been only a few detailed reports of HH in Chinese populations. Thus, there is insufficient patient information for population-based analyses in Chinese populations or comparative studies among different ethical groups. In the current work, we describe eight Chinese cases of hereditary hemochromatosis. Gene sequencing results revealed eight mutations (five novel mutations) in HFE, HFE2, TfR2, and SLC40A1 genes in these Chinese HH patients. In addition, we used Polymorphism Phenotyping v2 (Polyphen), Sorting Intolerant From Tolerant (SIFT), and a sequence alignment program to predict the molecular consequences of missense mutations.

  1. Hepatic iron overload following liver transplantation of a C282y homozygous allograft: a case report and literature review.

    LENUS (Irish Health Repository)

    Dwyer, Jeremy P

    2011-11-01

    Hereditary haemochromatosis is a common genetic disease associated with progressive iron overload and parenchymal organ damage including liver, pancreas and heart. We report a case of inadvertent transplantation of a liver from a haemochromatosis donor to a 56-year-old Asian female. Progressive iron overload occurred over a 2 year follow up as assessed by liver biopsy and iron studies in the absence of a secondary cause of iron overload, supporting a primary role of liver rather than small intestine in the regulation of iron homeostasis in hereditary haemochromatosis.

  2. Severe microcytic anemia but increased erythropoiesis in mice lacking Hfe or Tfr2 and Tmprss6.

    Science.gov (United States)

    Lee, Pauline; Hsu, Mei-Hui; Welser-Alves, Jennifer; Peng, Hongfan

    2012-03-15

    Cell surface proteins Hfe, Tfr2, hemojuvelin and Tmprss6 play key roles in iron homeostasis. Hfe and Tfr2 induce transcription of hepcidin, a small peptide that promotes the degradation of the iron transporter ferroportin. Hemojuvelin, a co-receptor for bone morphogenic proteins, induces hepcidin transcription through a Smad signaling pathway. Tmprss6 (also known as matriptase-2), a membrane serine protease that has been found to bind and degrade hemojuvelin in vitro, is a potent suppressor of hepcidin expression. In order to examine if Hfe and Tfr2 are substrates for Tmprss6, we generated mice lacking functional Hfe or Tfr2 and Tmprss6. We found that double mutant mice lacking functional Hfe or Tfr2 and Tmprss6 exhibited a severe iron deficiency microcytic anemia phenotype mimicking the phenotype of single mutant mice lacking functional Tmprss6 (Tmprss6msk/msk mutant) demonstrating that Hfe and Tfr2 are not substrates for Tmprss6. Nevertheless, the phenotype of the mice lacking Hfe or Tfr2 and Tmprss6 differed from Tmprss6 deficient mice alone, in that the double mutant mice exhibited much greater erythropoiesis. Hfe and Tfr2 have been shown to play important roles in the erythron, independent of their role in regulating liver hepcidin transcription. We demonstrate that lack of functional Tfr2 and Hfe allows for increased erythropoiesis even in the presence of high hepcidin expression, but the high levels of hepcidin levels significantly limit the availability of iron to the erythron, resulting in ineffective erythropoiesis. Furthermore, repression of hepcidin expression by hypoxia was unaffected by the loss of functional Hfe, Tfr2 and Tmprss6. Copyright © 2011 Elsevier Inc. All rights reserved.

  3. Pathophysiological consequences and benefits of HFE mutations: 20 years of research

    Science.gov (United States)

    Hollerer, Ina; Bachmann, André; Muckenthaler, Martina U.

    2017-01-01

    Mutations in the HFE (hemochromatosis) gene cause hereditary hemochromatosis, an iron overload disorder that is hallmarked by excessive accumulation of iron in parenchymal organs. The HFE mutation p.Cys282Tyr is pathologically most relevant and occurs in the Caucasian population with a carrier frequency of up to 1 in 8 in specific European regions. Despite this high prevalence, the mutation causes a clinically relevant phenotype only in a minority of cases. In this review, we summarize historical facts and recent research findings about hereditary hemochromatosis, and outline the pathological consequences of the associated gene defects. In addition, we discuss potential advantages of HFE mutations in asymptomatic carriers. PMID:28280078

  4. In situ proximity ligation assays indicate that hemochromatosis proteins Hfe and transferrin receptor 2 (Tfr2) do not interact.

    Science.gov (United States)

    Rishi, Gautam; Crampton, Emily M; Wallace, Daniel F; Subramaniam, V Nathan

    2013-01-01

    The hemochromatosis associated proteins HFE and Transferrin Receptor 2 (TFR2) have been shown to be important for the proper regulation of hepcidin. A number of in vitro studies using transient overexpression systems have suggested that an interaction between HFE and TFR2 is required for the regulation of hepcidin. This model of iron sensing which centers upon the requirement for an interaction between HFE and TFR2 has recently been questioned with in vivo studies in mice from our laboratory and others which suggest that Hfe and Tfr2 can regulate hepcidin independently of each other. To re-examine the postulated interaction between Hfe and Tfr2 we developed a novel expression system in which both proteins are stably co-expressed and used the proximity ligation assay to examine the interactions between Hfe, Tfr1 and Tfr2 at a cellular level. We were able to detect the previously described interaction between Hfe and Tfr1, and heterodimers between Tfr1 and Tfr2; however no interaction between Hfe and Tfr2 was observed in our system. The results from this study indicate that Hfe and Tfr2 do not interact with each other when they are stably expressed at similar levels. Furthermore, these results support in vivo studies which suggest that Hfe and Tfr2 can independently regulate hepcidin.

  5. In situ proximity ligation assays indicate that hemochromatosis proteins Hfe and transferrin receptor 2 (Tfr2 do not interact.

    Directory of Open Access Journals (Sweden)

    Gautam Rishi

    Full Text Available The hemochromatosis associated proteins HFE and Transferrin Receptor 2 (TFR2 have been shown to be important for the proper regulation of hepcidin. A number of in vitro studies using transient overexpression systems have suggested that an interaction between HFE and TFR2 is required for the regulation of hepcidin. This model of iron sensing which centers upon the requirement for an interaction between HFE and TFR2 has recently been questioned with in vivo studies in mice from our laboratory and others which suggest that Hfe and Tfr2 can regulate hepcidin independently of each other. To re-examine the postulated interaction between Hfe and Tfr2 we developed a novel expression system in which both proteins are stably co-expressed and used the proximity ligation assay to examine the interactions between Hfe, Tfr1 and Tfr2 at a cellular level. We were able to detect the previously described interaction between Hfe and Tfr1, and heterodimers between Tfr1 and Tfr2; however no interaction between Hfe and Tfr2 was observed in our system. The results from this study indicate that Hfe and Tfr2 do not interact with each other when they are stably expressed at similar levels. Furthermore, these results support in vivo studies which suggest that Hfe and Tfr2 can independently regulate hepcidin.

  6. Prevalence of HFE and TFR2 gene mutation in 118 Ligurian rheumatic patients.

    Science.gov (United States)

    Rovetta, G; Monteforte, P; Buffrini, L; Grignolo, M C; Franchin, F

    2004-12-01

    HFE gene is associated to haemochromatosis, an inherited autosomal recessive disorder responsible of an overload of iron in intestine, liver, pancreas, heart, cutis and joints. Articular and periarticular calcifications may occur. H63D mutation may play a role in the pathogenesis of rheumatoid arthritis. DNA of 118 consecutive patients (28 males, 90 females, mean age 58.5+/-13.44) living in Liguria and affected by different rheumatic diseases was examined to evaluate the presence of HFE mutations. Analysis data showed that in 45% (53/118) of patients almost one mutation of HFE gene was present and the presence of H63D mutation in the rheumatic patients was particularly elevated. Data obtained in this study have permitted to reveal that 25 patients of 53 (47.1%) with 1 of 11 HFE mutations suffered from symptomatic or silent chondrocalcinosis. The conclusion is drawn that this mutation may be correlated to various rheumatic diseases.

  7. Possible Alzheimer’s Disease in an Apolipoprotein E2 Homozygote

    OpenAIRE

    Ignatov, Ignat; Belden, Christine; Jacobson, Sandra; Connor, Donald; Sabbagh, Marwan N

    2009-01-01

    The objective of this study was to describe a case of Alzheimer’s disease in an ApoE ε2/ε2 homozygote. ApoE ε2/ε2 is the rarest of the apolipoprotein E genotypes, representing only 1.4% of the population. There is only one case reported in the literature of a nonagenarian with minimal cognitive changes whose brain showed AD pathology on postmortem study. Here we report an 87-year-old ApoE ε2/ε2 female who meets clinical criteria for Alzheimer’s disease, with confirmation from neuropsychologic...

  8. Spent nuclear fuel project, Cold Vacuum Drying Facility human factors engineering (HFE) analysis: Results and findings

    Energy Technology Data Exchange (ETDEWEB)

    Garvin, L.J.

    1998-07-17

    This report presents the background, methodology, and findings of a human factors engineering (HFE) analysis performed in May, 1998, of the Spent Nuclear Fuels (SNF) Project Cold Vacuum Drying Facility (CVDF), to support its Preliminary Safety Analysis Report (PSAR), in responding to the requirements of Department of Energy (DOE) Order 5480.23 (DOE 1992a) and drafted to DOE-STD-3009-94 format. This HFE analysis focused on general environment, physical and computer workstations, and handling devices involved in or directly supporting the technical operations of the facility. This report makes no attempt to interpret or evaluate the safety significance of the HFE analysis findings. The HFE findings presented in this report, along with the results of the CVDF PSAR Chapter 3, Hazards and Accident Analyses, provide the technical basis for preparing the CVDF PSAR Chapter 13, Human Factors Engineering, including interpretation and disposition of findings. The findings presented in this report allow the PSAR Chapter 13 to fully respond to HFE requirements established in DOE Order 5480.23. DOE 5480.23, Nuclear Safety Analysis Reports, Section 8b(3)(n) and Attachment 1, Section-M, require that HFE be analyzed in the PSAR for the adequacy of the current design and planned construction for internal and external communications, operational aids, instrumentation and controls, environmental factors such as heat, light, and noise and that an assessment of human performance under abnormal and emergency conditions be performed (DOE 1992a).

  9. Method for creating gas standards form liquid HFE-7100 and FC-72.

    Energy Technology Data Exchange (ETDEWEB)

    White, Michael K.; Brown, Jason R.; Thornberg, Steven Michael; Hochrein, James Michael; Irwin, Adriane Nadine

    2007-07-01

    HFE-7100 and FC-72 fluorinert are two fluids used during weapon component manufacturing. HFE-7100 is a solvent used in the cleaning of parts, and FC-72 is the blowing agent of a polymeric removable foam. The presence of either FC-72 or HFE-7100 gas in weapon components can provide valuable information as to the stability of the materials. Therefore, gas standards are needed so HFE-7100 and FC-72 gas concentrations can be accurately measured. There is no current established procedure for generating gas standards of either HFE-7100 or FC-72. This report outlines the development of a method to generate gas standards ranging in concentration from 0.1 ppm to 10% by volume. These standards were then run on a Jeol GC-Mate II mass spectrometer and analyzed to produce calibration curves. We present a manifold design that accurately generates gas standards of HFE-7100 and FC-72 and a procedure that allows the amount of each to be determined.

  10. Possible Alzheimer’s Disease in an Apolipoprotein E2 Homozygote

    Science.gov (United States)

    Ignatov, Ignat; Belden, Christine; Jacobson, Sandra; Connor, Donald; Sabbagh, Marwan N.

    2010-01-01

    The objective of this study was to describe a case of Alzheimer’s disease in an ApoE ε2/ε2 homozygote. ApoE ε2/ε2 is the rarest of the apolipoprotein E genotypes, representing only 1.4% of the population. There is only one case reported in the literature of a nonagenarian with minimal cognitive changes whose brain showed AD pathology on postmortem study. Here we report an 87-year-old ApoE ε2/ε2 female who meets clinical criteria for Alzheimer’s disease, with confirmation from neuropsychological testing and PET scan. Clinical course is typical for Alzheimer’s disease with decline on the Mini-Mental Status Examination from a score of 25 to 19 over 3.5 years. The patient is currently treated with donepezil and memantine. In conclusion, a clinically confirmed case of Alzheimer’s disease is rare in Apo E2 homozygotes but can occur. PMID:19158419

  11. Factors affecting the appreciation generated through applying human factors/ergonomics (HFE) principles to systems of work.

    Science.gov (United States)

    So, R H Y; Lam, S T

    2014-01-01

    This retrospective study examined the levels of appreciation (applause) given by clients to Human Factors/Ergonomic (HFE) specialists after they have modified the systems of work. Thirteen non-academic projects were chosen because the HFE interventions involved changed the way workers work at their workplaces. Companies involved range from multi-national corporations and military organizations with thousands of employees to small trading companies with less than 10 employees. In 5 cases the HFE recommendations were fully adopted and well appreciated. In 4 they were largely ignored and not appreciated, with partial adoption and some appreciation in the other 4 cases. Three factors that predict appreciation were identified: (i) alignment between the benefits HFE can provide and the project's key performance indices; (ii) awareness of HFE among the client's senior management; and (iii) a team organization appropriate for applying HFE recommendations. Having an HFE specialist on the client's side can greatly increase levels of appreciation, but lack of such a specialist will not affect levels of appreciation. A clear contractual requirement for HFE intervention does not promote appreciation significantly, but its absence can greatly reduce levels of appreciation. These relationships are discussed using the Kano's model of quality. Means to generate greater appreciation of the benefits of HFE are discussed. Copyright © 2013 Elsevier Ltd and The Ergonomics Society. All rights reserved.

  12. Development of a HFE program for an operating NPP: Balancing between existing design practices and human factors standards

    Energy Technology Data Exchange (ETDEWEB)

    Salo, Leena [Nuclear and Thermal Power, Fortum (Finland); Savioja, Paula [Human Factors in Complex Systems, VTT Technical Research Centre of Finland, Fortum (Finland)

    2014-08-15

    This paper describes HFE program development project conducted at a Finnish power company Fortum. The aim of developing a formal HFE program was to improve integration of human factors issues in design of technical systems and to systematically document the HFE process of the company. As Fortum has a long tradition of designing control room solutions, the starting point of the HFE program development was the existing own design practices. On the other hand, the aim was to create a program which would comply with international guidelines such as NUREG-0711. The program development was conducted by tracing the HFE design practices in an on-going I and C modernization project. This empirical work was carried out by interviews of designers and other HFE key stake holders. After the explication of the current practices, the gaps, overlaps and differences in relation to the international standards and guidelines were identified. Based on an analysis of current practices and guidelines and standards a new HFE process model was created. The design process model can be followed in modifications which concern systems with human user interfaces of any kind. The model consists of five separate phases which comply with the general engineering design process model utilized at the company. The HFE program is intended to be both a practical guide on how to take human factors issues into consideration in the design of NPP systems and also a tool for the management of HFE activities.

  13. Trends in HFE Methods and Tools and Their Applicability to Safety Reviews

    Energy Technology Data Exchange (ETDEWEB)

    O' Hara, J.M.; Plott, C.; Milanski, J.; Ronan, A.; Scheff, S.; Laux, L.; and Bzostek, J.

    2009-09-30

    The U.S. Nuclear Regulatory Commission's (NRC) conducts human factors engineering (HFE) safety reviews of applicant submittals for new plants and for changes to existing plants. The reviews include the evaluation of the methods and tools (M&T) used by applicants as part of their HFE program. The technology used to perform HFE activities has been rapidly evolving, resulting in a whole new generation of HFE M&Ts. The objectives of this research were to identify the current trends in HFE methods and tools, determine their applicability to NRC safety reviews, and identify topics for which the NRC may need additional guidance to support the NRC's safety reviews. We conducted a survey that identified over 100 new HFE M&Ts. The M&Ts were assessed to identify general trends. Seven trends were identified: Computer Applications for Performing Traditional Analyses, Computer-Aided Design, Integration of HFE Methods and Tools, Rapid Development Engineering, Analysis of Cognitive Tasks, Use of Virtual Environments and Visualizations, and Application of Human Performance Models. We assessed each trend to determine its applicability to the NRC's review by considering (1) whether the nuclear industry is making use of M&Ts for each trend, and (2) whether M&Ts reflecting the trend can be reviewed using the current design review guidance. We concluded that M&T trends that are applicable to the commercial nuclear industry and are expected to impact safety reviews may be considered for review guidance development. Three trends fell into this category: Analysis of Cognitive Tasks, Use of Virtual Environments and Visualizations, and Application of Human Performance Models. The other trends do not need to be addressed at this time.

  14. HFE Process Guidance and Standards for potential application to updating NRC guidance

    Energy Technology Data Exchange (ETDEWEB)

    Jacques Hugo; J. J. Persensky

    2012-07-01

    The U.S. Nuclear Regulatory Commission (NRC) reviews and evaluates the human factors engineering (HFE) programs of applicants for nuclear power plant construction permits, operating licenses, standard design certifications, and combined operating licenses. The purpose of these safety reviews is to help ensure that personnel performance and reliability are appropriately supported. Detailed design review procedures and guidance for the evaluations is provided in three key documents: the Standard Review Plan (NUREG-0800), the HFE Program Review Model (NUREG-0711), and the Human-System Interface Design Review Guidelines (NUREG-0700). These documents were last revised in 2007, 2004 and 2002, respectively. The NRC is committed to the periodic update and improvement of these guidance documents to ensure that they remain state-of-the-art design evaluation tools. Thus, the NRC has initiated a project with BNL to update the NRC guidance to remain current with recent research on human performance, advances in HFE methods and tools, and new technology. INL supported Brookhaven National Lab (BNL) to update the detailed HFE review criteria contained in NUREG-0711 and NUREG-0700 based on (1) feedback obtained from end users, (2) the results of NRC research and development efforts supporting the NRC staff’s HFE safety reviews, and (3) other material the project staff identify as applicable to the update effort. INL submitted comments on development plans and sections of NUREGs 0800, 0711, and 0700. The contractor prepared the report attached here as the deliverable for this work.

  15. Energy and Exergy Analyses of CO2/HFE7000 Cascade Cooling System

    Directory of Open Access Journals (Sweden)

    Fatih YILMAZ

    2017-10-01

    Full Text Available In this study, a new refrigerant HFE7000, has been investigated thermodynamically in the cascade cooling system. Energy (COP and exergy efficiency of cascade cooling system with CO2/HFE7000 refrigerants are performed. In this regard, the impacts of various parameters on the COP and exergy efficiency and exergy destruction rate of CCS are studied. Moreover, the CO2 refrigerant is used in the low-temperature circuit and HFE7000 is used in the high-temperature circuit. The COP and exergy efficiency of cascade cooling system are found as 2.313 and 0.5482, for cooling application. In the last section, comparison with R134a refrigerant is done, which is widely used in cascade cooling system.

  16. HFE Mutations Modulate the Effect of Iron on Serum Hepcidin-25 in Chronic Hemodialysis Patients

    Science.gov (United States)

    Girelli, Domenico; Valenti, Giovanni Francesco; Castagna, Annalisa; Como, Giovanna; Campostrini, Natascia; Rametta, Raffaela; Dongiovanni, Paola; Messa, Piergiorgio

    2009-01-01

    Background and objectives: Increased serum hepcidin has been reported in patients receiving chronic hemodialysis, and hypothesized to contribute to the alterations of iron metabolism of end-stage renal disease. However, no quantitative assessment is available to date; the clinical determinants are still under definition; and the role of genetic factors, namely HFE mutations, has not yet been evaluated. The aim of this study was to quantitatively assess serum hepcidin-25 in hemodialysis patients versus controls, and analyze the relationship between hepcidin, iron indices, HFE genotype, and erythropoietic parameters. Design, setting, participants & measurements: Sixty-five hemodialysis patients and 57 healthy controls were considered. Hepcidin-25 was evaluated by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, HFE genotype by restriction analysis. Results: Serum hepcidin-25 was higher in hemodialysis patients compared with controls. In patients, hepcidin-25 correlated positively with ferritin and C reactive protein, and negatively with serum iron after adjustment for confounders. Hepcidin/ferritin ratio was lower in patients with (n = 25) than in those without (n = 40) HFE mutations. At multivariate analysis, hepcidin-25 was independently associated with ferritin and HFE status. In a subgroup of 22 “stable” patients, i.e., with Hb levels on target, normal CRP levels, and absence of complications for at least 1 yr, hepcidin-25 was negatively correlated with Hb levels independently of confounders. Conclusions: Serum hepcidin-25 is increased in hemodialysis patients, regulated by iron stores and inflammation, and relatively reduced in subjects carrying frequent HFE mutations. Hepcidin-25 may contribute to the pathogenesis of anemia by decreasing iron availability. PMID:19541813

  17. An Excel Macro to Plot the HFE-Diagram to Identify Sea Water Intrusion Phases.

    Science.gov (United States)

    Giménez-Forcada, Elena; Sánchez San Román, F Javier

    2015-01-01

    A hydrochemical facies evolution diagram (HFE-D) is a multirectangular diagram, which is a useful tool in the interpretation of sea water intrusion processes. This method note describes a simple method for generating an HFE-D plot using the spreadsheet software package, Microsoft Excel. The code was applied to groundwater from the alluvial coastal plain of Grosseto (Tuscany, Italy), which is characterized by a complex salinization process in which sea water mixes with sulfate or bicarbonate recharge water. © 2014, National GroundWater Association.

  18. Reduced white matter MRI transverse relaxation rate in cognitively normal H63D-HFE human carriers and H67D-HFE mice.

    Science.gov (United States)

    Meadowcroft, Mark D; Wang, Jianli; Purnell, Carson J; Peters, Douglas G; Eslinger, Paul J; Neely, Elizabeth B; Gill, David J; Vasavada, Megha; Ali-Rahmani, Fatima; Yang, Qing X; Connor, James R

    2016-12-01

    Mutations within the HFE protein gene sequence have been associated with increased risk of developing a number of neurodegenerative disorders. To this effect, an animal model has been created which incorporates the mouse homologue to the human H63D-HFE mutation: the H67D-HFE knock-in mouse. These mice exhibit alterations in iron management proteins, have increased neuronal oxidative stress, and a disruption in cholesterol regulation. However, it remains undetermined how these differences translate to human H63D carriers in regards to white matter (WM) integrity. To this endeavor, MRI transverse relaxation rate (R2) parametrics were employed to test the hypothesis that WM alterations are present in H63D human carriers and are recapitulated in the H67D mice. H63D carriers exhibit widespread reductions in brain R2 compared to non-carriers within white matter association fibers in the brain. Similar R2 decreases within white matter tracts were observed in the H67D mouse brain. Additionally, an exacerbation of age-related R2 decrease is found in the H67D animal model in white matter regions of interest. The decrease in R2 within white matter tracts of both species is speculated to be multifaceted. The R2 changes are hypothesized to be due to alterations in axonal biochemical tissue composition. The R2 changes observed in both the human-H63D and mouse-H67D data suggest that modified white matter myelination is occurring in subjects with HFE mutations, potentially increasing vulnerability to neurodegenerative disorders.

  19. Apomixis and the problem of obtaining haploids and homozygote diploids in pear (Pyrus communis L.

    Directory of Open Access Journals (Sweden)

    Є. О. Долматов

    2013-02-01

    Full Text Available The article highlights results of research over simulative apomixes in pear and its utilization for obtaining haploids and homozygote diploids. It has been established that over 50% pear varieties with failed remote hybridization are capable of generating seeds of apomictic origin producing diploid plants. Genotypes displaying maximal inclination to apomixes have been singled out. Apomictic pear seedlings obtained from foreign pollination within the limits of the same combination are inherent in profound morphological diversity. Fruit-bearing apomicts originated from one and the same maternal plant differ to the same extent as hybrid seedlings of the same family. Genetic markers have enabled to establish that these are embryo sacs in which meiosis has completed that give rise to apomictic seeds. In vitro method as used for the purpose of increasing apomictic plants output has been illustrated. The greatest induction of apomictic shoots in vitro has been reached by alternation of BAP cytokinin at concentration of 1mg/l and 2 mg/l on the background of GA3 amounting to 1,5 mg/l. Grafting with shoots in vitro on non-sterile rootstocks of pear (Pyrus communis has increased the output of plants up to 80%. A cytological assessment of 9 apomictic samples is provided. The cytological analysis of samples of apomictic forms has certified the presence of simulative haploid parthenogenesis in pear.

  20. Condensation of HFE-7100 vapor in a loop heat pipe having a curvilinear fin

    Directory of Open Access Journals (Sweden)

    Lyulin Yuriy

    2017-01-01

    Full Text Available Vapor condensation of the HFE-7100 in loop heat pipe was studied experimentally and theoretically. Numerical calculations of the vapor condensation on the curvilinear fin have been performed. Numerical, theoretical and experimental data are in a good agreement. Minimal condensate film thickness on the top of the fin has been determined and increases monotonously with the increase in the temperature drop.

  1. Hereditary hemochromatosis (HFE) genotypes in heart failure: relation to etiology and prognosis

    DEFF Research Database (Denmark)

    Møller, Daniel Vega; Pecini, Redi; Gustafsson, Finn

    2010-01-01

    It is believed that hereditary hemochromatosis (HH) might play a role in cardiac disease (heart failure (HF) and ischemia). Mutations within several genes are HH-associated, the most common being the HFE gene. In a large cohort of HF patients, we sought to determine the etiological role...

  2. Experimental study on pool boiling of distilled water and HFE7500 fluid under microgravity

    Science.gov (United States)

    Yang, Yan-jie; Chen, Xiao-qian; Huang, Yi-yong; Li, Guang-yu

    2018-02-01

    The experimental study on bubble behavior and heat transfer of pool boiling for distilled water and HFE7500 fluid under microgravity has been conducted by using drop tower in the National Microgravity Laboratory of China (NMLC). Two MCH ceramic plates of 20 mm(L) × 10 mm(W) × 1.2 mm(H) were used as the heaters. The nucleate boiling evolution under microgravity was observed during the experiment. It has been found that at the same heat flux, the bubbles of HFE7500 (which has smaller contact angle) grew faster and bigger, moved quickly on the heater surface, and were easier to merge into a central big bubble with other bubbles than that of distilled water. The whole process of bubbles coalescence from seven to one was recorded by using video camera. For distilled water (with bigger contact angle), the bubbles tended to keep at the nucleate location on heater surface, and the central big bubble evolved at its nucleate cite by absorbing smaller bubbles nearby. Compared with the bubbles under normal gravity, bubble radius of distilled water under microgravity was about 1.4 times bigger and of HFE7500 was about more than 6 times bigger till the end of experiment. At the beginning, pool boiling heat transfer of distilled water was advanced and then impeded under microgravity. As to HFE7500, the pool boiling impedes the heat transfer from heater to liquid under microgravity throughout the experiment.

  3. Hereditary hemochromatosis (HFE) genotypes in heart failure: relation to etiology and prognosis

    DEFF Research Database (Denmark)

    Møller, Daniel Vega; Pecini, Redi; Gustafsson, Finn

    2010-01-01

    It is believed that hereditary hemochromatosis (HH) might play a role in cardiac disease (heart failure (HF) and ischemia). Mutations within several genes are HH-associated, the most common being the HFE gene. In a large cohort of HF patients, we sought to determine the etiological role and the p...

  4. A family with hereditary hemochromatosis carrying HFE gene splice site mutation: a case report

    Directory of Open Access Journals (Sweden)

    NING Huibin

    2017-01-01

    Full Text Available ObjectiveTo investigate a new type of HFE gene mutation in a family with hereditary hemochromatosis (HH. MethodsThe analysis of HFE gene was performed for one patient with a confirmed diagnosis of HH and five relatives. Blood genomic DNA was extracted and PCR multiplication was performed for the exon and intron splice sequences of related HFE, HJV, HAMP, transferrin receptor 2 (TfR2, and SLC40A1 genes. After agarose gel electrophoresis and purification, bi-directional direct sequencing was performed to detect mutation sites. ResultsThe proband had abnormal liver function and increases in serum iron, total iron binding capacity, serum ferritin, and transferrin saturation, as well as T→C homozygous mutation in the fourth base of intron 2 in the intervening sequence of the exon EXON2 of HFE gene (IVs 2+4T→C, C/C homozygous, splicing, abnormal. There were no abnormalities in HJV, HAMP, TfR2, and SLC40A1 genes. The proband′s son had the same homozygous mutation, three relatives had heterozygous mutations, and one relative had no abnormal mutations. ConclusionGene detection plays an important role in the diagnosis of hemochromatosis, and IVs 2+4T→C mutation may be a new pathogenic mutation for HH in China.

  5. high prevalence of the cys282tyr hfe mutation facilitates an improved ...

    African Journals Online (AJOL)

    HIGH PREVALENCE OF THE. CYS282TYR HFE MUTATION. FACILITATES AN IMPROVED. DIAGNOSTIC SERVICE FOR. HEREDITARY HAEMO-. CHROMATOSIS IN SOUTH AFRICA. J Nico P de Villiers, Renate Hillerman, Greetje de Jong. Elzet Langenhoven, Heleen Rossouw, Munro P Marx,. Maritha J Kotze. Objective.

  6. G6PD A- deficiency and severe malaria in The Gambia: heterozygote advantage and possible homozygote disadvantage.

    Science.gov (United States)

    Sirugo, Giorgio; Predazzi, Irene M; Bartlett, Jacquelaine; Tacconelli, Alessandra; Walther, Michael; Williams, Scott M

    2014-05-01

    Glucose-6-phosphate dehydrogenase (G6PD) deficiency is frequent in Africa, because it confers resistance to Plasmodium falciparum malaria; however, the nature of the protection and the genotypes associated with it have been controversial. In 1972, Bienzle and others described protection from malaria in West African females heterozygous for G6PD A-. They determined that G6PD A- heterozygotes had lower parasite counts than A- homozygotes, hemizygous males, and normal individuals. However, other studies have reached different conclusions about the protective genotypes. DNA samples from 135 children with severe malaria and 146 children with mild malaria from The Gambia were genotyped for the G6PD A- mutation that is most frequent among Gambians (G6PD 968 T->C); there was a marked deficiency of heterozygotes and an excess of homozygotes with severe malaria, producing a strong deviation from Hardy-Weinberg equilibrium. Our results support the protective effect in G6PD A- heterozygous females and suggest that homozygotes might be more susceptible to severe malaria attacks.

  7. Effects of simulated weightlessness on cellular morphology and biological characteristics of cell lines SGC-7901 and HFE-145

    National Research Council Canada - National Science Library

    Zhu, M; Jin, X W; Wu, B Y; Nie, J L; Li, Y H

    2014-01-01

    We investigated the effects of simulated weightlessness on cellular morphology, proliferation, cell cycle, and apoptosis of the human gastric carcinoma cell line SGC-7901 and the human gastric normal cell line HFE-145...

  8. Combined deletion of Hfe and transferrin receptor 2 in mice leads to marked dysregulation of hepcidin and iron overload.

    Science.gov (United States)

    Wallace, Daniel F; Summerville, Lesa; Crampton, Emily M; Frazer, David M; Anderson, Gregory J; Subramaniam, V Nathan

    2009-12-01

    Hepcidin is a central regulator of iron homeostasis. HFE and transferrin receptor 2 (TFR2) are mutated in adult-onset forms of hereditary hemochromatosis and regulate the expression of hepcidin in response to iron. Whether they act through the same or parallel pathways is unclear. To investigate this, we generated a mouse model with deletion of both Hfe and Tfr2 genes by crossing Hfe and Tfr2 null mice on a genetically identical background. Tissue and serum from wildtype, single-, and double-null mice were analyzed. Serum transferrin saturation and hepatic iron concentrations were determined. The expression of iron-related messenger RNA (mRNA) transcripts was analyzed by real-time polymerase chain reaction (PCR). Levels of the iron-related proteins Tfr1, Tfr2, ferritin, and prohepcidin, and the phosphorylation status of the cell signaling proteins extracellular signal-regulated kinase 1/2 (Erk1/2) and Smad1/5/8, were analyzed by immunoblotting. Double-null mice had more severe iron loading than mice lacking either Hfe or Tfr2; Tfr2 null mice had a greater iron burden than Hfe-null mice. Hepcidin expression relative to iron stores was reduced in the Hfe-null mice, with significantly lower values in the Tfr2-null mice. In the absence of both Hfe and Tfr2, hepcidin expression was reduced even further. A significant decrease in phospho-Erk1/2 in the livers of null mice and a reduction in phospho-Smad1/5/8 suggest that both the mitogen-activated protein kinase (MAPK) and bone morphogenetic protein / mothers against decapentaplegic homolog (BMP/SMAD) signaling pathways may be involved in Hfe- and Tfr2-mediated regulation of hepcidin. These studies demonstrate that iron overload due to deletion of Tfr2 is more severe than that due to Hfe, and that loss of both molecules results in pronounced iron overload. Analysis of Hfe/Tfr2 double-null mice suggests that Hfe and Tfr2 regulate hepcidin through parallel pathways involving Erk1/2 and Smad1/5/8.

  9. The hemochromatosis proteins HFE, TfR2, and HJV form a membrane-associated protein complex for hepcidin regulation.

    Science.gov (United States)

    D'Alessio, Flavia; Hentze, Matthias W; Muckenthaler, Martina U

    2012-11-01

    The hereditary hemochromatosis-associated membrane proteins HFE, TfR2, and HJV are required for adequate hepatic expression of the iron hormone hepcidin. While the genetic interactions are clear, it remains elusive how bone morphogenetic protein co-receptor HJV functions together with HFE and TfR2 to activate hepcidin transcription via the BMP-SMAD signaling pathway. Here, we investigate whether HFE, TfR2, and HJV physically interact on the surface of hepatocytes. We explore protein-protein interactions by glycerol gradient sedimentation assays and co-immunoprecipitation analyses in transfected HuH7 hepatoma-derived cells. Our data demonstrate that HFE and TfR2 bind HJV in a non-competitive manner. Co-immunoprecipitation analyses provide direct experimental evidence that HFE, TfR2, and HJV form a multi-protein membrane complex. Our experiments show that like TfR2, HJV competes with TfR1 for binding to HFE, indicating that the expression of TfR2 and HJV may be critical for iron sensing. We identify residues 120-139 of the TfR2 extra-cellular domain as the critical amino acids required for the binding of both HFE and HJV. Interestingly, RGMA, a central nervous system homolog, can substitute for HJV in the complex and promote hepcidin transcription, implicating RGMA in the local control of hepcidin in the CNS. Taken together, our findings provide a biochemical basis for hepcidin control by HFE, TfR2, and HJV. Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  10. Interaction of the Hereditary Hemochromatosis Protein, HFE, with Transferrin Receptor 2 Is Required for Transferrin-Induced Hepcidin Expression

    Science.gov (United States)

    Gao, Junwei; Chen, Juxing; Kramer, Maxwell; Tsukamoto, Hidekazu; Zhang, An-Sheng; Enns, Caroline A.

    2009-01-01

    SUMMARY The mechanisms that allow the body to sense iron levels in order to maintain iron homeostasis are unknown. Patients with the most common form of hereditary iron overload have mutations in the hereditary hemochromatosis protein, HFE. They have lower levels of hepcidin, than unaffected individuals. Hepcidin, a hepatic peptide hormone, negatively regulates iron efflux from the intestines into the blood. We report two hepatic cell lines, WIF-B cells and HepG2 cells transfected with HFE, where hepcidin expression responded to iron-loaded transferrin. The response was abolished when endogenous transferrin receptor 2 (TfR2) was suppressed or in primary hepatocytes lacking either functional TfR2 or HFE. Furthermore, transferrin-treated HepG2 cells transfected with HFE chimeras containing only the α3 and cytoplasmic domains could upregulate hepcidin expression. Since the HFE α3 domain interacts with TfR2, these results supported our finding that TfR2/HFE complex is required for transcriptional regulation of hepcidin by holo-Tf. PMID:19254567

  11. Parenteral vs. oral iron: influence on hepcidin signaling pathways through analysis of Hfe/Tfr2-null mice.

    Science.gov (United States)

    McDonald, Cameron J; Wallace, Daniel F; Ostini, Lesa; Subramaniam, V Nathan

    2014-01-01

    Treatment for iron deficiency anemia can involve iron supplementation via dietary or parenteral routes that result in different cellular iron distributions. The effect of the administered iron on the iron regulatory system and hepcidin in the liver has not been well studied. Hepcidin, the liver-expressed central iron-regulatory peptide, is itself regulated through the bone morphogenetic protein (BMP)/SMAD signaling pathway. Specifically, Bmp6 expression is upregulated in response to iron and induces hepcidin through phosphorylation of Smad1/5/8. The hemochromatosis-associated proteins Hfe and transferrin receptor 2 (Tfr2) are known upstream regulators of hepcidin, although their precise roles are still unclear. To investigate the mechanisms of this regulation and the roles of the Hfe and Tfr2, we subjected wild-type, Hfe(-/-), Tfr2(-/-), and Hfe(-/-)/Tfr2(-/-) mice to iron loading via dietary or parenteral routes. Systematic analysis demonstrated that Tfr2 is required for effective upregulation of Bmp6 in response to hepatocyte iron, but not nonparenchymal iron. Hfe is not required for Bmp6 upregulation, regardless of iron localization, but rather, is required for efficient downstream transmission of the regulatory signal. Our results demonstrate that Hfe and Tfr2 play separate roles in the regulatory responses to iron compartmentalized in different cell types and further elucidates the regulatory mechanisms controlling iron homeostasis.

  12. A systematic review of human factors and ergonomics (HFE)-based healthcare system redesign for quality of care and patient safety.

    Science.gov (United States)

    Xie, Anping; Carayon, Pascale

    2015-01-01

    Healthcare systems need to be redesigned to provide care that is safe, effective and efficient, and meets the multiple needs of patients. This systematic review examines how human factors and ergonomics (HFE) is applied to redesign healthcare work systems and processes and improve quality and safety of care. We identified 12 projects representing 23 studies and addressing different physical, cognitive and organisational HFE issues in a variety of healthcare systems and care settings. Some evidence exists for the effectiveness of HFE-based healthcare system redesign in improving process and outcome measures of quality and safety of care. We assessed risk of bias in 16 studies reporting the impact of HFE-based healthcare system redesign and found varying quality across studies. Future research should further assess the impact of HFE on quality and safety of care, and clearly define the mechanisms by which HFE-based system redesign can improve quality and safety of care.

  13. HFE Mutations Modulate the Effect of Iron on Serum Hepcidin-25 in Chronic Hemodialysis Patients

    OpenAIRE

    Valenti, Luca; Girelli, Domenico; Valenti, Giovanni Francesco; Castagna, Annalisa; Como, Giovanna; Campostrini, Natascia; Rametta, Raffaela; Dongiovanni, Paola; Messa, Piergiorgio; Fargion, Silvia

    2009-01-01

    Background and objectives: Increased serum hepcidin has been reported in patients receiving chronic hemodialysis, and hypothesized to contribute to the alterations of iron metabolism of end-stage renal disease. However, no quantitative assessment is available to date; the clinical determinants are still under definition; and the role of genetic factors, namely HFE mutations, has not yet been evaluated. The aim of this study was to quantitatively assess serum hepcidin-25 in hemodialysis patien...

  14. Co-localization of the mammalian hemochromatosis gene product (HFE) and a newly identified transferrin receptor (TfR2) in intestinal tissue and cells.

    Science.gov (United States)

    Griffiths, William J H; Cox, Timothy M

    2003-05-01

    Mutations in the HFE gene and a newly identified second transferrin receptor gene, TfR2, cause hemochromatosis. The cognate proteins, HFE and TfR2, are therefore of key importance in human iron homeostasis. HFE is expressed in small intestinal crypt cells where transferrin-iron entry may determine subsequent iron absorption by mature enterocytes, but the physiological function of TfR2 is unknown. Using specific peptide antisera, we examined the duodenal localization of HFE and TfR2 in humans and mice, with and without HFE deficiency, by confocal microscopy. We also investigated potential interactions of these proteins in human intestinal cells in situ. Duodenal expression of HFE and TfR2 (but not TfR1) in wild-type mice and humans was restricted to crypt cells, in which they co-localized. HFE deficiency disrupted this interaction, altering the cellular distribution of TfR2 in human crypts. In human Caco-2 cells, HFE and TfR2 co-localized to a distinct CD63-negative vesicular compartment showing marked signal enhancement on exposure to iron-saturated transferrin ligand, indicating that HFE preferentially interacts with TfR2 in a specialized early endosomal transport pathway for transferrin-iron. This interaction occurs specifically in small intestinal crypt cells that differentiate to become iron-absorbing enterocytes. Our immunohistochemical findings provide evidence for a novel mechanism for the regulation of iron balance in mammals.

  15. A systematic review of Human Factors and Ergonomics (HFE)-based healthcare system redesign for quality of care and patient safety

    Science.gov (United States)

    Xie, Anping; Carayon, Pascale

    2014-01-01

    Healthcare systems need to be redesigned to provide care that is safe, effective and efficient, and meets the multiple needs of patients. This systematic review examines how Human Factors and Ergonomics (HFE) is applied to redesign healthcare work systems and processes and improve quality and safety of care. We identified twelve projects representing 23 studies and addressing different physical, cognitive and organizational HFE issues in a variety of healthcare systems and care settings. Some evidence exists for the effectiveness of HFE-based healthcare system redesign in improving process and outcome measures of quality and safety of care. We assessed risk of bias in 16 studies reporting the impact of HFE-based healthcare system redesign and found varying quality across studies. Future research should further assess the impact of HFE on quality and safety of care, and clearly define the mechanisms by which HFE-based system redesign can improve quality and safety of care. Practitioner Summary Existing evidence shows that HFE-based healthcare system redesign has the potential to improve quality of care and patient safety. Healthcare organizations need to recognize the importance of HFE-based healthcare system redesign to quality of care and patient safety, and invest resources to integrate HFE in healthcare improvement activities. PMID:25323570

  16. Intracardiac and intracerebral thrombosis associated with methylenetetrahydrofolate reductase A1298C homozygote mutation in paediatric steroidresistant nephrotic syndrome

    Directory of Open Access Journals (Sweden)

    Rahime Renda

    2016-12-01

    Full Text Available Thromboembolic complications are a significant cause of morbidity and mortality in cases of nephrotic syndrome. Hereditary thrombophilias are also known to increase vascular thrombosis. We present a case that has been followed up for steroid-resistant nephrotic syndrome (NS in which intracardiac and intracranial thrombosis subsequently developed. The patient was found to have a homozygote mutation in the methylenetetrahydrofolate reductase (MTHFR gene as an additional risk factor for recurrent thrombosis. MTHFR mutation with NS was considered to have an important effect on the development of life-threatening thrombosis.

  17. Iron regulation of hepcidin despite attenuated Smad1,5,8 signaling in mice without transferrin receptor 2 or Hfe.

    Science.gov (United States)

    Corradini, Elena; Rozier, Molly; Meynard, Delphine; Odhiambo, Adam; Lin, Herbert Y; Feng, Qi; Migas, Mary C; Britton, Robert S; Babitt, Jodie L; Fleming, Robert E

    2011-11-01

    HFE and transferrin receptor 2 (TFR2) are each necessary for the normal relationship between body iron status and liver hepcidin expression. In murine Hfe and Tfr2 knockout models of hereditary hemochromatosis (HH), signal transduction to hepcidin via the bone morphogenetic protein 6 (Bmp6)/Smad1,5,8 pathway is attenuated. We examined the effect of dietary iron on regulation of hepcidin expression via the Bmp6/Smad1,5,8 pathway using mice with targeted disruption of Tfr2, Hfe, or both genes. Hepatic iron concentrations and messenger RNA expression of Bmp6 and hepcidin were compared with wild-type mice in each of the HH models on standard or iron-loading diets. Liver phospho-Smad (P-Smad)1,5,8 and Id1 messenger RNA levels were measured as markers of Bmp/Smad signaling. Whereas Bmp6 expression was increased, liver hepcidin and Id1 expression were decreased in each of the HH models compared with wild-type mice. Each of the HH models also showed attenuated P-Smad1,5,8 levels relative to liver iron status. Mice with combined Hfe/Tfr2 disruption were most affected. Dietary iron loading increased hepcidin and Id1 expression in each of the HH models. Compared with wild-type mice, HH mice demonstrated attenuated (Hfe knockout) or no increases in P-Smad1,5,8 levels in response to dietary iron loading. These observations show that Tfr2 and Hfe are each required for normal signaling of iron status to hepcidin via the Bmp6/Smad1,5,8 pathway. Mice with combined loss of Hfe and Tfr2 up-regulate hepcidin in response to dietary iron loading without increases in liver Bmp6 messenger RNA or steady-state P-Smad1,5,8 levels. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

  18. The hereditary hemochromatosis protein, HFE, specifically regulates transferrin-mediated iron uptake in HeLa cells.

    Science.gov (United States)

    Roy, C N; Penny, D M; Feder, J N; Enns, C A

    1999-03-26

    HFE is the protein product of the gene mutated in the autosomal recessive disease hereditary hemochromatosis (Feder, J. N., Gnirke, A., Thomas, W., Tsuchihashi, Z., Ruddy, D. A., Basava, A., Dormishian, F., Domingo, R. J., Ellis, M. C., Fullan, A., Hinton, L. M., Jones, N. L., Kimmel, B. E., Kronmal, G. S., Lauer, P., Lee, V. K., Loeb, D. B., Mapa, F. A., McClelland, E., Meyer, N. C., Mintier, G. A., Moeller, N., Moore, T., Morikang, E., Prasss, C. E., Quintana, L., Starnes, S. M., Schatzman, R. C., Brunke, K. J., Drayna, D. T., Risch, N. J., Bacon, B. R., and Wolff, R. R. (1996) Nat. Genet. 13, 399-408). At the cell surface, HFE complexes with transferrin receptor (TfR), increasing the dissociation constant of transferrin (Tf) for its receptor 10-fold (Gross, C. N., Irrinki, A., Feder, J. N., and Enns, C. A. (1998) J. Biol. Chem. 273, 22068-22074; Feder, J. N., Penny, D. M., Irrinki, A., Lee, V. K., Lebron, J. A., Watson, N. , Tsuchihashi, Z., Sigal, E., Bjorkman, P. J., and Schatzman, R. C. (1998) Proc. Natl. Acad. Sci. U S A 95, 1472-1477). HFE does not remain at the cell surface, but traffics with TfR to Tf-positive internal compartments (Gross et al., 1998). Using a HeLa cell line in which the expression of HFE is controlled by tetracycline, we show that the expression of HFE reduces 55Fe uptake from Tf by 33% but does not affect the endocytic or exocytic rates of TfR cycling. Therefore, HFE appears to reduce cellular acquisition of iron from Tf within endocytic compartments. HFE specifically reduces iron uptake from Tf, as non-Tf-mediated iron uptake from Fe-nitrilotriacetic acid is not altered. These results explain the decreased ferritin levels seen in our HeLa cell system and demonstrate the specific control of HFE over the Tf-mediated pathway of iron uptake. These results also have implications for the understanding of cellular iron homeostasis in organs such as the liver, pancreas, heart, and spleen that are iron loaded in hereditary hemochromatotic

  19. Association of mutations in the hemochromatosis gene with shorter life expectancy

    DEFF Research Database (Denmark)

    Bathum, L; Christiansen, L; Nybo, H

    2001-01-01

    in the distribution of mutations in exon 2 in the different age groups. CONCLUSIONS: In a high-carrier frequency population like Denmark, mutations in HFE show an age-related reduction in the frequency of heterozygotes for C282Y, which suggests that carrier status is associated with shorter life expectancy....

  20. Haemochromatosis gene mutation H63D is a risk factor for iron ...

    African Journals Online (AJOL)

    Introduction: Iron overload is the main cause of morbidity and mortality in patients with β-thalassemia. The Aim: The aim of this study was to evaluate the prevalence of genetic markers (HFE mutations C282Y and H63D) among Egyptian β-thalassemic. Children and its effect on their iron status. Patients and Methods: 59 ...

  1. Gestión de la calidad en paneles de puerta HFE

    OpenAIRE

    Sanz Aceves, Miguel

    2017-01-01

    Este Trabajo Fin de Máster detalla las actividades realizadas en control y seguimiento de la calidad en los proyectos HFE de producción de paneles de puerta, durante el período de prácticas curriculares. En esta estancia he podido colaborar con otros técnicos de calidad responsables de la calidad de estos proyectos. Las tareas principales han sido gestión de proveedores, seguimiento de la calidad en el área de retoque final y muro de calidad Departamento de Construcciones Ar...

  2. Ultrasensitive detection of scrapie prion protein derived from ARQ and AHQ homozygote sheep by interspecies in vitro amplification.

    Science.gov (United States)

    Murayama, Yuichi; Imamura, Morikazu; Masujin, Kentaro; Shimozaki, Noriko; Yoshioka, Miyako; Mohri, Shirou; Yokoyama, Takashi

    2012-08-01

    Prions, infectious agents causing TSEs, are composed primarily of the pathogenic form (PrP(Sc)) of the PrP(C). The susceptibility of sheep to scrapie is determined by polymorphisms in the coding region of the PRNP, mainly at codons 136, 154, and 171. The efficiency of in vitro amplification of sheep PrP(Sc) seems to be linked also to the PrP genotype. PrP(Sc) derived from sheep with V(136)R(154)Q(171)-associated genotypes can be amplified efficiently by PMCA in the presence of additional polyanion such as poly A, but there are no reports that cite ultrasensitive detection of PrP(Sc) derived from sheep of other PrP genotypes. We report here that sheep PrP(Sc) derived from ARQ and AHQ homozygotes was amplified efficiently by serial PMCA using mouse brain homogenate as PrP(C) substrate. ARQ/ARQ PrP(Sc) was detected in infected brain homogenates diluted up to 10(-10) after five rounds of amplification, and AHQ/AHQ PrP(Sc) was detected in samples diluted up to 10(-8) after four rounds of amplification. On the other hand, amplification of PrP(Sc) from VRQ/ARQ sheep seemed to be less efficient under the experimental conditions used. The interspecies PMCA developed in this study may be useful in the detailed analysis of PrP(Sc) distribution in classical scrapie-infected ARQ and AHQ homozygote sheep. © 2012 The Societies and Blackwell Publishing Asia Pty Ltd.

  3. Mudd's disease (MAT I/III deficiency): a survey of data for MAT1A homozygotes and compound heterozygotes.

    Science.gov (United States)

    Chien, Yin-Hsiu; Abdenur, Jose E; Baronio, Federico; Bannick, Allison Anne; Corrales, Fernando; Couce, Maria; Donner, Markus G; Ficicioglu, Can; Freehauf, Cynthia; Frithiof, Deborah; Gotway, Garrett; Hirabayashi, Koichi; Hofstede, Floris; Hoganson, George; Hwu, Wuh-Liang; James, Philip; Kim, Sook; Korman, Stanley H; Lachmann, Robin; Levy, Harvey; Lindner, Martin; Lykopoulou, Lilia; Mayatepek, Ertan; Muntau, Ania; Okano, Yoshiyuki; Raymond, Kimiyo; Rubio-Gozalbo, Estela; Scholl-Bürgi, Sabine; Schulze, Andreas; Singh, Rani; Stabler, Sally; Stuy, Mary; Thomas, Janet; Wagner, Conrad; Wilson, William G; Wortmann, Saskia; Yamamoto, Shigenori; Pao, Maryland; Blom, Henk J

    2015-08-20

    This paper summarizes the results of a group effort to bring together the worldwide available data on patients who are either homozygotes or compound heterozygotes for mutations in MAT1A. MAT1A encodes the subunit that forms two methionine adenosyltransferase isoenzymes, tetrameric MAT I and dimeric MAT III, that catalyze the conversion of methionine and ATP to S-adenosylmethionine (AdoMet). Subnormal MAT I/III activity leads to hypermethioninemia. Individuals, with hypermethioninemia due to one of the MAT1A mutations that in heterozygotes cause relatively mild and clinically benign hypermethioninemia are currently often being flagged in screening programs measuring methionine elevation to identify newborns with defective cystathionine β-synthase activity. Homozygotes or compound heterozygotes for MAT1A mutations are less frequent. Some but not all, such individuals have manifested demyelination or other CNS abnormalities. The goals of the present effort have been to determine the frequency of such abnormalities, to find how best to predict whether they will occur, and to evaluate the outcomes of the variety of treatment regimens that have been used. Data have been gathered for 64 patients, of whom 32 have some evidence of CNS abnormalities (based mainly on MRI findings), and 32 do not have such evidence. The results show that mean plasma methionine concentrations provide the best indication of the group into which a given patient will fall: those with means of 800 μM or higher usually have evidence of CNS abnormalities, whereas those with lower means usually do not. Data are reported for individual patients for MAT1A genotypes, plasma methionine, total homocysteine (tHcy), and AdoMet concentrations, liver function studies, results of 15 pregnancies, and the outcomes of dietary methionine restriction and/or AdoMet supplementation. Possible pathophysiological mechanisms that might contribute to CNS damage are discussed, and tentative suggestions are put forth as

  4. Interaction of Dietary and Genetic Factors Influencing Body Iron Status and Risk of Type 2 Diabetes Within the EPIC-InterAct Study

    DEFF Research Database (Denmark)

    Meidtner, Karina; Podmore, Clara; Kröger, Janine

    2018-01-01

    ferritin levels (β = 0.113 [95% CI 0.082; 0.144]), but not with transferrin (-0.019 [-0.043; 0.006]) or transferrin saturation (0.016 [-0.006; 0.037]). Five SNPs located in four genes (rs1799945 [HFE H63D], rs1800562 [HFE C282Y], rs236918 [PCK7], rs744653 [SLC40A1], and rs855791 [TMPRSS6 V736A]) were...

  5. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22.

    Science.gov (United States)

    Camaschella, C; Roetto, A; Calì, A; De Gobbi, M; Garozzo, G; Carella, M; Majorano, N; Totaro, A; Gasparini, P

    2000-05-01

    Haemochromatosis is a common recessive disorder characterized by progressive iron overload, which may lead to severe clinical complications. Most patients are homozygous for the C282Y mutation in HFE on 6p (refs 1-5). A locus for juvenile haemochromatosis (HFE2) maps to 1q (ref. 7). Here we report a new locus (HFE3) on 7q22 and show that a homozygous nonsense mutation in the gene encoding transferrin receptor-2 (TFR2) is found in people with haemochromatosis that maps to HFE3.

  6. Hemochromatosis (HFE) gene mutations and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study

    NARCIS (Netherlands)

    Agudo, A.; Bonet, C.; Sala, N.; Munoz, X.; Aranda, N.; Fonseca-Nunes, A.; Clavel-Chapelon, F.; Boutron-Ruault, M.C.; Vineis, P.; Panico, S; Palli, D.; Tumino, R.; Grioni, S.; Quiros, J.R.; Molina, E.; Navarro, C.; Barricarte, A; Chamosa, S.; Allen, N.E.; Khaw, K.T.; Bueno-de-Mesquita, H.B.; Siersema, P.D.; Numans, M.E.; Trichopoulou, A.; Lagiou, P.; Trichopoulos, D.; Kaaks, R.; Canzian, F.; Boeing, H; Meidtner, K.; Johansson, M.; Sund, M.; Manjer, J.; Overvad, K.; Tjonneland, A.; Lund, E.; Weiderpass, E; Jenab, M.; Fedirko, V.; Offerhaus, G.J.A.; Riboli, E.; Gonzalez, CA; Jakszyn, P.

    2013-01-01

    Hereditary hemochromatosis (HH) is a strong risk factor for hepatocellular cancer, and mutations in the HFE gene associated with HH and iron overload may be related to other tumors, but no studies have been reported for gastric cancer (GC). A nested case- control study was conducted within the

  7. Total and cause-specific mortality by elevated transferrin saturation and hemochromatosis genotype in individuals with diabetes - two general population studies

    DEFF Research Database (Denmark)

    Ellervik, Christina; Mandrup-Poulsen, Thomas; Tybjærg-Hansen, Anne

    2013-01-01

    ObjectiveMortality is increased in patients with hereditary hemochromatosis, in individuals from the general population with increased transferrin saturation(TS), and also in patients with diabetes type 1 and increased TS from a highly specialised diabetes clinic. Thus, we have recommended targeted...... and hemochromatosis genotype(HFE) C282Y/C282Y in individuals with diabetes(type 1,N=118;type 2,N=3228;total,N=3346).ResultsThe cumulative survival was reduced in individuals with diabetes with TS≥50% vs....

  8. In-silico Molecular Analysis of Mutated Sequences of HFE1, HFE2, TFR2 and SLC40A1 causing Hemochromatosis Disease

    Directory of Open Access Journals (Sweden)

    Bilal Hussain

    2011-05-01

    Full Text Available Hemochromatosis is a disorder in iron metabolism that is characterized by excess iron absorption. There are two forms of hemochromatosis: primary hemochromatosis is caused by a problem with your genes. Secondary or acquired hemochromatosis can be caused by other diseases. The main objective of this study is to analyze structure of different types of proteins involved in hemochromatosis. As this is the most threatening disease all over the world including Pakistan but unfortunately no data is available about it so it will be a great step to analyze the structure of its different proteins by using different online tools that gave different results according to their potential as each tool must show the same results for the same protein. Protein structure prediction is one of the most important goals persuaded by Bioinformatics for evolutionary studies and drug designing. Other objective of this project is to provide the prevalence of hemochromatosis in Faisalabad and structure prediction of its proteins to find the conserved regions. At the end the creation of a database is done that would contain all necessary information about diseases. Hereditary hemochromatosis is mainly caused by a defect in a gene called HFE. There are several types of genetic hemochromatosis. These include: Type I or Classic (HHC; Type II or Juvenile (JHC; Type III or Transferrin Receptor Mutation; and Type IV or Ferroportin Mutation. Most types of hereditary haemochromatosis have autosomal recessive inheritance, while type IV has autosomal dominant inheritance.

  9. Mutation in HFE gene decreases manganese accumulation and oxidative stress in the brain after olfactory manganese exposure.

    Science.gov (United States)

    Ye, Qi; Kim, Jonghan

    2016-06-01

    Increased accumulation of manganese (Mn) in the brain is significantly associated with neurobehavioral deficits and impaired brain function. Airborne Mn has a high systemic bioavailability and can be directly taken up into the brain, making it highly neurotoxic. While Mn transport is in part mediated by several iron transporters, the expression of these transporters is altered by the iron regulatory gene, HFE. Mutations in the HFE gene are the major cause of the iron overload disorder, hereditary hemochromatosis, one of the prevalent genetic diseases in humans. However, whether or not HFE mutation modifies Mn-induced neurotoxicity has not been evaluated. Therefore, our goal was to define the role of HFE mutation in Mn deposition in the brain and the resultant neurotoxic effects after olfactory Mn exposure. Mice carrying the H67D HFE mutation, which is homologous to the H63D mutation in humans, and their control, wild-type mice, were intranasally instilled with MnCl2 with different doses (0, 0.2, 1.0 and 5.0 mg kg(-1)) daily for 3 days. Mn levels in the blood, liver and brain were determined using inductively-coupled plasma mass spectrometry (ICP-MS). H67D mutant mice showed significantly lower Mn levels in the blood, liver, and most brain regions, especially in the striatum, while mice fed an iron-overload diet did not. Moreover, mRNA expression of ferroportin, an essential exporter of iron and Mn, was up-regulated in the striatum. In addition, the levels of isoprostane, a marker of lipid peroxidation, were increased in the striatum after Mn exposure in wild-type mice, but were unchanged in H67D mice. Together, our results suggest that the H67D mutation provides decreased susceptibility to Mn accumulation in the brain and neurotoxicity induced by inhaled Mn.

  10. Arvelig hemokromatose - nytten av screening

    Directory of Open Access Journals (Sweden)

    Arne Åsberg

    2009-10-01

    Full Text Available Arvelig hemokromatose fører til jernopphopning i kroppen, men gir sjelden alvorlig helseskade. Nesten alle hemokromatosepasienter i vårt land er homozygote for C282Y-mutasjonen i HFE-genet. Omtrent 7 per 1000 innbyggere har denne genotypen. Alvorlig syke blir bare omkring 5-15% av homozygote menn og nesten ingen kvinner. Likevel er det holdepunkter for at screening for hemokromatose blant friske, yngre menn kan være kostnadseffektivt. Det er relativt lett å påvise om en person er disponert for sykdommen, i god tid før den bryter ut, og forebyggende behandling er billig og effektiv. Imidlertid kan vi ikke forutsi hvilke screeningpositive personer som ubehandlet får alvorlig sykdom. Et kontrollert forsøk med screening bør gjennomføresHereditary hemochromatosis – benefits of screening. Hereditary hemochromatosis leads to iron accumulation in the body; however, serious illness due to hemochromatosis is rare. In Norway, almost all patients with hemochromatosis are homozygous for the C282Ymutation in the HFE-gene, a genotype carried by about 7 per 1000 inhabitants. Serious complications are seen in only about 5-15% of homozygous men and in very few women. Nevertheless, screening young men for hemochromatosis may be cost-effective. Detecting predisposed men is relatively straightforward, and prophylactic treatment is cheap and effective. However, we can not predict, among screen-positive men, the few who untreated will become seriously ill. A controlled screening trial should be conducted.

  11. Seasonal Changes in Brain Serotonin Transporter Binding in Short Serotonin Transporter Linked Polymorphic Region-Allele Carriers but Not in Long-Allele Homozygotes

    DEFF Research Database (Denmark)

    Kalbitzer, Jan; Erritzoe, David; Holst, Klaus K

    2010-01-01

    of the short 5-HTTLPR allele but not in homozygote carriers of the long allele. Conclusions: Our findings are in line with S-carriers having an increased response in neural circuits involved in emotional processing to stressful environmental stimuli but here demonstrated as a endophenotype with dynamic changes...

  12. Structural and Functional Abnormalities of the Neuromuscular Junction in the Trembler-J Homozygote Mouse Model of Congenital Hypomyelinating Neuropathy.

    Science.gov (United States)

    Scurry, Alexandra N; Heredia, Dante J; Feng, Cheng-Yuan; Gephart, Gregory B; Hennig, Grant W; Gould, Thomas W

    2016-04-01

    Mutations in peripheral myelin protein 22 (PMP22) result in the most common form of Charcot-Marie-Tooth (CMT) disease, CMT1A. This hereditary peripheral neuropathy is characterized by dysmyelination of peripheral nerves, reduced nerve conduction velocity, and muscle weakness. APMP22 point mutation in L16P (leucine 16 to proline) underlies a form of human CMT1A as well as the Trembler-J mouse model of CMT1A. Homozygote Trembler-J mice (Tr(J)) die early postnatally, fail to make peripheral myelin, and, therefore, are more similar to patients with congenital hypomyelinating neuropathy than those with CMT1A. Because recent studies of inherited neuropathies in humans and mice have demonstrated that dysfunction and degeneration of neuromuscular synapses or junctions (NMJs) often precede impairments in axonal conduction, we examined the structure and function of NMJs in Tr(J)mice. Although synapses appeared to be normally innervated even in end-stage Tr(J)mice, the growth and maturation of the NMJs were altered. In addition, the amplitudes of nerve-evoked muscle endplate potentials were reduced and there was transmission failure during sustained nerve stimulation. These results suggest that the severe congenital hypomyelinating neuropathy that characterizes Tr(J)mice results in structural and functional deficits of the developing NMJ. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

  13. The Homozygote VCPR155H/R155H Mouse Model Exhibits Accelerated Human VCP-Associated Disease Pathology

    Science.gov (United States)

    Nalbandian, Angèle; Llewellyn, Katrina J.; Kitazawa, Masashi; Yin, Hong Z.; Badadani, Mallikarjun; Khanlou, Negar; Edwards, Robert; Nguyen, Christopher; Mukherjee, Jogeshwar; Mozaffar, Tahseen; Watts, Giles; Weiss, John; Kimonis, Virginia E.

    2012-01-01

    Valosin containing protein (VCP) mutations are the cause of hereditary inclusion body myopathy, Paget's disease of bone, frontotemporal dementia (IBMPFD). VCP gene mutations have also been linked to 2% of isolated familial amyotrophic lateral sclerosis (ALS). VCP is at the intersection of disrupted ubiquitin proteasome and autophagy pathways, mechanisms responsible for the intracellular protein degradation and abnormal pathology seen in muscle, brain and spinal cord. We have developed the homozygous knock-in VCP mouse (VCPR155H/R155H) model carrying the common R155H mutations, which develops many clinical features typical of the VCP-associated human diseases. Homozygote VCPR155H/R155H mice typically survive less than 21 days, exhibit weakness and myopathic changes on EMG. MicroCT imaging of the bones reveal non-symmetrical radiolucencies of the proximal tibiae and bone, highly suggestive of PDB. The VCPR155H/R155H mice manifest prominent muscle, heart, brain and spinal cord pathology, including striking mitochondrial abnormalities, in addition to disrupted autophagy and ubiquitin pathologies. The VCPR155H/R155H homozygous mouse thus represents an accelerated model of VCP disease and can be utilized to elucidate the intricate molecular mechanisms involved in the pathogenesis of VCP-associated neurodegenerative diseases and for the development of novel therapeutic strategies. PMID:23029473

  14. Mutations in HFE and TFR2 genes in a Spanish patient with hemochromatosis.

    Science.gov (United States)

    Rueda, Alejandro del Castillo; Grande, Nuria Cuadrado; Fernández, Emilio Alvarez; Enríquez de Salamanca, Rafael; Sala, Luis Antonio Alvarez; Jiménez, María Josefa Morán

    2011-07-01

    Iron overload disease has a wide variety of genotypes. The genetic study of this disease confirms its hereditary nature and enables us to provide genetic counseling for first-degree relatives. We performed magnetic resonance imaging and liver biopsy in an asymptomatic patient with more than 1,000 µg/L of serum ferritin and studied the genes involved in this condition. The phenotype of iron overload is confirmed by a predominantly periportal pattern of iron deposits in the liver suggestive of genetic disease. In the case we present the molecular study revealed a double heterozygosity for the mutations c.187C>G (p.H63D) and c.840C>G (p.F280L) in the HFE and transferrin receptor 2 (TFR2) genes, respectively.

  15. Frekvensen af haemokromatoseassocierede mutationer i haemokromatosegenet i den danske befolkning. ØsterbroundersØgelsen

    DEFF Research Database (Denmark)

    Larsen, Lisbeth Enggaard; Ellervik, Christina; Appleyard, Merete

    2002-01-01

    INTRODUCTION: Hereditary haemochromatosis is an autosomal recessive condition characterised by systemic iron overload. In Northern Europe, 85-90% of patients with haemochromatosis are homozygous for the C282Y mutation in the HFE gene. In the present study, we determined the prevalence...... hereditary haemochromatosis the potentially most common inherited disorder in Denmark. However, in new studies from USA of the association between genotype and disease in unselected populations the penetrance is very low. On this background, population screening for the presence of these mutations...... of the haemochromatosis-associated mutations, C282Y and H63D, in the Danish general population. MATERIAL AND METHODS: We genotyped 9174 individuals from a random sample of the Danish general population (The Copenhagen City Heart Study), stratified by gender and age in 10-year age groups, for the presence of C282Y and H63...

  16. Hemochromatosis mutations in the general population

    DEFF Research Database (Denmark)

    Andersen, Rolf Vaern; Tybjaerg-Hansen, Anne; Appleyard, Merete

    2004-01-01

    The progression rate of iron overload in hereditary hemochromatosis in individuals in the general population is unknown. We therefore examined in the general population iron overload progression rate in C282Y homozygotes. Using a cohort study of the Danish general population, The Copenhagen City ...

  17. Etude de l’hémogramme dans la drépanocytose homozygote: à propos de 87 patients

    Science.gov (United States)

    Dahmani, Fatima; Benkirane, Souad; Kouzih, Jaafar; Woumki, Aziz; Mamad, Hassan; Masrar, Azlarab

    2016-01-01

    La drépanocytose homozygote, fait partie des hémoglobinopathies les plus fréquentes au Maroc. La drépanocytose est caractérisée par une grande variabilité d’expressions clinique et biologique qui dépendent des facteurs génétiques modulateurs et environnementaux. Elle se manifeste par une anémie régénérative de gravité très variable selon les individus. L’évolution spontanée en l’absence de traitement est le décès précoce. La drépanocytose est caractérisée par une grande variabilité d’expression clinique et biologique qui dépend des facteurs génétiques et environnementaux. Un tableau clinique sévère marqué par une fréquence de transfusion élevée et précoce, des complications infectieuses graves et une mortalité précoce. Un état inflammatoire constant caractérisé par des protéines inflammatoires élevées et état nutritionnel compromis. L’objectif est de déterminer le profil des paramètres hématologiques du drépanocytaire homozygote (SS) marocain au cours des stades stationnaires. Nous avons fait une étude descriptive transversale de 87 patients drépanocytaires (SS). Nous avons réalisé une étude biologique comportant: l’hémogramme avec étude morphologique des globules rouges en coloration MGG et numération automatique des réticulocytes. Les électrophorèses de l’hémoglobine à pH alcalin (8.8) sur gel d’agarose avec intégration densitométrique. L’âge moyen est de 13.22 ans ± 16.36 avec un sex- ratio (H/F) de 1.175 et des extrêmes allant de 0.6 à 36 ans. La répercussion de l’anémie sur le plan biologique, est intense chez 88.5% des patients, 67.8% ont une anémie normocytaire contre 29.9% présentant une microcytose, et 2.3% qui présentaient une macrocytose. Le degré d’anisocytose est lié au degré d’anémie, très évocatrice chez les drépanocytaires homozygotes S/S (95,4%). Une réticulocytose était observée chez nos patients (81,6%) et 52.9% présentaient une

  18. Potyviral resistance derived from cultivars of Phaseolus vulgaris carrying bc-3 co-segregates with homozygotic presence of a mutated eIF4E allele

    DEFF Research Database (Denmark)

    Naderpour, M; Lund, O Søgaard; Larsen, R

    2008-01-01

    -binding proteins, eIF4E, eIF(iso)4E and nCBP. In cultivars reported to carry bc-3 resistance, eIF4E was found to display non-silent mutations at codons 53, 65, 76 and 111 closely resembling a pattern of eIF4E mutations determining potyvirus resistance in other plant species. By application of a molecular marker...... in a segregating F2 population of P. vulgaris, BCMV resistance was found to co-segregate with homozygotic presence of the mutant eIF4E allele. , BCMV resistance was found to co-segregate with homozygotic presence of the mutant allele. Silent mutations were found in eIF(iso)4E, but without correspondence to P...

  19. Differing impact of the deletion of hemochromatosis-associated molecules HFE and transferrin receptor-2 on the iron phenotype of mice lacking bone morphogenetic protein 6 or hemojuvelin.

    Science.gov (United States)

    Latour, Chloé; Besson-Fournier, Céline; Meynard, Delphine; Silvestri, Laura; Gourbeyre, Ophélie; Aguilar-Martinez, Patricia; Schmidt, Paul J; Fleming, Mark D; Roth, Marie-Paule; Coppin, Hélène

    2016-01-01

    Hereditary hemochromatosis, which is characterized by inappropriately low levels of hepcidin, increased dietary iron uptake, and systemic iron accumulation, has been associated with mutations in the HFE, transferrin receptor-2 (TfR2), and hemojuvelin (HJV) genes. However, it is still not clear whether these molecules intersect in vivo with bone morphogenetic protein 6 (BMP6)/mothers against decapentaplegic (SMAD) homolog signaling, the main pathway up-regulating hepcidin expression in response to elevated hepatic iron. To answer this question, we produced double knockout mice for Bmp6 and β2-microglobulin (a surrogate for the loss of Hfe) and for Bmp6 and Tfr2, and we compared their phenotype (hepcidin expression, Bmp/Smad signaling, hepatic and extrahepatic tissue iron accumulation) with that of single Bmp6-deficient mice and that of mice deficient for Hjv, alone or in combination with Hfe or Tfr2. Whereas the phenotype of Hjv-deficient females was not affected by loss of Hfe or Tfr2, that of Bmp6-deficient females was considerably worsened, with decreased Smad5 phosphorylation, compared with single Bmp6-deficient mice, further repression of hepcidin gene expression, undetectable serum hepcidin, and massive iron accumulation not only in the liver but also in the pancreas, the heart, and the kidneys. These results show that (1) BMP6 does not require HJV to transduce signal to hepcidin in response to intracellular iron, even if the loss of HJV partly reduces this signal, (2) another BMP ligand can replace BMP6 and significantly induce hepcidin expression in response to extracellular iron, and (3) BMP6 alone is as efficient at inducing hepcidin as the other BMPs in association with the HJV/HFE/TfR2 complex; they provide an explanation for the compensatory effect of BMP6 treatment on the molecular defect underlying Hfe hemochromatosis in mice. © 2015 by the American Association for the Study of Liver Diseases.

  20. Associations of common variants in HFE and TMPRSS6 with iron parameters are independent of serum hepcidin in a general population: a replication study.

    Science.gov (United States)

    Galesloot, Tessel E; Geurts-Moespot, Anneke J; den Heijer, Martin; Sweep, Fred C G J; Fleming, Robert E; Kiemeney, Lambertus A L M; Vermeulen, Sita H; Swinkels, Dorine W

    2013-09-01

    Genome-wide association studies have convincingly shown that single nucleotide polymorphisms (SNPs) in HFE and TMPRSS6 are associated with iron parameters. It was commonly thought that these associations could be explained by the intermediate effect on hepcidin concentration. A recent study in an isolated Italian population, however, concluded that these associations were not exclusively dependent on hepcidin values. We report here the second study to investigate the role of hepcidin in the associations between common variants in HFE and TMPRSS6 with iron parameters. We extracted 101 SNPs in HFE and TMPRSS6 from genome-wide imputed SNP data of 1832 individuals from the general population (Nijmegen Biomedical Study). Single locus and haplotype associations with serum iron parameters and hepcidin were studied using linear regression analyses. We found that HFE rs1800562 and TMPRSS6 rs855791 are the main determinants of HFE and TMPRSS6 related variation in serum iron, ferritin, transferrin saturation, and total iron binding capacity. These SNPs are associated with the ratios hepcidin/ferritin (p0.2). Adjustment for hepcidin or the ratio hepcidin/ferritin did not decrease the strength of the SNP-iron parameter associations. Our results do not support an intermediate role for hepcidin in the SNP-iron parameter associations, which confirms previous findings, and indicate a pleiotropic SNP effect on the hepcidin ratios and the iron parameters. Taken together, this suggests that there might be other, yet unknown, serum hepcidin independent mechanisms which play a role in the association of HFE and TMPRSS6 variants with serum iron parameters.

  1. A novel (Leu183Pro-)mutation in the HFE-gene co-inherited with the Cys282Tyr mutation in two unrelated Dutch hemochromatosis patients.

    NARCIS (Netherlands)

    Swinkels, D.W.; Venselaar, H.; Wiegerinck, E.T.G.; Bakker, E.; Joosten, I.; Jaspers, C.A.; Vasmel, W.L.; Breuning, M.H.

    2008-01-01

    We describe a novel heterozygous mutation in exon 3 of the HFE-gene that was co-inherited with Cys282Tyr in two unrelated Dutch men both presenting a classical form of hereditary hemochromatosis. Heterozygosity for this mutation was also found in one out of 100 healthy controls of Dutch descent.

  2. Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis

    Directory of Open Access Journals (Sweden)

    Tiago L. Duarte

    2017-04-01

    Conclusions: The genetic disruption of Nrf2 promotes the transition from iron accumulation (siderosis to liver injury in Hfe-/- mice, representing the first demonstration of spontaneous hepatic fibrosis in the long term in a mouse model of hereditary hemochromatosis displaying mildly elevated liver iron.

  3. A novel (Leu183Pro-)mutation in the HFE-gene co-inherited with the Cys282Tyr mutation in two unrelated Dutch hemochromatosis patients.

    Science.gov (United States)

    Swinkels, Dorine W; Venselaar, Hanka; Wiegerinck, Erwin T; Bakker, Egbert; Joosten, Irma; Jaspers, Christian A J J; Vasmel, Wies L; Breuning, Martijn H

    2008-01-01

    We describe a novel heterozygous mutation in exon 3 of the HFE-gene that was co-inherited with Cys282Tyr in two unrelated Dutch men both presenting a classical form of hereditary hemochromatosis. Heterozygosity for this mutation was also found in one out of 100 healthy controls of Dutch descent. This c.548T>C mutation converts a leucine to a proline residue at position 183 in the alpha2-helix of the HFE-protein (Leu183Pro). Standard bioinformatics analysis shows that the mutation is likely to disturb the HFE interaction with TfR1. This disrupting role of the mutation in the iron regulatory pathway is further corroborated by the familial co-occurrence of the observed compound heterozygosity with increased serum iron parameters. Haplotype analysis strongly suggests that this novel mutation arose from a common ancestor in the distant past. These findings may have implications for HFE-testing of iron overloaded heterozygous Cys282Tyr-patients of Northern European origin and their relatives.

  4. The beta + IVS, I-NT no. 6 (T --> C) thalassaemia in heterozygotes with an associated Hb Valletta or Hb S heterozygosity in homozygotes from Malta.

    Science.gov (United States)

    Scerri, C A; Abela, W; Galdies, R; Pizzuto, M; Grech, J L; Felice, A E

    1993-04-01

    In vitro DNA amplification and dot blot analysis with synthetic allele specific oligonucleotides (ASO) identified the beta + IVS, I-6 (T --> C) thalassaemia in 78% of 32 chromosomes from 16 beta-thalassaemia homozygotes in Malta. The preponderance of a single thalassaemia mutation in one population is unusual. The beta + IVS, I-6C thalassaemia mutation was also found in three carriers who had an associated beta globin heterozygosity, i.e. Hb Valletta (or alpha 2 beta 2 87PRO) or Hb S (or alpha 2 beta 2 6VAL). The proportion of Hb A in these cases (av. = 29.7%) provided objective documentation of the relatively mild effect of this mutation on in vivo globin gene expression. However, the expression of homozygous disease was more severe in developing children compared to adults. The beta + IVS, I-6C mutation complicates population testing because heterozygotes can have Hb A2 levels below those classically associated with beta thalassaemia.

  5. Application of human factors engineering (HFE) to the design of a naloxone auto-injector for the treatment of opioid emergencies.

    Science.gov (United States)

    Raffa, Robert B; Taylor, Robert; Pergolizzi, Joseph V; Nalamachu, Srinivas; Edwards, Eric S; Edwards, Evan T

    2017-02-01

    The increased use of opioids for chronic treatment of pain and the resulting epidemic of opioid overdoses have created a major public health challenge. Parenteral naloxone has been used since the 1970's to treat opioid overdose. Recently, a novel naloxone auto-injector device (EVZIO, kaleo, Inc., Richmond, VA) was approved by the Food and Drug Administration. In this article, we review the Human Factors Engineering (HFE) process used in the development and testing of this novel naloxone auto-injector currently used in nonmedical settings for the emergency treatment of known or suspected opioid overdose. HFE methods were employed throughout the product development process for the naloxone auto-injector including formative and summative studies in order to optimize the auto-injector's user interface, mitigate use-related hazards and increase reliability during an opioid emergency use scenario. HFE was also used to optimize the product's design and user interface in order to reduce or prevent user confusion and misuse. The naloxone auto-injector went through a rigorous HFE process that included perceptual, cognitive, and physical action analysis; formative usability evaluations; use error analysis and summative design validation studies. Applying HFE resulted in the development of a product that is safe, fast, easy and predictably reliable to deliver a potentially life-saving dose of naloxone during an opioid overdose emergency. The naloxone auto-injector may be considered as a universal precaution option for at-risk patients prescribed opioids or those who are at increased risk for an opioid overdose emergency.

  6. TFR2-related hereditary hemochromatosis as a frequent cause of primary iron overload in patients from Central-Southern Italy.

    Science.gov (United States)

    Radio, Francesca Clementina; Majore, Silvia; Binni, Francesco; Valiante, Michele; Ricerca, Bianca Maria; De Bernardo, Carmelilia; Morrone, Aldo; Grammatico, Paola

    2014-01-01

    Hereditary hemochromatosis (HH) is a common Mendelian disorder of iron metabolism. Eighty percent of northern Europeans descendant HH patients carry the same mutation (p.C282Y) in the HFE gene. Simultaneously, due to a founder effect, its frequency varies considerably between different populations. In Central-Southern Italy the prevalence of p.C282Y mutation is low and in several patients the disease has different causes. Four additional rarer forms have been described. Type 3 HH has been reported in about 50 families and no more than 30 TFR2 pathogenic mutations have been globally identified. The aim of this study is to assess the TFR2 role in non-HFE HH pathogenesis. TFR2 sequence analysis was performed on 45 Italian patients without HFE mutations. This study revealed TFR2 biallelic pathogenic mutations in 7/45 (15.6%) individuals. Moreover monoallelic TFR2 deleterious defects (18%) or polymorphisms with unclear meaning (36%) were identified. Besides, we recognized 10 novel variants and 9 described changes. We believe this to be the largest series of type 3 HH patients described so far. Present findings support the hypothesis of a main role of the TFR2 gene in HH pathogenesis in those regions, such as Central-Southern Italy, where the p.C282Y frequency is low. © 2013.

  7. A Survey on the HFE-related Technologies for the Improvements of Human Performance of Safety Personnel in Rail System

    Energy Technology Data Exchange (ETDEWEB)

    Koo, I. S.; Park, G. O.; Suh, S. M.; Sim, Y. R.; Go, J. H.; Jeong, J. H.; Son, C. H

    2005-08-15

    Many studies have shown that the most cases of rail accidents have occurred because of performing his/her tasks in inappropriate way. It is generally recognised that the rail system without human element could never be happened quite long time. So human element in rail system is going to be the major factor to the next tragic accident. This state-of-the-art report describes three major HFE-related technologies, training simulator, the integrated test facility for human factors engineering, and human performance evaluation system, that are used in the other industries including nuclear power industry for the purpose of increasing rail safety through out the improvement of human task performance. Base on this report, the way of developing those technologies that should be applied to the korean rail system is presented.

  8. Mutations in HFE and TFR2 genes in a Spanish patient with hemochromatosis Mutaciones en los genes HFE y TFR2 en un paciente español con hemocromatosis

    Directory of Open Access Journals (Sweden)

    Alejandro del-Castillo-Rueda

    2011-07-01

    Full Text Available Iron overload disease has a wide variety of genotypes. The genetic study of this disease confirms its hereditary nature and enables us to provide genetic counseling for first-degree relatives. We performed magnetic resonance imaging and liver biopsy in an asymptomatic patient with more than 1,000 µg/L of serum ferritin and studied the genes involved in this condition. The phenotype of iron overload is confirmed by a predominantly periportal pattern of iron deposits in the liver suggestive of genetic disease. In the case we present the molecular study revealed a double heterozygosity for the mutations c.187C>G (p.H63D and c.840C>G (p.F280L in the HFE and transferrin receptor 2 (TFR2 genes, respectively.La enfermedad por sobrecarga de hierro está originada por diversas anomalías genéticas. El estudio genético de esta enfermedad confirma su carácter hereditario y nos permite ofrecer consejo genético a los familiares en primer grado. Hemos realizado resonancia magnética y biopsia de hígado en un paciente asintomático con más de 1.000 µg/l de ferritina en suero, y hemos analizado los genes implicados en el metabolismo del hierro. El fenotipo de sobrecarga de hierro se confirmó por la presencia de un patrón de depósito de hierro en el hígado con predominio periportal que sugiere la existencia de una enfermedad genética. En el caso que presentamos, el estudio genético reveló que el paciente es doble heterocigoto para las mutaciones c.187C>G (p.H63D y c.840C>G (p.F280L en los genes HFE y receptor 2 de transferrina (TFR2, respectivamente.

  9. The genetic basis of asymptomatic codon 8 frame-shift (HBB:c25_26delAA) β(0) -thalassaemia homozygotes.

    Science.gov (United States)

    Jiang, Zhihua; Luo, Hong-Yuan; Huang, Shengwen; Farrell, John J; Davis, Lance; Théberge, Roger; Benson, Katherine A; Riolueang, Suchada; Viprakasit, Vip; Al-Allawi, Nasir A S; Ünal, Sule; Gümrük, Fatma; Akar, Nejat; Başak, A Nazli; Osorio, Leonor; Badens, Catherine; Pissard, Serge; Joly, Philippe; Campbell, Andrew D; Gallagher, Patrick G; Steinberg, Martin H; Forget, Bernard G; Chui, David H K

    2016-03-01

    Two 21-year old dizygotic twin men of Iraqi descent were homozygous for HBB codon 8, deletion of two nucleotides (-AA) frame-shift β(0) -thalassaemia mutation (FSC8; HBB:c25_26delAA). Both were clinically well, had splenomegaly, and were never transfused. They had mild microcytic anaemia (Hb 120-130 g/l) and 98% of their haemoglobin was fetal haemoglobin (HbF). Both were carriers of Hph α-thalassaemia mutation. On the three major HbF quantitative trait loci (QTL), the twins were homozygous for G>A HBG2 Xmn1 site at single nucleotide polymorphism (SNP) rs7482144, homozygous for 3-bp deletion HBS1L-MYB intergenic polymorphism (HMIP) at rs66650371, and heterozygous for the A>C BCL11A intron 2 polymorphism at rs766432. These findings were compared with those found in 22 other FSC8 homozygote patients: four presented with thalassaemia intermedia phenotype, and 18 were transfusion dependent. The inheritance of homozygosity for HMIP 3-bp deletion at rs66650371 and heterozygosity for Hph α-thalassaemia mutation was found in the twins and not found in any of the other 22 patients. Further studies are needed to uncover likely additional genetic variants that could contribute to the exceptionally high HbF levels and mild phenotype in these twins. © 2016 John Wiley & Sons Ltd.

  10. The homozygote VCP(R¹⁵⁵H/R¹⁵⁵H mouse model exhibits accelerated human VCP-associated disease pathology.

    Directory of Open Access Journals (Sweden)

    Angèle Nalbandian

    Full Text Available Valosin containing protein (VCP mutations are the cause of hereditary inclusion body myopathy, Paget's disease of bone, frontotemporal dementia (IBMPFD. VCP gene mutations have also been linked to 2% of isolated familial amyotrophic lateral sclerosis (ALS. VCP is at the intersection of disrupted ubiquitin proteasome and autophagy pathways, mechanisms responsible for the intracellular protein degradation and abnormal pathology seen in muscle, brain and spinal cord. We have developed the homozygous knock-in VCP mouse (VCP(R155H/R155H model carrying the common R155H mutations, which develops many clinical features typical of the VCP-associated human diseases. Homozygote VCP(R155H/R155H mice typically survive less than 21 days, exhibit weakness and myopathic changes on EMG. MicroCT imaging of the bones reveal non-symmetrical radiolucencies of the proximal tibiae and bone, highly suggestive of PDB. The VCP(R155H/R155H mice manifest prominent muscle, heart, brain and spinal cord pathology, including striking mitochondrial abnormalities, in addition to disrupted autophagy and ubiquitin pathologies. The VCP(R155H/R155H homozygous mouse thus represents an accelerated model of VCP disease and can be utilized to elucidate the intricate molecular mechanisms involved in the pathogenesis of VCP-associated neurodegenerative diseases and for the development of novel therapeutic strategies.

  11. The homozygote VCP(R¹⁵⁵H/R¹⁵⁵H) mouse model exhibits accelerated human VCP-associated disease pathology.

    Science.gov (United States)

    Nalbandian, Angèle; Llewellyn, Katrina J; Kitazawa, Masashi; Yin, Hong Z; Badadani, Mallikarjun; Khanlou, Negar; Edwards, Robert; Nguyen, Christopher; Mukherjee, Jogeshwar; Mozaffar, Tahseen; Watts, Giles; Weiss, John; Kimonis, Virginia E

    2012-01-01

    Valosin containing protein (VCP) mutations are the cause of hereditary inclusion body myopathy, Paget's disease of bone, frontotemporal dementia (IBMPFD). VCP gene mutations have also been linked to 2% of isolated familial amyotrophic lateral sclerosis (ALS). VCP is at the intersection of disrupted ubiquitin proteasome and autophagy pathways, mechanisms responsible for the intracellular protein degradation and abnormal pathology seen in muscle, brain and spinal cord. We have developed the homozygous knock-in VCP mouse (VCP(R155H/R155H)) model carrying the common R155H mutations, which develops many clinical features typical of the VCP-associated human diseases. Homozygote VCP(R155H/R155H) mice typically survive less than 21 days, exhibit weakness and myopathic changes on EMG. MicroCT imaging of the bones reveal non-symmetrical radiolucencies of the proximal tibiae and bone, highly suggestive of PDB. The VCP(R155H/R155H) mice manifest prominent muscle, heart, brain and spinal cord pathology, including striking mitochondrial abnormalities, in addition to disrupted autophagy and ubiquitin pathologies. The VCP(R155H/R155H) homozygous mouse thus represents an accelerated model of VCP disease and can be utilized to elucidate the intricate molecular mechanisms involved in the pathogenesis of VCP-associated neurodegenerative diseases and for the development of novel therapeutic strategies.

  12. The effects of okra (Abelmoschus esculentus Linn.) on the cellular events associated with Alzheimer's disease in a stably expressed HFE neuroblastoma SH-SY5Y cell line.

    Science.gov (United States)

    Mairuae, Nootchanat; Connor, James R; Lee, Sang Y; Cheepsunthorn, Poonlarp; Tongjaroenbuangam, Walaiporn

    2015-08-31

    It has been reported that persons carrying the H63D variant in their hemochromatosis (HFE) gene are at increased risk of Alzheimer's disease (AD). We investigated the possibility that okra (Abelmoschus esculentus) and quercetin could mitigate this risk factor by examining its effect on AD-associated cellular events in HFE stably expressing SH-SY5Y cells. Treatment of H63D HFE cells either with okra or quercetin significantly decreased reactive oxygen species (ROS), hydrogen peroxide (H2O2), and protein oxidation compared to untreated cells. The levels of tau phosphorylation at serine-199, serine-202, and serine-396 sites were also significantly decreased when cells were treated with okra. Exposure of the H63D and wild type (WT) cells to iron increased tau phosphorylation, but this response was decreased significantly when cells were treated with okra. The mechanism responsible for these changes appears to be related to decreased glycogen synthase kinase (GSK)-3β activity, an upstream signaling kinase of tau phosphorylation. We also established that okra treatment dramatically decreases intracellular iron levels in H63D cells compared to untreated cells. Our results provide important in vitro data on the effects of okra on various AD-associated cellular processes in H63D variant HFE cells. These results suggest okra may be beneficial in people expressing the H63D variant to reduce the risk of AD and other neurodegenerative diseases related to oxidative stress. Further in vivo studies would help confirm this. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  13. Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6.

    Science.gov (United States)

    Truksa, Jaroslav; Peng, Hongfan; Lee, Pauline; Beutler, Ernest

    2006-07-05

    Recently, it has been suggested that hepcidin, a peptide involved in iron homeostasis, is regulated by bone morphogenetic proteins (BMPs), apparently by binding to hemojuvelin (Hjv) as a coreceptor and signaling through Smad4. We investigate the role of Hfe, Tfr2 (transferrin receptor 2), and IL-6 in BMP2-, BMP4-, and BMP9-stimulated up-regulation of murine hepcidin, because these molecules, like Hjv, are known to be involved in hepcidin signaling. We show that the BMP signaling pathway acts independently of Hfe, Tfr2, and IL-6: The response to BMP2, BMP4, and BMP9 is similar in isolated hepatocytes of wild-type, Hfe(-/-), IL-6(-/-), and Tfr2(m) mutant mice. The potency of different human BMPs in stimulating hepcidin transcription by murine primary hepatocytes is BMP9 > BMP4 > BMP2. However, in human HepG2 cells, BMP4 and BMP9 are equally potent, whereas BMP2 requires a higher dose to become an effective hepcidin activator. Moreover, all of the tested BMPs are more potent regulators of hepcidin than IL-6 and thus are the most potent known stimulators of hepcidin transcription.

  14. White matter alterations related to attention-deficit hyperactivity disorder and COMT val158met polymorphism: children with valine homozygote attention-deficit hyperactivity disorder have altered white matter connectivity in the right cingulum (cingulate gyrus)

    Science.gov (United States)

    Kabukcu Basay, Burge; Buber, Ahmet; Basay, Omer; Alacam, Huseyin; Ozturk, Onder; Suren, Serkan; Izci Ay, Ozlem; Acikel, Cengizhan; Agladıoglu, Kadir; Erdal, Mehmet Emin; Ercan, Eyup Sabri; Herken, Hasan

    2016-01-01

    Introduction In this article, the COMT gene val158met polymorphism and attention-deficit hyperactivity disorder (ADHD)-related differences in diffusion-tensor-imaging-measured white matter (WM) structure in children with ADHD and controls were investigated. Patients and methods A total of 71 children diagnosed with ADHD and 24 controls aged 8–15 years were recruited. Using diffusion tensor imaging, COMT polymorphism and ADHD-related WM alterations were investigated, and any interaction effect between the COMT polymorphism and ADHD was also examined. The effects of age, sex, and estimated total IQ were controlled by multivariate analysis of covariance (MANCOVA). Results First, an interaction between the COMT val158met polymorphism and ADHD in the right (R) cingulum (cingulate gyrus) (CGC) was found. According to this, valine (val) homozygote ADHD-diagnosed children had significantly lower fractional anisotropy (FA) and higher radial diffusivity (RD) in the R-CGC than ADHD-diagnosed methionine (met) carriers, and val homozygote controls had higher FA and lower RD in the R-CGC than val homozygote ADHD patients. Second, met carriers had higher FA and axial diffusivity in the left (L)-uncinate fasciculus and lower RD in the L-posterior corona radiata and L-posterior thalamic radiation (include optic radiation) than the val homozygotes, independent of ADHD diagnosis. Third, children with ADHD had lower FA in the L-CGC and R-retrolenticular part of the internal capsule than the controls, independent of the COMT polymorphism. Conclusion Significant differences reported here may be evidence that the COMT gene val158met polymorphism variants, as well as ADHD, could affect brain development. ADHD and the COMT polymorphism might be interactively affecting WM development in the R-CGC to alter the WM connectivity in children with val homozygote ADHD. PMID:27143897

  15. Influence of diet, menstruation and genetic factors on iron status: a cross-sectional study in Spanish women of childbearing age.

    Science.gov (United States)

    Blanco-Rojo, Ruth; Toxqui, Laura; López-Parra, Ana M; Baeza-Richer, Carlos; Pérez-Granados, Ana M; Arroyo-Pardo, Eduardo; Vaquero, M Pilar

    2014-03-06

    The aim of this study was to investigate the combined influence of diet, menstruation and genetic factors on iron status in Spanish menstruating women (n = 142). Dietary intake was assessed by a 72-h detailed dietary report and menstrual blood loss by a questionnaire, to determine a Menstrual Blood Loss Coefficient (MBLC). Five selected SNPs were genotyped: rs3811647, rs1799852 (Tf gene); rs1375515 (CACNA2D3 gene); and rs1800562 and rs1799945 (HFE gene, mutations C282Y and H63D, respectively). Iron biomarkers were determined and cluster analysis was performed. Differences among clusters in dietary intake, menstrual blood loss parameters and genotype frequencies distribution were studied. A categorical regression was performed to identify factors associated with cluster belonging. Three clusters were identified: women with poor iron status close to developing iron deficiency anemia (Cluster 1, n = 26); women with mild iron deficiency (Cluster 2, n = 59) and women with normal iron status (Cluster 3, n = 57). Three independent factors, red meat consumption, MBLC and mutation C282Y, were included in the model that better explained cluster belonging (R2 = 0.142, p < 0.001). In conclusion, the combination of high red meat consumption, low menstrual blood loss and the HFE C282Y mutation may protect from iron deficiency in women of childbearing age. These findings could be useful to implement adequate strategies to prevent iron deficiency anemia.

  16. Carriers of the Complex Allele HFE c.[187C>G;340+4T>C] Have Increased Risk of Iron Overload in São Miguel Island Population (Azores, Portugal).

    Science.gov (United States)

    Branco, Claudia C; Gomes, Cidália T; De Fez, Laura; Bulhões, Sara; Brilhante, Maria José; Pereirinha, Tânia; Cabral, Rita; Rego, Ana Catarina; Fraga, Cristina; Miguel, António G; Brasil, Gracinda; Macedo, Paula; Mota-Vieira, Luisa

    2015-01-01

    Iron overload is associated with acquired and genetic conditions, the most common being hereditary hemochromatosis (HH) type-I, caused by HFE mutations. Here, we conducted a hospital-based case-control study of 41 patients from the São Miguel Island (Azores, Portugal), six belonging to a family with HH type-I pseudodominant inheritance, and 35 unrelated individuals fulfilling the biochemical criteria of iron overload compatible with HH type-I. For this purpose, we analyzed the most common HFE mutations- c.845G>A [p.Cys282Tyr], c.187C>G [p.His63Asp], and c.193A>T [p.Ser65Cys]. Results revealed that the family's HH pseudodominant pattern is due to consanguineous marriage of HFE-c.845G>A carriers, and to marriage with a genetically unrelated spouse that is a -c.187G carrier. Regarding unrelated patients, six were homozygous for c.845A, and three were c.845A/c.187G compound heterozygous. We then performed sequencing of HFE exons 2, 4, 5 and their intron-flanking regions. No other mutations were observed, but we identified the -c.340+4C [IVS2+4C] splice variant in 26 (74.3%) patients. Functionally, the c.340+4C may generate alternative splicing by HFE exon 2 skipping and consequently, a protein missing the α1-domain essential for HFE/ transferrin receptor-1 interactions. Finally, we investigated HFE mutations configuration with iron overload by determining haplotypes and genotypic profiles. Results evidenced that carriers of HFE-c.187G allele also carry -c.340+4C, suggesting in-cis configuration. This data is corroborated by the association analysis where carriers of the complex allele HFE-c.[187C>G;340+4T>C] have an increased iron overload risk (RR = 2.08, 95% CI = 1.40-2.94, pG;340+4T>C] has a role, as genetic predisposition factor, on iron overload in the São Miguel population. Independent replication studies in other populations are needed to confirm this association.

  17. Theoretical studies on kinetics, mechanism and thermochemistry of gas-phase reactions of HFE-449mec-f with OH radicals and Cl atom.

    Science.gov (United States)

    Deka, Ramesh Chandra; Mishra, Bhupesh Kumar

    2014-09-01

    A theoretical study on the mechanism and kinetics of the gas phase reactions of CF3CHFCF2OCH2CF3 (HFE-449mec-f) with the OH radicals and Cl atom have been performed using meta-hybrid modern density functional M06-2X using 6-31+G(d,p) basis set. Two conformers have been identified for CF3CHFCF2OCH2CF3 and the most stable one is considered for detailed study. Reaction profiles for OH-initiated hydrogen abstraction are modeled including the formation of pre-reactive and post-reactive complexes at entrance and exit channels. Our calculations reveal that hydrogen abstraction from the CH2 group is thermodynamically and kinetically more facile than that from the CHF group. Using group-balanced isodesmic reactions, the standard enthalpies of formation for HFE-449mecf and radicals generated by hydrogen abstraction, are also reported. The calculated bond dissociation energies for CH bonds are in good agreement with experimental results. The rate constants of the two reactions are determined for the first time in a wide temperature range of 250-450K. The calculated rate constant values are found to be 9.10×10(-15) and 4.77×10(-17)cm(3)molecule(-1)s(-1) for reactions with OH radicals and Cl atom, respectively. At 298K, the total calculated rate coefficient for reactions with OH radical is in good agreement with the experimental results. The atmospheric life time of HFE-449mec-f is estimated to be 0.287 years. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. White matter alterations related to attention-deficit hyperactivity disorder and COMT val158met polymorphism: children with valine homozygote attention-deficit hyperactivity disorder have altered white matter connectivity in the right cingulum (cingulate gyrus

    Directory of Open Access Journals (Sweden)

    Kabukcu Basay B

    2016-04-01

    Full Text Available Burge Kabukcu Basay,1 Ahmet Buber,1 Omer Basay,1 Huseyin Alacam,2 Onder Ozturk,1 Serkan Suren,3 Ozlem Izci Ay,4 Cengizhan Acikel,5 Kadir Agladioglu,6 Mehmet Emin Erdal,4 Eyup Sabri Ercan,7 Hasan Herken21Child and Adolescent Psychiatry Department, Pamukkale University Medical Faculty, Denizli, 2Psychiatry Department, Pamukkale University Medical Faculty, Denizli, 3Medical Park Samsun Hospital, Samsun, 4Medical Biology and Genetics Department, Mersin University Medical Faculty, Mersin, 5Biostatistics Department, GATA (GMMA, Ankara, 6Radiology Department, Pamukkale University Medical Faculty, Denizli, 7Child and Adolescent Psychiatry Department, Ege University Medical Faculty, Izmir, TurkeyIntroduction: In this article, the COMT gene val158met polymorphism and attention-deficit hyperactivity disorder (ADHD-related differences in diffusion-tensor-imaging-measured white matter (WM structure in children with ADHD and controls were investigated.Patients and methods: A total of 71 children diagnosed with ADHD and 24 controls aged 8–15 years were recruited. Using diffusion tensor imaging, COMT polymorphism and ADHD-related WM alterations were investigated, and any interaction effect between the COMT polymorphism and ADHD was also examined. The effects of age, sex, and estimated total IQ were controlled by multivariate analysis of covariance (MANCOVA.Results: First, an interaction between the COMT val158met polymorphism and ADHD in the right (R cingulum (cingulate gyrus (CGC was found. According to this, valine (val homozygote ADHD-diagnosed children had significantly lower fractional anisotropy (FA and higher radial diffusivity (RD in the R-CGC than ADHD-diagnosed methionine (met carriers, and val homozygote controls had higher FA and lower RD in the R-CGC than val homozygote ADHD patients. Second, met carriers had higher FA and axial diffusivity in the left (L-uncinate fasciculus and lower RD in the L-posterior corona radiata and L

  19. Experimental investigation and numerical simulation of a copper micro-channel heat exchanger with HFE-7200 working fluid

    Science.gov (United States)

    Borquist, Eric

    Ever increasing cost and consumption of global energy resources has inspired the development of energy harvesting techniques which increase system efficiency, sustainability, and environmental impact by using waste energy otherwise lost to the surroundings. As part of a larger effort to produce a multi-energy source prototype, this study focused on the fabrication and testing of a waste heat recovery micro-channel heat exchanger. Reducing cost and facility requirements were a priority for potential industry and commercial adoption of such energy harvesting devices. During development of the micro-channel heat exchanger, a new fabrication process using mature technologies was created that reduced cost, time, and required equipment. Testing involved filling the micro-channel heat exchanger with 3MTM NovecTM HFE-7200 working fluid. The working fluid was chosen for appropriate physical and environmental properties for the prototypes intended application. Using a dry heat exchanger as the baseline, the addition of the working fluid proved advantageous by increasing energy output by 8% while decreasing overall device temperatures. Upon successful experimental testing of the physical device, internal operation was determined based on implementation of the lattice Boltzmann method, a physics-based statistical method that actively tracked the phase change occurring in a simulated micro-channel. The simulation demonstrated three primary areas of phase change occurring, surfaces adjacent to where the heat source and heat sink were located and the bulk vapor-liquid interface, which agreed with initial device design intentions. Condensation film thickness grew to 5microm over the time interval, while the bulk interface tracked from initial 12microm from the lid to 20microm from the lid. Surface tension effects dominating vapor pressure kept the liquid near the heat source; however, the temperature and pressure VLE data suggested vapor interface growth from the heated surface to

  20. Associations of iron metabolism genes with blood manganese levels: a population-based study with validation data from animal models

    Science.gov (United States)

    2011-01-01

    Background Given mounting evidence for adverse effects from excess manganese exposure, it is critical to understand host factors, such as genetics, that affect manganese metabolism. Methods Archived blood samples, collected from 332 Mexican women at delivery, were analyzed for manganese. We evaluated associations of manganese with functional variants in three candidate iron metabolism genes: HFE [hemochromatosis], TF [transferrin], and ALAD [δ-aminolevulinic acid dehydratase]. We used a knockout mouse model to parallel our significant results as a novel method of validating the observed associations between genotype and blood manganese in our epidemiologic data. Results Percentage of participants carrying at least one copy of HFE C282Y, HFE H63D, TF P570S, and ALAD K59N variant alleles was 2.4%, 17.7%, 20.1%, and 6.4%, respectively. Percentage carrying at least one copy of either C282Y or H63D allele in HFE gene was 19.6%. Geometric mean (geometric standard deviation) manganese concentrations were 17.0 (1.5) μg/l. Women with any HFE variant allele had 12% lower blood manganese concentrations than women with no variant alleles (β = -0.12 [95% CI = -0.23 to -0.01]). TF and ALAD variants were not significant predictors of blood manganese. In animal models, Hfe-/- mice displayed a significant reduction in blood manganese compared with Hfe+/+ mice, replicating the altered manganese metabolism found in our human research. Conclusions Our study suggests that genetic variants in iron metabolism genes may contribute to variability in manganese exposure by affecting manganese absorption, distribution, or excretion. Genetic background may be critical to consider in studies that rely on environmental manganese measurements. PMID:22074419

  1. Associations of iron metabolism genes with blood manganese levels: a population-based study with validation data from animal models

    Directory of Open Access Journals (Sweden)

    Claus Henn Birgit

    2011-11-01

    Full Text Available Abstract Background Given mounting evidence for adverse effects from excess manganese exposure, it is critical to understand host factors, such as genetics, that affect manganese metabolism. Methods Archived blood samples, collected from 332 Mexican women at delivery, were analyzed for manganese. We evaluated associations of manganese with functional variants in three candidate iron metabolism genes: HFE [hemochromatosis], TF [transferrin], and ALAD [δ-aminolevulinic acid dehydratase]. We used a knockout mouse model to parallel our significant results as a novel method of validating the observed associations between genotype and blood manganese in our epidemiologic data. Results Percentage of participants carrying at least one copy of HFE C282Y, HFE H63D, TF P570S, and ALAD K59N variant alleles was 2.4%, 17.7%, 20.1%, and 6.4%, respectively. Percentage carrying at least one copy of either C282Y or H63D allele in HFE gene was 19.6%. Geometric mean (geometric standard deviation manganese concentrations were 17.0 (1.5 μg/l. Women with any HFE variant allele had 12% lower blood manganese concentrations than women with no variant alleles (β = -0.12 [95% CI = -0.23 to -0.01]. TF and ALAD variants were not significant predictors of blood manganese. In animal models, Hfe-/- mice displayed a significant reduction in blood manganese compared with Hfe+/+ mice, replicating the altered manganese metabolism found in our human research. Conclusions Our study suggests that genetic variants in iron metabolism genes may contribute to variability in manganese exposure by affecting manganese absorption, distribution, or excretion. Genetic background may be critical to consider in studies that rely on environmental manganese measurements.

  2. Evaluation of a high throughput method for the detection of mutations associated with thrombosis and hereditary hemochromatosis in Brazilian blood donors.

    Directory of Open Access Journals (Sweden)

    Vivian Dionisio Tavares Niewiadonski

    Full Text Available The aim of this study was to evaluate the OpenArray platform for genetic testing of blood donors and to assess the genotype frequencies of nucleotide-polymorphisms (SNPs associated with venous thrombosis (G1691A and G20210A, hyperhomocysteinemia (C677T, A1298C, and hereditary hemochromatosis (C282Y, H63D and S65C in blood donors from Sao Paulo, Brazil.We examined 400 blood donor samples collected from October to November 2011. The SNPs were detected using OpenArray technology. The blood samples were also examined using a real-time PCR-FRET system to compare the results and determine the accuracy of the OpenArray method.We observed 100% agreement in all assays tested, except HFE C282Y, which showed 99.75% agreement. The HFE C282Y assay was further confirmed through direct sequencing, and the results showed that OpenArray analysis was accurate. The calculated frequencies of each SNP were FV G1691A 98.8% (G/G, 1.2% (G/A; FII G2021A 99.5% (G/G, 0.5% (G/A; MTHFR C677T 45.5% (C/C, 44.8% (C/T, 9.8% (T/T; MTHFR A1298C 60.3% (A/A, 33.6% (A/C, 6.1% (C/C; HFE C282Y 96%(G/G, 4%(G/A, HFE H63D 78.1%(C/C, 20.3% (C/G, 1.6% (G/G; and HFE S65C 98.1% (A/A, 1.9% (A/T.Taken together, these results describe the frequencies of SNPs associated with diseases and are important to enhance our current knowledge of the genetic profiles of Brazilian blood donors, although a larger study is needed for a more accurate determination of the frequency of the alleles. Furthermore, the OpenArray platform showed a high concordance rate with standard FRET RT-PCR.

  3. The Effects of Degraded Digital Instrumentation and Control Systems on Human-system Interfaces and Operator Performance: HFE Review Guidance and Technical Basis

    Energy Technology Data Exchange (ETDEWEB)

    O' Hara, J.M.; W. Gunther, G. Martinez-Guridi

    2010-02-26

    New and advanced reactors will use integrated digital instrumentation and control (I&C) systems to support operators in their monitoring and control functions. Even though digital systems are typically highly reliable, their potential for degradation or failure could significantly affect operator performance and, consequently, impact plant safety. The U.S. Nuclear Regulatory Commission (NRC) supported this research project to investigate the effects of degraded I&C systems on human performance and plant operations. The objective was to develop human factors engineering (HFE) review guidance addressing the detection and management of degraded digital I&C conditions by plant operators. We reviewed pertinent standards and guidelines, empirical studies, and plant operating experience. In addition, we conducted an evaluation of the potential effects of selected failure modes of the digital feedwater system on human-system interfaces (HSIs) and operator performance. The results indicated that I&C degradations are prevalent in plants employing digital systems and the overall effects on plant behavior can be significant, such as causing a reactor trip or causing equipment to operate unexpectedly. I&C degradations can impact the HSIs used by operators to monitor and control the plant. For example, sensor degradations can make displays difficult to interpret and can sometimes mislead operators by making it appear that a process disturbance has occurred. We used the information obtained as the technical basis upon which to develop HFE review guidance. The guidance addresses the treatment of degraded I&C conditions as part of the design process and the HSI features and functions that support operators to monitor I&C performance and manage I&C degradations when they occur. In addition, we identified topics for future research.

  4. AVAQ 594-597 deletion of the TfR2 gene in a Japanese family with hemochromatosis.

    Science.gov (United States)

    Hattori, Ai; Wakusawa, Shinnya; Hayashi, Hisao; Harashima, Ai; Sanae, Fujiko; Kawanaka, Miwa; Yamada, Gohtaro; Yano, Motoyashi; Yoshioka, Kenntaro

    2003-06-01

    The majority of Caucasian patients with hemochromatosis are homozygous for C282Y mutation of the HFE gene. In contrast to its high prevalence in Caucasians, hemochromatosis is a rare disorder in Japan. This may be due to the low prevalence of the C282Y mutation of the HFE gene in Japanese. Recent reports suggest that the mutations of transferrin receptor 2 (TfR2) gene may be involved in non-HFE hemochromatosis. Therefore, we investigated the TfR2 gene of 6 sporadic and 5 familiar cases of Japanese hemochromatosis. Three siblings in one family were found to be homozygous for an AVAQ 594-597 deletion. All three had severe iron deposits in the hepatocytes and bile ducts, but none was affected by diabetes mellitus. This mutation was not detected in 100 control individuals. Further study was undertaken to investigate whether the large deletion of the TfR2 gene is the mutation responsible for some of the Japanese hemochromatosis cases.

  5. Transferrin receptor-2 (TFR2) mutation Y250X in Alabama Caucasian and African American subjects with and without primary iron overload.

    Science.gov (United States)

    Barton, E H; West, P A; Rivers, C A; Barton, J C; Acton, R T

    2001-01-01

    Most cases of hemochromatosis are associated with mutations of the HFE gene on Ch6p. In southern Italy and central Alabama, the percentages of patients with hemochromatosis who have "atypical" HFE genotypes (defined as lack of C282Y homozygosity, C282Y/H63D compound heterozygosity, or H63D homozygosity) are relatively great. A mutation of the transferrin receptor-2 gene (TFR2; exon 6, nt 750 C --> G, replaces TAC with stop signal TAG; Y250X) on Ch7q22 was recently identified in two Sicilian families with HFE mutation-negative hemochromatosis. We wanted to estimate the frequency of this mutation in persons from central Alabama. We evaluated Caucasian hemochromatosis probands with atypical HFE genotypes and African Americans with primary iron overload. We also studied control Caucasians, including persons of southern Italian/Sicilian heritage, and control African Americans. Analysis of genomic DNA was performed using a PCR-sequence-specific priming assay and positive control specimens from Sicilian hemochromatosis subjects heterozygous and homozygous for Y250X. Among Alabama subjects, this allele was not detected in 113 Caucasians, including 21 hemochromatosis probands with atypical HFE genotypes and 92 normal control subjects (including 27 of southern Italian/Sicilian descent). In African Americans, Y250X was not detected in 20 index cases with primary iron overload or in 274 unrelated control subjects. We conclude that Y250X is uncommon in Caucasians with hemochromatosis associated with atypical HFE genotypes, in African Americans with primary iron overload, and in the general Caucasian and African American population subgroups in central Alabama. Copyright 2001 Academic Press.

  6. Lymphocyte gene expression signatures from patients and mouse models of hereditary hemochromatosis reveal a function of HFE as a negative regulator of CD8+ T-lymphocyte activation and differentiation in vivo.

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    Mónica Costa

    Full Text Available Abnormally low CD8+ T-lymphocyte numbers is characteristic of some patients with hereditary hemochromatosis (HH, a MHC-linked disorder of iron overload. Both environmental and genetic components are known to influence CD8+ T-lymphocyte homeostasis but the role of the HH associated protein HFE is still insufficiently understood. Genome-wide expression profiling was performed in peripheral blood CD8+ T lymphocytes from HH patients selected according to CD8+ T-lymphocyte numbers and from Hfe-/- mice maintained either under normal or high iron diet conditions. In addition, T-lymphocyte apoptosis and cell cycle progression were analyzed by flow cytometry in HH patients. HH patients with low CD8+ T-lymphocyte numbers show a differential expression of genes related to lymphocyte differentiation and maturation namely CCR7, LEF1, ACTN1, NAA50, P2RY8 and FOSL2, whose expression correlates with the relative proportions of naïve, central and effector memory subsets. In addition, expression levels of LEF1 and P2RY8 in memory cells as well as the proportions of CD8+ T cells in G2/M cell cycle phase are significantly different in HH patients compared to controls. Hfe-/- mice do not show alterations in CD8+ T-lymphocyte numbers but differential gene response patterns. We found an increased expression of S100a8 and S100a9 that is most pronounced in high iron diet conditions. Similarly, CD8+ T lymphocytes from HH patients display higher S100a9 expression both at the mRNA and protein level. Altogether, our results support a role for HFE as a negative regulator of CD8+ T-lymphocyte activation. While the activation markers S100a8 and S100a9 are strongly increased in CD8+ T cells from both, Hfe-/- mice and HH patients, a differential profile of genes related to differentiation/maturation of CD8+ T memory cells is evident in HH patients only. This supports the notion that HFE contributes, at least in part, to the generation of low peripheral blood CD8+ T lymphocytes

  7. A case of sudden unexpected infant death involving a homozygotic twin with the thermolabile CPT2 variant, accompanied by rotavirus infection and treatment with an antibiotic containing pivalic acid.

    Science.gov (United States)

    Takahashi, Yoichiro; Sano, Rie; Kominato, Yoshihiko; Kubo, Rieko; Takahashi, Keiko; Nakajima, Tamiko; Takeshita, Haruo; Ishige, Takashi

    2016-09-01

    We investigated a case of sudden unexpected death involving a 22-month-old male homozygotic twin infant. After both of the twins had suffered from gastroenteritis, one was found dead in his bed, but his brother survived and has since been healthy. Notably, only the deceased had been treated with an antibiotic containing pivalic acid, which may sometimes cause hypocarnitinemia. Postmortem computed tomography and medicolegal autopsy demonstrated severe liver steatosis, and subsequent genetic analysis revealed that the twin had the thermolabile variant of carnitine palmitoyl transferase 2 (CPT2). On the basis of these facts, we concluded that the cause of death had been fatty acid oxidation deficiency accelerated by an antibiotic containing pivalic acid and virus infection in this infant harboring the thermolabile genetic variant of CPT2. Although each factor alone was not fatal, their combination appeared to have resulted in sudden unexpected infant death. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  8. The Correlation of Cardiac and Hepatic Hemosiderosis as Measured by T2*MRI Technique with Ferritin Levels and Hemochromatosis Gene Mutations in Iranian Patients with Beta Thalassemia Major.

    Science.gov (United States)

    Soltanpour, Mohammad Soleiman; Davari, Kambiz

    2018-01-01

    Organ-specific hemosiderosis and iron overload complications are more serious and more frequent in some patients with beta thalassemia major (BTM) compared with others. We investigated whether coinheritance of HFE H63D or C282Y gene mutations in patients with BTM contributes to the phenotypic variation of iron overload complications and assessed the correlation of cardiac and hepatic hemosiderosis with plasma ferritin levels. We studied 60 patients with BTM with a mean age of 17.5±9.1 years from the Northwest of Iran. HFE gene mutations were analyzed using the polymerase chain reaction-restriction fragment length polymorphism method. Cardiac and hepatic hemosiderosis was assessed using T2*magnetic resonance imaging (MRI). Ferritin levels were measured using the enzyme immunoassay method. Ferritin levels showed a strong inverse correlation with hepatic T2*MRI values (r = -0.631, p = 0.001) but a poor correlation with cardiac T2*MRI values (r = -0.297, p = 0.044). The correlation between cardiac T2*MRI values and hepatic T2*MRI values was poor and insignificant (r = 0.287, p = 0.058). Genotype and allele distribution of HFE H63D and C282Y mutation did not differ significantly between patients with and without hepatic or cardiac hemosiderosis ( p > 0.050). However, carriers of HFE 63D allele had significantly higher ferritin levels compared with non-carriers (1 903±993 vs. 992±683, p < 0.001). Cardiac T2*MRI values showed a poor correlation with hepatic T2*MRI values and ferritin levels. Accurate assessment of cardiac iron overload in patients with BTM can only be done using the T2*MRI technique. Additionally, HFE H63D is a significant determinant factor for elevated ferritin levels in BTM patients.

  9. The Correlation of Cardiac and Hepatic Hemosiderosis as Measured by T2*MRI Technique with Ferritin Levels and Hemochromatosis Gene Mutations in Iranian Patients with Beta Thalassemia Major

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    Mohammad Soleiman Soltanpour

    2018-01-01

    Full Text Available Objectives: Organ-specific hemosiderosis and iron overload complications are more serious and more frequent in some patients with beta thalassemia major (BTM compared with others. We investigated whether coinheritance of HFE H63D or C282Y gene mutations in patients with BTM contributes to the phenotypic variation of iron overload complications and assessed the correlation of cardiac and hepatic hemosiderosis with plasma ferritin levels. Methods: We studied 60 patients with BTM with a mean age of 17.5±9.1 years from the Northwest of Iran. HFE gene mutations were analyzed using the polymerase chain reaction-restriction fragment length polymorphism method. Cardiac and hepatic hemosiderosis was assessed using T2*magnetic resonance imaging (MRI. Ferritin levels were measured using the enzyme immunoassay method. Results: Ferritin levels showed a strong inverse correlation with hepatic T2*MRI values (r = -0.631, p = 0.001 but a poor correlation with cardiac T2*MRI values (r = -0.297, p = 0.044. The correlation between cardiac T2*MRI values and hepatic T2*MRI values was poor and insignificant (r = 0.287, p = 0.058. Genotype and allele distribution of HFE H63D and C282Y mutation did not differ significantly between patients with and without hepatic or cardiac hemosiderosis (p > 0.050. However, carriers of HFE 63D allele had significantly higher ferritin levels compared with non-carriers (1 903±993 vs. 992±683, p < 0.001. Conclusions: Cardiac T2*MRI values showed a poor correlation with hepatic T2*MRI values and ferritin levels. Accurate assessment of cardiac iron overload in patients with BTM can only be done using the T2*MRI technique. Additionally, HFE H63D is a significant determinant factor for elevated ferritin levels in BTM patients.

  10. Novel Method Probe-based Real-Time PCR to Detect 2 Single-Nucleotide Polymorphisms Close to Each Other: HFE Hemochromatosis Gene Model.

    Science.gov (United States)

    Malta, Frederico S V; Reis, Zilma N; Cabral, Antônio C V

    2016-10-01

    Hereditary hemochromatosis is known as the most common genetic disorder among individuals of European genetic background. It is possible to find 2 mutations closely placed in the HFE gene (H63D and S65C) and this proximity can cause errors when genotyped by real-time polymerase chain reaction (PCR) genotyping assay. The aim of this study was to develop a hydrolysis probe-based PCR assay for detection of the H63D and S65C mutations without interference from on each other. Herein the study involved the standardization of an improvement of the real-time PCR 5' nuclease assay to detect the desired mutations close placed using a same probe system. The assay analytical properties performances were tested, including the primers selectivity and detection limits. Also, the interexaminer reproducibility and repeatability of assay were estimated in 30 blood samples. Others 153 results of samples were compared with reference method (PCR_RFLP) and the accordance of the results evaluated by Fleiss' κ method. The results of variation of interexaminer reproducibility and repeatability of assay were not statistically relevant (Pmethods by Fleiss' κ analysis showed that 5' nuclease assay identified the H63D and S65C haplotype as well as the reference method in all 153 tested samples. Our results showed that novel method probe-based real-time PCR were capable to detect 2 adjacent polymorphisms without errors in genotyping.

  11. A homozygote for the c.459+1G>A mutation in the ARSA gene presents with cerebellar ataxia as the only first clinical sign of metachromatic leukodystrophy.

    Science.gov (United States)

    Lugowska, Agnieszka; Mierzewska, Hanna; Bekiesińska-Figatowska, Monika; Szczepanik, Elżbieta; Goszczańska-Ciuchta, Alicja; Bednarska-Makaruk, Małgorzata

    2014-03-15

    Metachromatic leukodystrophy (MLD) is a rare lysosomal disorder caused by deficient activity of arylsulfatase A or the lack of saposin B, which results in the accumulation of sulfatide in the oligodendrocytes and in the Schwann cells. Three main clinical types of MLD can be distinguished according to the age of onset and the dynamics of clinical outcome: late infantile, juvenile, and adult. We report on a case of late infantile MLD presenting with cerebellar ataxia as the only first clinical sign preceding even changes in white matter visible in MR imaging. The diagnosis was made on the basis of successive MRI, characteristic of demyelination, which developed in the course of the disease, and on the results of the following biochemical and molecular analyses. Very low residual activity of arylsulfatase A was demonstrated in blood leukocytes and the patient was a homozygote for a common mutation c.459+1G>A in the ARSA gene. Since cerebellar ataxia is a relatively common but unspecific neurological symptom in toddlers, it is recommended that MLD be considered as part of the differential diagnosis even if the initial neuroimaging studies are normal and ataxia is the only clinical symptom of the disease. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. Hereditary hemochromatosis and risk of ischemic heart disease

    DEFF Research Database (Denmark)

    Ellervik, Christina; Tybjaerg-Hansen, Anne; Grande, Peer

    2005-01-01

    BACKGROUND: We tested the hypothesis that the hereditary hemochromatosis genotypes C282Y/C282Y, C282Y/H63D, or C282Y/wild-type are risk factors for ischemic heart disease (IHD) and myocardial infarction (MI). METHODS AND RESULTS: We performed a prospective study of 9178 individuals from the Danish...

  13. HFE-associated hereditary hemochromatosis

    NARCIS (Netherlands)

    Eijkelkamp, EJ; Yapp, TR; Powell, LW

    Hereditary hemochromatosis is a common inherited disorder of the iron metabolism Screening studies indicate that it has a prevalence of one in 200 to 400, depending on the population studied, and a carrier rate of about one in seven to one in 10. Feder et al identified the hereditary hemochromatosis

  14. Mutaciones del gen de la Hemocromatosis en donantes de sangre voluntarios y en pacientes con Porfiria cutánea tarda en Chile Mutations of hemochromatosis gene in volunteer blood donors and Chilean porphyria cutanea tarda patients

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    Carlos Wolff F

    2006-10-01

    Full Text Available La acumulación de hierro hepático asociada a mutaciones en el gen HFE de la hemocromatosis hereditaria (HH en los pacientes con porfiria cutánea tarda (PCT podría tener un papel en la etiología y en la expresión clínica de esta enfermedad. Se estudió la frecuencia de las mutaciones H63D y C282Y en un grupo de pacientes con PCT y se la comparó con la observada en un grupo de donantes voluntarios de sangre. Los pacientes con PCT fueron catalogados como portadores de la forma hereditaria o adquirida de la enfermedad, según presentaran o no mutaciones en el gen uroporfirinógeno decarboxilasa (UROD. El 50% de los pacientes con PCT eran portadores de la forma genética de la enfermedad, porcentaje significativamente mayor que lo informado en otras series. El 23% de los donantes voluntarios de sangre eran portadores de la mutación H63D y 2.4% lo era de la mutación C282Y. Frecuencias similares a lo encontrado por otros autores en población chilena de etnia blanca, en población argentina y española, pero significativamente más alta que lo encontrado en estudios en población aborigen araucana. Esto tiene, probablemente, relación con el predominio de ascendencia española en la población blanca chilena. La frecuencia de mutación en el gen HFE en pacientes con PCT no fue significativamente diferente que la observada en donantes voluntarios de sangre. Tampoco hubo diferencias significativas en la frecuencia de estas mutaciones entre los casos con PCT adquirida respecto de aquellos en que ésta era de origen genético. Los resultados obtenidos no permiten afirmar que exista asociación entre la PCT y la condición de portador de mutaciones del gen HFE de la hemocromatosis hereditaria.In patients with porphyria cutanea tarda (PCT, hepatic iron accumulation associated to hereditary hemochromatosis (HH could play a role in the etiology and in the clinical expression of the disease. The H63D and C282Y mutations of the HFE gene frequency were

  15. Associations among Behavior-Related Susceptibility Factors in Porphyria Cutanea Tarda

    Science.gov (United States)

    Jalil, Sajid; Grady, James J.; Lee, Chul; Anderson, Karl E.

    2009-01-01

    Background & Aims Porphyria cutanea tarda (PCT) is the most common of the human porphyrias and results from an acquired deficiency of hepatic uroporphyrinogen decarboxylase (UROD). Some susceptibility factors have been identified; we examined associations among multiple factors in a large cohort of patients. Methods Multiple known or suspected susceptibility factors and demographic and clinical features of 143 patients (mean age 52 years, 66% male, 88% Caucasian) with documented PCT (mean onset at 41±8.8 yrs) were tabulated; associations were examined by contingency tables, classification and regression tree (CART) analysis and logistic regression. Results The most common susceptibility factors for PCT were ethanol use (87%), smoking (81%), chronic hepatitis C virus (HCV) infection (69%), and HFE mutations (53%; 6% C282Y/C282Y and 8% C282Y/H63D). Of those who underwent hepatic biopsy or ultrasound, 56% had evidence of hepatic steatosis. Of those with PCT, 66% of females took estrogen, 8% were diabetic, 13% had human immunodeficiency virus (HIV) infection, and 17% had inherited uroporphyrinogen decarboxylase (UROD) deficiency (determined by low erythrocyte UROD activity). HCV infection in patients with PCT was significantly associated with other behavior-related factors such as ethanol use (odds ratio [OR] 6.3) and smoking (OR 11.9). Conclusions Susceptibility factors for PCT were similar to previous studies; most patients had 3 or more. Associations between PCT and HCV, ethanol or smoking could be accounted for by a history of multiple substance abuse; other factors are distributed more randomly amongpatients. PMID:19948245

  16. Iranian hereditary hemochromatosis patients: Baseline characteristics, laboratory data and gene mutations

    Science.gov (United States)

    Zamani, Farhad; Bagheri, Zohreh; Bayat, Maryam; Fereshtehnejad, Seyed-Mohammad; Basi, Ali; Najmabadi, Hossein; Ajdarkosh, Hossein

    2012-01-01

    Summary Background Hereditary hemochromatosis (HH) is the most common autosomal recessive disorder in white people, characterized by highly abnormal uptake of iron from the gastrointestinal tracts. Recently, mutation studies have focused to detect the genes responsible for HH. Material/Methods In this cross-sectional study, 12 HH patients were recruited, who were referred to Firoozgar Hospital, Tehran, Iran. In addition to the clinical assessments, a complete laboratory evaluation, imaging modalities, histopathologic assessment, atomic absorption spectrophotometry and gene mutation study were performed. The genetic study for HFE gene mutation was examined for all of the patients since 2006, while non-HFE mutation was conducted since December 2010 (only for 1 of them). Results Twelve patients were evaluated consisting of 11 men and 1 woman, with the mean age of 39.58±12.68 yr. The average of atomic iron loads was 13.25±4.83-fold higher than normal standards. Four patients had heterozygotic mutation of H63D (33.3%). There was no significant difference in either the iron load of liver (P=0.927) and heart (P=0.164) or serum concentration of ferritin (P=0.907) and TIBC (P=0.937) between the HFE-mutant and without HFE mutation HH cases. Conclusions In contrast to other studies, C282Y mutation was not detected in any of our Iranian HH patients. Heterozygotic mutations of H63D (HFE) and TFR2 (non-HFE) genes were found to be more common in these patients. Similar to previous reports, these mutations were not found to be significantly associated with severity of presentation in HH patients. PMID:23018356

  17. Wilson's disease and hemochromatosis.

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    Neimark, Ezequiel; Schilsky, Michael L; Shneider, Benjamin L

    2004-02-01

    Wilson's disease (WD) and hereditary hemochromatosis (HH) are two inherited disorders with potentially devastating and life-threatening complications. Their eminent treatability makes diagnosis in adolescence or young adulthood critical. WD is the result of abnormal copper homeostasis, causing copper overload and end-organ damage. Chelation therapy can be highly efficacious in preventing manifestations of WD. HH is caused by inappropriate absorption of dietary iron, typically as the result of a specific mutation, C282Y, in the HFE gene. End-organ disease from iron accumulation is protean and includes progressive damage of the liver, pancreas, skin, heart, and pituitary. It is important to permit therapeutic phlebotomy to commence before the onset of complications.

  18. Hepcidin is decreased in TFR2 hemochromatosis.

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    Nemeth, Elizabeta; Roetto, Antonella; Garozzo, Giovanni; Ganz, Tomas; Camaschella, Clara

    2005-02-15

    The hepatic peptide hepcidin is the key regulator of iron metabolism in mammals. Recent evidence indicates that certain forms of hereditary hemochromatosis are caused by hepcidin deficiency. Juvenile hemochromatosis is associated with hepcidin or hemojuvelin mutations, and these patients have low or absent urinary hepcidin. Patients with C282Y HFE hemochromatosis also have inappropriately low hepcidin levels for the degree of iron loading. The relationship between the hemochromatosis due to transferrin receptor 2 (TFR2) mutations and hepcidin was unknown. We measured urinary hepcidin levels in 10 patients homozygous for TFR2 mutations, all with increased transferrin saturation. Urinary hepcidin was low or undetectable in 8 of 10 cases irrespective of the previous phlebotomy treatments. The only 2 cases with normal hepcidin values had concomitant inflammatory conditions. Our data indicate that TFR2 is a modulator of hepcidin production in response to iron.

  19. Haemochromatosis genotype and iron overload: association with hypertension and left ventricular hypertrophy

    DEFF Research Database (Denmark)

    Ellervik, C; Tybjaerg-Hansen, A; Appleyard, M

    2010-01-01

    We hypothesized that there is an association between haemochromatosis genotype C282Y/C282Y and/or iron overload and risk of hypertension and/or left ventricular hypertrophy (LVH).......We hypothesized that there is an association between haemochromatosis genotype C282Y/C282Y and/or iron overload and risk of hypertension and/or left ventricular hypertrophy (LVH)....

  20. Early onset hereditary hemochromatosis resulting from a novel TFR2 gene nonsense mutation (R105X) in two siblings of north French descent.

    Science.gov (United States)

    Le Gac, G; Mons, F; Jacolot, S; Scotet, V; Férec, C; Frébourg, T

    2004-06-01

    The molecular basis of hereditary hemochromatosis (HH) is more complex than previously expected. More than 80% of hemochromatosis probands of Northern European descent are homozygous for the C282Y HFE gene mutation. However, five novel non-related-HFE HH forms have now been identified. The transferrin receptor(TFR2)-linked form is inherited in an autosomal recessive pattern and is considered to be an adult-onset syndrome. Until now, it has been associated with five mutations that have only been detected in Japanese and southern European patients. Here, we report the identification of a novel TFR2 nonsense mutation in two related French adolescents. We discuss the phenotype of this sibling pair from precedent biological and clinical findings as well as the expected role of TFR2 in iron homeostasis. Finally, we suggest that iron overload phenotypes associated with mutations in TFR2 may be intermediate between those related to mutations in HFE and those related to mutations in juvenile hemochromatosis genes.

  1. Identification of novel mutations in hemochromatosis genes by targeted next generation sequencing in Italian patients with unexplained iron overload.

    Science.gov (United States)

    Badar, Sadaf; Busti, Fabiana; Ferrarini, Alberto; Xumerle, Luciano; Bozzini, Paolo; Capelli, Paola; Pozzi-Mucelli, Roberto; Campostrini, Natascia; De Matteis, Giovanna; Marin Vargas, Sergio; Giorgetti, Alejandro; Delledonne, Massimo; Olivieri, Oliviero; Girelli, Domenico

    2016-06-01

    Hereditary hemochromatosis, one of the commonest genetic disorder in Caucasians, is mainly associated to homozygosity for the C282Y mutation in the HFE gene, which is highly prevalent (allele frequency up to near 10% in Northern Europe) and easily detectable through a widely available "first level" molecular test. However, in certain geographical regions like the Mediterranean area, up to 30% of patients with a HH phenotype has a negative or non-diagnostic (i.e. simple heterozygosity) test, because of a known heterogeneity involving at least four other genes (HAMP, HJV, TFR2, and SLC40A1). Mutations in such genes are generally rare/private, making the diagnosis of atypical HH essentially a matter of exclusion in clinical practice (from here the term of "non-HFE" HH), unless cumbersome traditional sequencing is applied. We developed a Next Generation Sequencing (NGS)-based test targeting the five HH genes, and applied it to patients with clinically relevant iron overload (IO) and a non-diagnostic first level genetic test. We identified several mutations, some of which were novel (i.e. HFE W163X, HAMP R59X, and TFR2 D555N) and allowed molecular reclassification of "non-HFE" HH clinical diagnosis, particularly in some highly selected IO patients without concurring acquired risk factors. This NGS-based "second level" genetic test may represent a useful tool for molecular diagnosis of HH in patients in whom HH phenotype remains unexplained after the search of common HFE mutations. © 2016 Wiley Periodicals, Inc.

  2. Characteristics of gene mutation in Chinese patients with hereditary hemochromatosis

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    LYU Tingxia

    2016-08-01

    Full Text Available ObjectiveTo investigate the characteristics of gene mutation in Chinese patients with hereditary hemochromatosis (HH. MethodsA total of 9 patients with HH who visited Beijing Friendship Hospital, Capital Medical University from January 2013 to December 2015 were enrolled. The genomic DNA was extracted, and PCR amplification and Sanger sequencing were performed for all the exons of four genotypes of HH, i.e., HFE (type Ⅰ, HJV (type ⅡA, HAMP (type ⅡB, TFR2 (type Ⅲ, and SLC40A1 (type Ⅳ to analyze gene mutations. A total of 50 healthy subjects were enrolled as control group to analyze the prevalence of identified gene mutations in a healthy population. ResultsOf all patients, 2 had H63D mutation of HFE gene in type Ⅰ HH, 1 had E3D mutation of HJV gene in type ⅡA HH, 2 had I238M mutation of TFR2 gene in type Ⅲ HH, and 1 had IVS 3+10 del GTT splice mutation of SLC40A1 gene in type Ⅳ HH. No patients had C282Y mutation of HFE gene in type Ⅰ HH which was commonly seen in European and American populations. Five patients had no missense mutation or splice mutation. In addition, it was found in a family that a HH patient had E3D mutation of HJV gene, H63D mutation of HFE gene, and I238M mutation of TFR2 gene, but the healthy brother and sister carrying two of these mutations did not had the phenotype of HH. ConclusionHH gene mutations vary significantly across patients of different races, and non-HFE-HH is dominant in the Chinese population. There may be HH genes which are different from known genes, and further investigation is needed.

  3. Iron-related gene variants and brain iron in multiple sclerosis and healthy individuals.

    Science.gov (United States)

    Hagemeier, Jesper; Ramanathan, Murali; Schweser, Ferdinand; Dwyer, Michael G; Lin, Fuchun; Bergsland, Niels; Weinstock-Guttman, Bianca; Zivadinov, Robert

    2018-01-01

    Brain iron homeostasis is known to be disturbed in multiple sclerosis (MS), yet little is known about the association of common gene variants linked to iron regulation and pathological tissue changes in the brain. In this study, we investigated the association of genetic determinants linked to iron regulation with deep gray matter (GM) magnetic susceptibility in both healthy controls (HC) and MS patients. Four hundred (400) patients with MS and 150 age- and sex-matched HCs were enrolled and obtained 3 T MRI examination. Three (3) single nucleotide polymorphisms (SNPs) associated with iron regulation were genotyped: two SNPs in the human hereditary hemochromatosis protein gene HFE : rs1800562 (C282Y mutation) and rs1799945 (H63D mutation), as well as the rs1049296 SNP in the transferrin gene (C2 mutation). The effects of disease and genetic status were studied using quantitative susceptibility mapping (QSM) voxel-based analysis (VBA) and region-of-interest (ROI) analysis of the deep GM. The general linear model framework was used to compare groups. Analyses were corrected for age and sex, and adjusted for false discovery rate. We found moderate increases in susceptibility in the right putamen of participants with the C282Y (+ 6.1 ppb) and H63D (+ 6.9 ppb) gene variants vs. non-carriers, as well as a decrease in thalamic susceptibility of progressive MS patients with the C282Y mutation (left: - 5.3 ppb, right: - 6.7 ppb, p < 0.05). Female MS patients had lower susceptibility in the caudate (- 6.0 ppb) and putamen (left: - 3.9 ppb, right: - 4.6 ppb) than men, but only when they had a wild-type allele (p < 0.05). Iron-gene linked increases in putamen susceptibility (in HC and relapsing remitting MS) and decreases in thalamus susceptibility (in progressive MS), coupled with apparent sex interactions, indicate that brain iron in healthy and disease states may be influenced by genetic factors.

  4. A rare cause of osteonecrosis

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    Paolo Agostinis

    2012-01-01

    Full Text Available IntroductionHereditary hemochromatosis (HH is an autosomal recessive disorder caused by mutations in the HFE gene, which increase intestinal iron absorption. The prevalence of C282Y homozygosity, which causes the disorder, is 0.5% in Caucasian populations. The clinical manifestations are related to excess iron in the tissues, especially the liver, heart, pancreas, pituitary, and skin. They include fatigue, loss of libido or impotence in males, liver disease, skin pigmentation, diabetes mellitus, cardiac enlargement—with or without heart failure, and conduction defects. The classic triad of cirrhosis, diabetes mellitus, and skin pigmentation (“bronze diabetes” results from a combination of iron deposits and melanin. It occurs late in the disease, when the total body iron content is more than five times the normal value, about 20 grams. Left untreated, approximately half of all patients with HH eventually develop arthralgia or arthropathy. Chondrocalcinosis, chronic pseudo-osteoarthritis, and osteoporosis are the major rheumatic manifestations of HH. The cause of the arthropathy is still unknown. Iron deposits within joints may trigger a number of pathologic events, such as free radical generation and crystal deposition, which stimulate immune complex formation and inflammation.Materials and methodsWe describe the case of a 48-year-old male suffering from chronic bilateral ankle pain.ResultsThe work-up revealed osteonecrosis of ankle. The patient also presented high plasma ferritin levels and homozygosity for the C282Y mutation. Other than HH, which was confirmed by liver biopsy, the patient had no other risk factors for osteonecrosis.DiscussionHH represents a rare cause of osteonecrosis, and there are no prior reports of aseptic osteonecrosis of the ankle in a patient with this disease. The pathogenetic mechanism remains unknown.

  5. Genetic Aspects of Scurvy and the European Famine of 1845–1848

    Directory of Open Access Journals (Sweden)

    Michel R. Langlois

    2013-09-01

    Full Text Available The view of scurvy being exclusively a nutritional disorder needs to be updated. Genetic polymorphisms of HFE and haptoglobin (Hp may explain the geographic variability of mortality caused by the European famine of the mid-19th century. In this period, potatoes had fallen victim to the potato blight and Ireland was more severely hit than continental Europe. Hereditary hemochromatosis is a genetic disorder with mutations in the HFE gene, characterized by iron overload (with a reduced vitamin C stability and with a predominance of affected men. The Irish have the world’s highest frequency of the C282Y mutation and the particular iron metabolism of the Irish helps to understand the size of the catastrophe and the observed overrepresentation of male skeletons showing scurvy. Hp is a plasma α2-glycoprotein characterized by 3 common phenotypes (Hp 1-1, Hp 2-1 and Hp 2-2. When the antioxidant capacity of Hp is insufficient, its role is taken over by hemopexin and vitamin C. The relative number of scurvy victims corresponds with the Hp 2-2 frequency, which is associated with iron conservation and has an impact on vitamin C stability. As iron is more abundant in males, males are overrepresented in the group of skeletons showing scurvy signs.

  6. Atmospheric chemistry of HFE-7000 (CF(3)CF (2)CF (2)OCH (3)) and 2,2,3,3,4,4,4-heptafluoro-1-butanol (CF (3)CF (2)CF (2)CH (2)OH): kinetic rate coefficients and temperature dependence of reactions with chlorine atoms.

    Science.gov (United States)

    Díaz-de-Mera, Yolanda; Aranda, Alfonso; Bravo, Iván; Rodríguez, Diana; Rodríguez, Ana; Moreno, Elena

    2008-10-01

    The adverse environmental impacts of chlorinated hydrocarbons on the Earth's ozone layer have focused attention on the effort to replace these compounds by nonchlorinated substitutes with environmental acceptability. Hydrofluoroethers (HFEs) and fluorinated alcohols are currently being introduced in many applications for this purpose. Nevertheless, the presence of a great number of C-F bonds drives to atmospheric long-lived compounds with infrared absorption features. Thus, it is necessary to improve our knowledge about lifetimes and global warming potentials (GWP) for these compounds in order to get a complete evaluation of their environmental impact. Tropospheric degradation is expected to be initiated mainly by OH reactions in the gas phase. Nevertheless, Cl atoms reaction may also be important since rate constants are generally larger than those of OH. In the present work, we report the results obtained in the study of the reactions of Cl radicals with HFE-7000 (CF(3)CF(2)CF(2)OCH(3)) (1) and its isomer CF(3)CF(2)CF(2)CH(2)OH (2). Kinetic rate coefficients with Cl atoms have been measured using the discharge flow tube-mass spectrometric technique at 1 Torr of total pressure. The reactions of these chlorofluorocarbons (CFCs) substitutes have been studied under pseudo-first-order kinetic conditions in excess of the fluorinated compounds over Cl atoms. The temperature ranges were 266-333 and 298-353 K for reactions of HFE-7000 and CF(3)CF(2)CF(2)CH(2)OH, respectively. The measured room temperature rate constants were k(Cl+CF(3)CF(2)CF(2)OCH(3)) = (1.24 +/- 0.28) x 10(-13) cm(3) molecule(-1) s(-1)and k(Cl+CF(3)CF(2)CF(2)CH(2)OH) = (8.35 +/- 1.63) x 10(-13) cm(3) molecule(-1) s(-1) (errors are 2sigma + 10% to cover systematic errors). The Arrhenius expression for reaction 1 was k (1)(266-333 K) = (6.1 +/- 3.8) x 10(-13)exp[-(445 +/- 186)/T] cm(3) molecule(-1) s(-1) and k (2)(298-353 K) = (1.9 +/- 0.7) x 10(-12)exp[-(244 +/- 125)/T] cm(3) molecule(-1) s(-1) (errors

  7. Alterações moleculares associadas à hemocromatose hereditária Molecular changes associated with hereditary hemochromatosis

    Directory of Open Access Journals (Sweden)

    Paulo C. J. L. Santos

    2009-01-01

    Full Text Available A hemocromatose hereditária (HH é a mais comum doença autossômica em caucasianos e caracteriza-se pelo aumento da absorção intestinal de ferro, o qual resulta em acúmulo progressivo de ferro no organismo. A classificação da HH é realizada de acordo com a alteração genética encontrada, sendo os casos divididos em tipos 1, 2A, 2B, 3 e 4, quando a sobrecarga de ferro for associada aos genes HFE, HJV, HAMP, TFR2 e SLC40A1, respectivamente. Não existem estudos brasileiros que avaliaram a presença de mutações em genes relacionados à fisiopatologia da HH (genes HJV, HAMP, TFR2 e SLC40A1, além da pesquisa das três mutações no gene HFE (C282Y, H63D e S65C. Porém, está descrito, nos estudos realizados no Brasil, que alguns pacientes com sobrecarga de ferro primária não são portadores da HH tipo 1 (associada ao gene HFE. Portanto, é de suma importância a identificação das características genéticas dessa população, uma vez que outras mutações nos genes HJV, HAMP, TFR2 e SLC40A1 podem estar associadas à fisiopatologia da doença, podendo haver interações entre os genes alterados, de forma que possa auxiliar no entendimento da fisiopatologia da HH em pacientes brasileiros.Hereditary Hemochromatosis (HH is the most common autosomal disease in Caucasians. It is characterized by an increase in intestinal absorption of iron, which results in a progressive accumulation of iron in the body. The classification of HH is carried out according to the genetic alteration found; thus cases of HH are divided into Types 1, 2A, 2B, 3 and 4, when the iron overload is associated to the HFE, HJV, HAMP, TFR2 and SLC40A1 genes, respectively. There is research on the three HFE gene mutations (C282Y, H63D and S65C in the Brazilian population however there are no Brazilian studies that evaluate the presence of mutations in other genes related to the pathophysiology of HH (HJV, HAMP, TFR2 and SLC40A1 genes. Nevertheless, studies conducted in

  8. [Diagnosis and therapy of inheritable liver diseases: hemochromatisis, Wilson's disease and alpha-1-antitrypsin deficiency].

    Science.gov (United States)

    Strassburg, Ch P

    2005-01-19

    The recent years have seen significant progress in the area of genetically determined liver diseases. For hereditary hemochromatosis, Wilson's disease and alpha-1 antitrypsin deficiency the underlying genetic defects have been described and well characterized. Although a direct relationship between genetic defect and disease manifestation exists genetic test only have a limited diagnostic usefulness which requires exact knowledge of the underlying molecular pathology. The classical C282Y and H63D mutations of the HFE gene only show a penetrance of 10-20% in hemochromatosis and are not useful for population screening. Genetic screening for ATP7B (Wilson's disease) and alpha-1 antitrypsin deficiency variants is limited by the existence of a plethora of individual mutations. Genetic tests are mainly restricted to the counseling of families in whom these diseases are present. Foremost the diagnosis of the three diseases is reached by clinical, biochemical and in some instances also histological means which are supplemented and confirmed by the use of appropriate genetic tests.

  9. Iron supplementation in athletes--first do no harm.

    Science.gov (United States)

    Zoller, Heinz; Vogel, Wolfgang

    2004-01-01

    Although it generally does not improve performance, iron is often used by elite athletes. The physiologic changes induced by exercise can mimic iron deficiency and decrease hemoglobin and ferritin concentrations. Determination of serum transferrin receptor concentrations may identify true iron deficiency, which occurs particularly in young athletes. In contrast, increased iron stores in the body are a frequent finding in elite athletes who have used long-term iron supplementation. Elite runners have increased intestinal blood loss, but this usually can be compensated by enhanced absorption of dietary iron. The combination of exercise-induced hemolysis with enhanced intestinal blood loss in various endurance sports leads to severe abnormalities of routine tests, and extreme physical activity may be responsible for positive fecal occult blood determinations. Indiscriminate iron supplementation carries the risk of inducing hemochromatosis in individuals homozygous for the widespread C282Y allele of the HFE gene. This polymorphism is common and can be found in about 1% of individuals of Northern European descent; moreover, iron supplementation can modify the presentation of important underlying diseases such as celiac disease or colon carcinoma. In conclusion, iron supplements should be prescribed for athletes with iron-deficiency anemia and carefully monitored if given for prophylaxis; unless a therapeutic response occurs, investigations to establish the cause of iron deficiency should be initiated.

  10. Association between sex, systemic iron variation and probability of Parkinson's disease.

    Science.gov (United States)

    Mariani, S; Ventriglia, M; Simonelli, I; Bucossi, S; Siotto, M; Donno, S; Vernieri, F; Squitti, R

    2016-01-01

    Iron homeostasis appears altered in Parkinson's disease (PD). Recent genetic studies and meta-analyses have produced heterogeneous and inconclusive results. In order to verify the possible role of iron status in PD, we have screened some of the main metal gene variants, evaluated their effects on iron systemic status, and checked for possible interactions with PD. In 92 PD patients and 112 healthy controls, we screened the D544E and R793H variants of the ceruloplasmin gene (CP), the P589S variant of the transferrin gene (TF), and the H63D and C282Y variants of the HFE gene, encoding for homologous proteins, respectively. Furthermore, we analyzed serum concentrations of iron, copper and their related proteins. The genetic investigation revealed no significant differences in allelic and genotype distributions between patients and controls. Two different multivariable forward stepwise logistic models showed that, when the effect of sex is considered, an increase of the probability of having PD is associated with low iron concentration and Tf-saturation. This study provides new evidence of the involvement of iron metabolism in PD pathogenesis and reveals a biological effect of sex.

  11. Interaction of Dietary and Genetic Factors Influencing Body Iron Status and Risk of Type 2 Diabetes Within the EPIC-InterAct Study.

    Science.gov (United States)

    Meidtner, Karina; Podmore, Clara; Kröger, Janine; van der Schouw, Yvonne T; Bendinelli, Benedetta; Agnoli, Claudia; Arriola, Larraitz; Barricarte, Aurelio; Boeing, Heiner; Cross, Amanda J; Dow, Courtney; Ekblom, Kim; Fagherazzi, Guy; Franks, Paul W; Gunter, Marc J; Huerta, José María; Jakszyn, Paula; Jenab, Mazda; Katzke, Verena A; Key, Timothy J; Khaw, Kay Tee; Kühn, Tilman; Kyrø, Cecilie; Mancini, Francesca Romana; Melander, Olle; Nilsson, Peter M; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Quirós, J Ramón; Rodríguez-Barranco, Miguel; Sacerdote, Carlotta; Sluijs, Ivonne; Stepien, Magdalena; Tjonneland, Anne; Tumino, Rosario; Forouhi, Nita G; Sharp, Stephen J; Langenberg, Claudia; Schulze, Matthias B; Riboli, Elio; Wareham, Nicholas J

    2018-02-01

    Meat intake has been consistently shown to be positively associated with incident type 2 diabetes. Part of that association may be mediated by body iron status, which is influenced by genetic factors. We aimed to test for interactions of genetic and dietary factors influencing body iron status in relation to the risk of incident type 2 diabetes. The case-cohort comprised 9,347 case subjects and 12,301 subcohort participants from eight European countries. Single nucleotide polymorphisms (SNPs) were selected from genome-wide association studies on iron status biomarkers and candidate gene studies. A ferritin-related gene score was constructed. Multiplicative and additive interactions of heme iron and SNPs as well as the gene score were evaluated using Cox proportional hazards regression. Higher heme iron intake (per 1 SD) was associated with higher ferritin levels (β = 0.113 [95% CI 0.082; 0.144]), but not with transferrin (-0.019 [-0.043; 0.006]) or transferrin saturation (0.016 [-0.006; 0.037]). Five SNPs located in four genes (rs1799945 [ HFE H63D], rs1800562 [ HFE C282Y], rs236918 [ PCK7 ], rs744653 [ SLC40A1 ], and rs855791 [ TMPRSS6 V736A]) were associated with ferritin. We did not detect an interaction of heme iron and the gene score on the risk of diabetes in the overall study population ( P add = 0.16, P mult = 0.21) but did detect a trend toward a negative interaction in men ( P add = 0.04, P mult = 0.03). We found no convincing evidence that the interplay of dietary and genetic factors related to body iron status associates with type 2 diabetes risk above the level expected from the sum or product of the two individual exposures. © 2017 by the American Diabetes Association.

  12. Towards A Unified HFE Process For The Nuclear Industry

    Energy Technology Data Exchange (ETDEWEB)

    Jacques Hugo

    2012-07-01

    As nuclear power utilities embark on projects to upgrade and modernize power plants, they are likely to discover that traditional engineering methods do not typically make provision for the integration of human considerations. In addition, human factors professionals will find that traditional human performance methods such as function allocation, task analysis, human reliability analysis and human-machine interface design do not scale well to the complexity of a large-scale nuclear power upgrade project. Up-to-date human factors engineering processes, methods, techniques and tools are required to perform these kinds of analyses. This need is recognized widely in industry and an important part of the Department of Energy’s Light Water Reactor Sustainability Program deals with identifying potential impacts of emerging technologies on human performance and the technical bases needed to address them. However, so far no formal initiative has been launched to deal with the lack of integrated processes. Although human factors integration frameworks do exist in industries such as aviation or defense, no formal integrated human factors process exists in the nuclear industry. As a first step towards creating such a process, a “unified human factors engineering process” is proposed as a framework within which engineering organizations, human factors practitioners and regulatory bodies can ensure that human factors requirements are embedded in engineering activities throughout the upgrade project life cycle.

  13. Intragenic haplotype analysis of common HFE mutations in the ...

    Indian Academy of Sciences (India)

    CHUC), 3000 Coimbra, Portugal. [Toste S., Relvas L., Pinto .... Restriction. Digestion. SNP ID. Ta (◦C) sequence product (bp) enzyme product (bp) Reference rs1800702. 54. 5′-GATCCTTTAACCGAGGAGAT-3′. 567. BbvI. G: 511, 56. Rochette.

  14. Human Factors Evaluation Automated Tool (HFE-AT) Project

    Data.gov (United States)

    National Aeronautics and Space Administration — In this proposal, TiER1 Performance Solutions and Alion Science and Technology offer to identify requirements and specifications, and implement a proof-of-concept...

  15. HFE (Human Factors Engineering) Technology for Navy Weapon System Acquisition.

    Science.gov (United States)

    1979-07-01

    The above techniques are based in part on the manual Linear Programming technique reported by Freud and Sadosky (1967). The manual approach uses...components. The program determines the execution time of each task (visual, motor transitions), ana performance reliability (product of reliabilities for...effectiveness evaluation data * Analyze and revise system - Field job performance data - Instructional system re- vision. 3-99 -. - ANA "" A technique

  16. [A sickle cell homozygote with transfusion deadlock. Favorable outcome with hydroxyurea treatment].

    Science.gov (United States)

    Monsaingeon-Lion, A; Le Pennec, P Y; Bridey, F; Girard, M; Ricard, R; Gross, E; Tchernia, G

    1993-12-01

    Alloimmunization following multiple transfusions, a frequently observed complication in sickle cell anemia patients, may make subsequent transfusion attempts extremely hazardous. The case of a young woman with sickle-cell anemia is reported; she was hospitalized for the treatment of extensive invalidating leg ulcers. The transfusion program that was initiated as a prerequisite to skin allografts had to be stopped, due to rapid occurrence of multiple alloimmunization. Broad spectrum alloantibodies precluded further selection of compatible blood units. In an attempt to get round this impossibility, a treatment with Hydroxyurea was initiated in order to boost synthesis of F-hemoglobin. After one year under this treatment, the patient's clinical status has clearly improved without requiring any new blood transfusion.

  17. Change in Attachment Predicts Change in Emotion Regulation Particularly among "5-HTTLPR" Short-Allele Homozygotes

    Science.gov (United States)

    Viddal, Kristine Rensvik; Berg-Nielsen, Turid Suzanne; Belsky, Jay; Wichstrøm, Lars

    2017-01-01

    In view of the theory that the attachment relationship provides a foundation for the development of emotion regulation, here, we evaluated (a) whether change in attachment security from 4 to 6 years predicts change in emotion regulation from 6 to 8 years and (b) whether "5-HTTLPR" moderates this relation in a Norwegian community sample…

  18. Homozygotic intronic GAA mutation in three siblings with late-onset Pompe's disease.

    Science.gov (United States)

    Grzesiuk, Anderson Kuntz; Shinjo, Sueli Mieko Oba; da Silva, Roseli; Machado, Marcela; Galera, Marcial Francis; Marie, Suely Kazue Nagahashi

    2010-04-01

    Pompe's disease (PD) is a metabolic myopathy caused by the accumulation of lysosomal glycogen, secondary to acid alpha-glucosidase (GAA) enzyme deficiency. Childhood and late-onset forms are described, differing by the age of onset and symptoms. In this study were analyzed affected siblings with Pompe's disease (PD) and their distinct clinical and pathological presentations. Diagnosis was performed by the clinical presentation of limb-girdle dystrophies and respiratory compromise. Confirmatory diagnoses were conducted by muscle biopsy, GAA activity measurement and by GAA gene genotyping. The findings suggested muscular involvement due to GAA deficiency. GAA genotyping showed they are homozygous for the c.-32-3C>A mutation. Herein we reported a family where three out of five siblings were diagnosed with late-onset PD, although it is a rare metabolic disease inherited in an autossomal recessive manner. We emphasize the importance of including this presentation within the differential diagnoses of the limb-girdle dystrophies once enzyme replacement therapy is available.

  19. Maternal hemochromatosis gene H63D single-nucleotide polymorphism and lead levels of placental tissue, maternal and umbilical cord blood

    Energy Technology Data Exchange (ETDEWEB)

    Kayaalti, Zeliha, E-mail: kayaalti@ankara.edu.tr [Ankara University, Institute of Forensic Sciences, Ankara (Turkey); Kaya-Akyüzlü, Dilek [Ankara University, Institute of Forensic Sciences, Ankara (Turkey); Söylemez, Esma [Ankara University, Institute of Forensic Sciences, Ankara (Turkey); Middle Black Sea Passage Generation of Agricultural Research Station Director, Tokat (Turkey); Söylemezoğlu, Tülin [Ankara University, Institute of Forensic Sciences, Ankara (Turkey)

    2015-07-15

    Human hemochromatosis protein (HFE), a major histocompatibility complex class I-like integral membrane protein, participates in the down regulation of intestinal iron absorption by binding to transferrin receptor (TR). HFE competes with transferrin-bound iron for the TR and thus reduces uptake of iron into cells. On the other hand, a lack of HFE increases the intestinal absorption of iron similarly to iron deficiency associated with increasing in absorption and deposition of lead. During pregnancy, placenta cannot prevent transfer lead to the fetus; even low-level lead poisoning causes neurodevelopmental toxicity in children. The aim of this study was to determine the association between the maternal HFE H63D single-nucleotide polymorphism and lead levels in placental tissue, maternal blood and umbilical cord bloods. The study population comprised 93 mother–placenta pairs. Venous blood from mother was collected to investigate lead levels and HFE polymorphism that was detected by standard PCR–RFLP technique. Cord bloods and placentas were collected for lead levels which were analyzed by dual atomic absorption spectrometer system. The HFE H63D genotype frequencies of mothers were found as 75.3% homozygote typical (HH), 23.6% heterozygote (HD) and 1.1% homozygote atypical (DD). Our study results showed that the placental tissue, umbilical cord and maternal blood lead levels of mothers with HD+DD genotypes were significantly higher than those with HH genotype (p<0.05). The present study indicated for the first time that mothers with H63D gene variants have higher lead levels of their newborn's placentas and umbilical cord bloods. - Highlights: • Mothers with H63D gene variants have higher lead levels of their newborn's umbilical cord blood. • Unborn child of women with HD+DD genotypes may be at increased risk of internal exposure to lead. • Maternal HFE status may have an effect on increased placenta, maternal and cord blood lead levels.

  20. Association between inherited monogenic liver disorders and chronic hepatitis C.

    Science.gov (United States)

    Piekuse, Linda; Kreile, Madara; Zarina, Agnese; Steinberga, Zane; Sondore, Valentina; Keiss, Jazeps; Lace, Baiba; Krumina, Astrida

    2014-02-27

    To determine the frequencies of mutations that cause inherited monogenic liver disorders in patients with chronic hepatitis C. This study included 86 patients with chronic hepatitis C (55 men, 31 women; mean age at diagnosis, 38.36 ± 14.52 years) who had undergone antiviral therapy comprising pegylated interferon and ribavirin. Viral load, biochemical parameter changes, and liver biopsy morphological data were evaluated in all patients. The control group comprised 271 unrelated individuals representing the general population of Latvia for mutation frequency calculations. The most frequent mutations that cause inherited liver disorders [gene (mutation): ATP7B (H1069Q), HFE (C282Y, H63D), UGT1A1 (TA)7, and SERPINA1 (PiZ)] were detected by polymerase chain reaction (PCR), bidirectional PCR allele-specific amplification, restriction fragment length polymorphism analysis, and sequencing. The viral genotype was detected in 80 of the 86 patients. Viral genotypes 1, 2, and 3 were present in 61 (76%), 7 (9%), and 12 (15%) patients, respectively. Among all 86 patients, 50 (58%) reached an early viral response and 70 (81%) reached a sustained viral response. All 16 patients who did not reach a sustained viral response had viral genotype 1. Case-control analysis revealed a statistically significant difference in only the H1069Q mutation between patients and controls (patients, 0.057; controls, 0.012; odds ratio, 5.514; 95%CI: 1.119-29.827, P = 0.022). However, the H1069Q mutation was not associated with antiviral treatment outcomes or biochemical indices. The (TA) 7 mutation of the UGT1A1 gene was associated with decreased ferritin levels (beta regression coefficient = -295.7, P = 0.0087). Genetic mutations that cause inherited liver diseases in patients with hepatitis C should be studied in detail.

  1. Non-coding keratin variants associate with liver fibrosis progression in patients with hemochromatosis.

    Directory of Open Access Journals (Sweden)

    Pavel Strnad

    Full Text Available BACKGROUND: Keratins 8 and 18 (K8/K18 are intermediate filament proteins that protect the liver from various forms of injury. Exonic K8/K18 variants associate with adverse outcome in acute liver failure and with liver fibrosis progression in patients with chronic hepatitis C infection or primary biliary cirrhosis. Given the association of K8/K18 variants with end-stage liver disease and progression in several chronic liver disorders, we studied the importance of keratin variants in patients with hemochromatosis. METHODS: The entire K8/K18 exonic regions were analyzed in 162 hemochromatosis patients carrying homozygous C282Y HFE (hemochromatosis gene mutations. 234 liver-healthy subjects were used as controls. Exonic regions were PCR-amplified and analyzed using denaturing high-performance liquid chromatography and DNA sequencing. Previously-generated transgenic mice overexpressing K8 G62C were studied for their susceptibility to iron overload. Susceptibility to iron toxicity of primary hepatocytes that express K8 wild-type and G62C was also assessed. RESULTS: We identified amino-acid-altering keratin heterozygous variants in 10 of 162 hemochromatosis patients (6.2% and non-coding heterozygous variants in 6 additional patients (3.7%. Two novel K8 variants (Q169E/R275W were found. K8 R341H was the most common amino-acid altering variant (4 patients, and exclusively associated with an intronic KRT8 IVS7+10delC deletion. Intronic, but not amino-acid-altering variants associated with the development of liver fibrosis. In mice, or ex vivo, the K8 G62C variant did not affect iron-accumulation in response to iron-rich diet or the extent of iron-induced hepatocellular injury. CONCLUSION: In patients with hemochromatosis, intronic but not exonic K8/K18 variants associate with liver fibrosis development.

  2. Polymorphic microsatellite sites in the PRNP region point to excess of homozygotes in Creutzfeldt-Jakob disease patients.

    Science.gov (United States)

    Geldermann, Hermann; Bartenschlager, Heinz; Preuss, Siegfried; Melchinger-Wild, Elke; Herzog, Katja; Zerr, Inga

    2006-11-01

    Polymorphic microsatellite sites within 148 kb of the human prion gene complex, including the genes PRNP, PRND and PRNT, were analysed together with the Codon129 variants regarding 50 CJD (Creutzfeldt-Jakob Disease) patients and 46 non-diseased control persons. Three of the sites (MM03, MM04, Codon129) differed significantly (P<0.05) for their allele frequencies between the two groups--the predominant allele being always more frequent in the CJD group. Deviations from Hardy-Weinberg Equilibrium were mainly obtained in the CJD group--in all cases with a reduction of the observed heterozygosity. The sites MM03, MM04 and Codon129 were also analysed for their haplotypes. The predominant homozygous haplotype combination was more frequently observed in the CJD group (0.875) than in the non-diseased group (0.38). Thus the different polymorphic sites indicate that high CJD disposition is associated with homozygosity in the PRNP gene.

  3. Omeprazole hydroxylation is inhibited by a single dose of moclobemide in homozygotic EM genotype for CYP2C19

    Science.gov (United States)

    Cho, Joo-Youn; Yu, Kyung-Sang; Jang, In-Jin; Yang, Byung-Hwan; Shin, Sang-Goo; Yim, Dong-Seok

    2002-01-01

    Aims The pharmacokinetics of omeprazole and its metabolites in healthy subjects were evaluated to determine if a single dose of moclobemide inhibited CYP2C19 activity. Methods Sixteen volunteers, of whom eight were extensive metabolizers (EM) and eight were poor metabolizers for CYP2C19, participated in two studies. Venous blood samples were collected for 24 h after oral ingestion of 40 mg omeprazole with or without 300 mg moclobemide coadministration. The pharmacokinetic change of omeprazole, omeprazole sulphone and 5-hydroxyomeprazole concentrations were assessed to test for an interaction between omeprazole and moclobemide. Results The coadministration of moclobemide in EMs approximately doubled the mean AUC (from 1834 to 3760 ng ml−1 h) and Cmax (from 987 to 1649 ng ml−1) of omeprazole, and increased the AUC of omeprazole sulphone without changing AUC ratio of omeprazole to omeprazole sulphone. Moclobemide coadministration more than doubled the AUC ratio of omeprazole to 5-hydroxyomeprazole (from 2.5 to 5.3) in EMs, too. There was a significant decrease in Cmax and AUC of 5-hydroxyomeprazole in PMs but no significant changes were seen in the results for omeprazole and omeprazole sulphone AUCs. Conclusions A single dose of moclobemide resulted in significant suppression of CYP2C19 activity in EMs. We conclude that physicians prescribing moclobemide should pay attention to its pharmacokinetic interactions even on the first day of coadministration with CYP2C19 substrates. PMID:11966672

  4. A germline homozygote deletion of the glutathione-s-transferase Mu 1 gene predisposes to bladder cancer

    NARCIS (Netherlands)

    Mungan, N.A.; Aben, K.K.H.; Beeks, E.; Kampman, E.; Bunschoten, A.; Bussemakers, M.; Witjes, J.A.

    2000-01-01

    Introduction and Objectives: Numerous studies have shown smoking and specific occupational exposures to be risk factors for bladder cancer. The risk of bladder cancer may be modified by the activity of carcinogen metabolizing enzymes. The glutathione-S-transferase Mu1 enzyme (GSTM1) detoxifies

  5. Hemochromatosis and diabetes mellitus: case report and literature review

    Directory of Open Access Journals (Sweden)

    Karina Biavatti

    2008-12-01

    Full Text Available Hemochromatosis is a disorder characterized by iron storage amended. The acquired form of the disease can be caused by iron overload, alcoholism, infection by  C virus hepatitis, non-alcoholic hepatitis and chronic liver disease. The hereditary form can be caused by different mutations, being the C282Y and H63D the most frequent, 83% of cases are homozigotous for C282Y and 4% are compound heterozygous (C282Y/H63D. Hemochromatosis is a condition that can affect several organs, including: heart, joints, liver, hypothalamus, pituitary, pancreas and gonads. The aim of this study was to report a case of hemochromatosis and review the literature, with special attention to the association of hemochromatosis and diabetes mellitus. Patient 53 years, male presented to the doctor with arthralgia metacarpophalangeal, ankles, knees, coxofemoral right, and cervical and lumbar, complaints of fatigue and weight loss. Between 3 brothers, one of them had a diagnosis of hereditary hemochromatosis, with PCR demonstrating homozygous for C282Y. Labs: GOT 128 U/L, ALT 231 U/L, alkaline phosphatase 258 U/L, abdominal ultrasound with hepatomegaly and spleen at the upper limit of normal. Liver biopsy demonstrated portal fibrosis extension with hemosiderosis intense. It also made the diagnosis of diabetes mellitus. The research confirmed the same mutation of the changing family: homozygous for C282Y

  6. H63D mutation in HFE gene is common in Indians and is associated ...

    Indian Academy of Sciences (India)

    Department of Haematology, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India; Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Uppal Road, Hyderabad 500 007, India; Department of Hepatology, Postgraduate Institute of Medical Education and ...

  7. LHD 7 (USS Iwo Jima) Human Factors Engineering (HFE)/Safety Ship Design Lessons Learned Report

    Science.gov (United States)

    2007-07-02

    APPENDIX C: Access Aids – Doors and Arches Compartment Name/Number/Type/Equipment(s): Main Galley/Galley - Mess/ Reefer Issue(s)/Hazard(s...Description: Step up into reefer is 11" high. This step height is excessive while moving either in or out of the reefer , especially while material handling... reefer in order to bring the reefer threshold down to the deck height outside of the reefer . If this is not feasible, alternately provide movable

  8. Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice

    National Research Council Canada - National Science Library

    Gao, Junwei; Chen, Juxing; De Domenico, Ivana; Koeller, David M; Harding, Cary O; Fleming, Robert E; Koeberl, Dwight D; Enns, Caroline A

    2010-01-01

    ...), transferrin-receptor 2 (TfR2), hemojuvelin, hepcidin, or ferroportin genes. Hepcidin is a key iron regulator, which is secreted by the liver, and decreases serum iron levels by causing the down-regulation of the iron transporter, ferroportin...

  9. Osteoporosis in HFE2 juvenile hemochromatosis. A case report and review of the literature.

    Science.gov (United States)

    Angelopoulos, Nicholas G; Goula, Anastasia K; Papanikolaou, George; Tolis, George

    2006-01-01

    Juvenile hemochromatosis (JH) is a severe form of hemochromatosis, which involves rapid iron overload and leads to organ damage, typically before the age of 30. We report a single case of a 25-year-old man suffering from juvenile hemochromatosis, with aggressive clinical manifestations, typically characterized by transaminasemia and progressive erectile dysfunction, due to hypogonadotropic hypogonadism. The clinical case appears interesting, as the patient also had secondary osteoporosis accompanied by increased bone resorption, which prevalently affected trabecular bone. Approximately 6 months after normalization of serum ferritin levels was achieved by frequent phlebotomies, he became eugonadal and bone mineral density of the lumbar spine increased. Our observations suggest that osteoporosis might occur in the state of JH even at a young age, mainly due to the deprivation of sex steroids and the direct tissue toxicity of iron.

  10. Detection of five rare cystic fibrosis mutations peculiar to Southern Italy: implications in screening for the disease and phenotype characterization for patients with homozygote mutations.

    Science.gov (United States)

    Castaldo, G; Fuccio, A; Cazeneuve, C; Picci, L; Salvatore, D; Raia, V; Scarpa, M; Goossens, M; Salvatore, F

    1999-07-01

    The search for the eight most frequent mutations (i.e., DeltaF508, G542X, W1282X, N1303K, 1717-1G-->A, R553X, 2183AA-->G, and I148T) by allele-specific oligonucleotide dot-blot analysis revealed 78% of 396 cystic fibrosis alleles in Southern Italy. The observation of frequent haplotypes on the unidentified cystic fibrosis alleles suggested that a few mutations could account for a large number of unidentified alleles. We screened most of the coding sequence of the cystic fibrosis transmembrane regulator gene by denaturing gradient gel electrophoresis to determine the spectrum of these mutations in 68 unrelated cystic fibrosis patients bearing one or both unidentified mutations. The screening revealed five mutations, R1158X, 711+1G-->T, 4016insT, L1065P, and G1244E, each of which had a frequency of 1.3-1.8% (7% collectively). The 7% increase in the detection rate (85% vs 78%) reduces by >50% the residual risk of being cystic fibrosis carriers for couples who had tested negative by molecular analysis. We therefore designed a second allele-specific oligonucleotide set to analyze the five mutations. Among the patients analyzed, one patient homozygous for the L1065P mutation expressed a mild pulmonary and intestinal form of the disease with pancreatic insufficiency. Two other patients, homozygous for mutations R1158X and 4016insT, both expressed a severe cystic fibrosis phenotype. Five cystic fibrosis mutations are peculiar to patients from Southern Italy. The method described for their analysis is efficient, inexpensive, and can be semi-automated by use of a robotic workstation. The results obtained in patients from Southern Italy may have an impact on laboratories in other countries, given the large migrations of populations from Southern Italy to other countries in the last two centuries.

  11. Potyviral resistance derived from cultivars of Phaseolus vulgaris carrying bc-3 is associated with the homozygotic presence of a mutated eIF4E allele

    DEFF Research Database (Denmark)

    Naderpour, Masoud; Lund, Ole Søgaard; Larsen, Richard

    2010-01-01

    Eukaryotic translation initiation factors (eIFs) play a central role in potyviral infection. Accordingly, mutations in the gene encoding eIF4E have been identified as a source of recessive resistance in several plant species. In common bean, Phaseolus vulgaris, four recessive genes, bc-1, bc-2, bc......-3 and bc-u, have been proposed to control resistance to the potyviruses Bean common mosaic virus (BCMV) and Bean common mosaic necrosis virus. In order to identify molecular entities for these genes, we cloned and sequenced P. vulgaris homologues of genes encoding the eIF proteins eIF4E, eIF(iso)4E...... resistance and eIF4E genotype was subsequently analysed in an F2 population derived from the P. vulgaris all-susceptible genotype and a genotype carrying bc-3. F2 plants homozygous for the eIF4E mutant allele were found to display at least the same level of resistance to BCMV as the parental resistant...

  12. TT Mutant Homozygote of Is a Key Factor for Increasing Basal Metabolic Rate and Resting Metabolic Rate in Korean Elementary School Children

    Directory of Open Access Journals (Sweden)

    Jung Ran Choi

    2013-12-01

    Full Text Available We investigated the contribution of genetic variations of KLF5 to basal metabolic rate (BMR and resting metabolic rate (RMR and the inhibition of obesity in Korean children. A variation of KLF5 (rs3782933 was genotyped in 62 Korean children. Using multiple linear regression analysis, we developed a model to predict BMR in children. We divided them into several groups; normal versus overweight by body mass index (BMI and low BMR versus high BMR by BMR. There were no differences in the distributions of alleles and genotypes between each group. The genetic variation of KLF5 gene showed a significant correlation with several clinical factors, such as BMR, muscle, low-density lipoprotein cholesterol, and insulin. Children with the TT had significantly higher BMR than those with CC (p = 0.030. The highest muscle was observed in the children with TT compared with CC (p = 0.032. The insulin and C-peptide values were higher in children with TT than those with CC (p= 0.029 vs. p = 0.004, respectively. In linear regression analysis, BMI and muscle mass were correlated with BMR, whereas insulin and C-peptide were not associated with BMR. In the high-BMR group, we observed that higher muscle, fat mass, and C-peptide affect the increase of BMR in children with TT (p < 0.001, p < 0.001, and p = 0.018, respectively, while Rohrer's index could explain the usual decrease in BMR (adjust r2 = 1.000, p < 0.001, respectively. We identified a novel association between TT of KLF5 rs3782933 and BMR in Korean children. We could make better use of the variation within KLF5 in a future clinical intervention study of obesity.

  13. Marked Alteration of Rosuvastatin Pharmacokinetics in Healthy Chinese with ABCG2 34G>A and 421C>A Homozygote or Compound Heterozygote.

    Science.gov (United States)

    Wan, Zirui; Wang, Guo; Li, Tailin; Xu, Biaobo; Pei, Qi; Peng, Yan; Sun, Hong; Cheng, Lijuan; Zeng, Ying; Yang, Guoping; Zhu, Yuan-Shan

    2015-09-01

    Rosuvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor used to lower blood low-density lipoprotein cholesterol, is a substrate of the membrane ABCG2 exporter. ABCG2 variants have been shown to alter rosuvastatin disposition. The objective of this study is to determine the impact of ABCG2 34/421 compound haplotypes on rosuvastatin pharmacokinetics in healthy Chinese volunteer subjects. Eight hundred healthy Chinese males were genotyped by polymerase chain reaction-pyrosequencing for ABCG2 34G>A, ABCG2 421C>A, SLCO1B1 521T>C, and CYP2C9*3 variants. Sixty-two male subjects with wild-type SLCO1B1 c.521TT and CYP2C9*3 were recruited for this pharmacokinetic study of rosuvastatin. A single oral dose of 10 mg rosuvastatin was administrated to each subject, and blood samples were collected before and at various time points after drug administration. Plasma concentration of rosuvastatin was determined by high-performance liquid chromatography-tandem mass spectrometry, and pharmacokinetic analysis was carried out using the WinNonlin program. In Chinese males, high allele frequency of ABCG2 c.34G>A (0.275) and c.421C>A (0.282) was observed, resulting in a considerable portion (23.3%) of subjects being ABCG2 34/421 compound heterozygotes. Compared with subjects with ABCG2 wild-type (c.34GG/421CC), plasma rosuvastatin Cmax and area under the curve, AUC0-∞, were significantly higher, while the apparent oral clearance, CL/F, was significantly lower in subjects with c.34AA, c.421AA, and c.34GA/421CA genotypes. Both t1/2 and Tmax were similar among subjects with different genotypes. A high frequency of ABCG2 c.34G>A and c.421C>A variants was present in Chinese males, and the disposition of rosuvastatin was significantly affected by both variants. These data suggest that it is advisable to genotype these variants when prescribing rosuvastatin to Chinese subjects, leading to a precise dose for each individual. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  14. Homozygote c.35delG Mutation im Connexin 26 Gen bei einem ehemaligen Frühgeborenen mit Trisomie 21

    OpenAIRE

    Pantel, G; Fischer-Krall, E; Streicher, B.; Lang-Roth, R

    2013-01-01

    Hintergrund: Die Trisomie 21 ist assoziiert mit einem deutlich erhöhten Risiko für eine Hörminderung. Die in der Literatur angegebenen Häufigkeiten betragen 38-82%. Die Schwerhörigkeiten sind jedoch überwiegend gering- bis mittelgradige Schallleitungs- oder kombinierte Schwerhörigkeiten . Mutationen im Connexin 26 Gen sind ursächlich für bis zu 60% der nicht syndromalen genetisch determinierten Schwerhörigkeiten . Frühgeburtlichkeit, ein Geburtsgewicht von unter 1.500g sowie die Notwendigkei...

  15. Mutations in HFE and TFR2 genes in a Spanish patient with hemochromatosis Mutaciones en los genes HFE y TFR2 en un paciente español con hemocromatosis

    National Research Council Canada - National Science Library

    Alejandro del-Castillo-Rueda; Nuria Cuadrado-Grande; Emilio Álvarez-Fernández; Rafael Enríquez-de-Salamanca; Luis Antonio Álvarez-Sala; María Josefa Morán-Jiménez

    2011-01-01

    ... 1,000 µg/L of serum ferritin and studied the genes involved in this condition. The phenotype of iron overload is confirmed by a predominantly periportal pattern of iron deposits in the liver suggestive of genetic disease...

  16. Variation in the HFE gene is associated with the development of bleomycin-induced pulmonary toxicity in testicular cancer patients

    NARCIS (Netherlands)

    Schoot, van der Garbiela G.F.; Westerink, Nico-Derk L; Lubberts, Sjoukje; Nuver, Janine; Zwart, Nynke; Walenkamp, Annemiek M E; Wempe, Johan B; Meijer, Coby; Gietema, Jourik A

    BACKGROUND: Bleomycin and cisplatin are of key importance in testicular cancer treatment. Known potential serious adverse effects are bleomycin-induced pulmonary toxicity (BIP) and cisplatin-induced renal toxicity. Iron handling may play a role in development of this toxicity. Carriage of allelic

  17. Course of iron parameters in HFE-hemochromatosis patients during initial treatment with erythrocytapheresis compared to phlebotomy.

    Science.gov (United States)

    Rombout-Sestrienkova, Eva; Koek, Ger H; Neslo, Rabin; van Kraaij, Marian; Menheere, Paul P; Masclee, Ad; Swinkels, Dorine W

    2016-12-01

    Current treatment for newly diagnosed patients with hereditary hemochromatosis (HH) and iron overload consist of weekly phlebotomy or less frequent and more personalized erythrocytapheresis. Previous observations during phlebotomy suggest an increase in intestinal iron uptake caused by lowering of hepcidin as a result of intensive bloodletting. It is not known whether such an effect is present or even more pronounced using erythrocytapheresis since a larger amount of iron is extracted per procedure. In this study we aimed to assess the effect of erythrocytapheresis on the course of iron parameters, with special focus on serum hepcidin. We performed a retrospective proof-of-principle observational study, comparing serum iron parameters in 12 males during the depletion phase using either phlebotomy (n = 6) or erythrocytapheresis (n = 6). Decreases in serum ferritin over time were similar for both treatments but more pronounced using erythrocytapheresis when expressed per treatment procedure. Hemoglobin did not change during erythrocytapheresis, whereas during phlebotomy decreased with 10%. Increase of erythropoietin and soluble transferrin receptor and decrease in transferrin saturation were similar for both treatments. Reduction in serum hepcidin was higher (50% versus 25% of initial value) and occurred more early using phlebotomy (10 versus 20 weeks after start). In aggregate, compared to phlebotomy, the less frequent and more personalized erythrocytapheresis leads to a more pronounced decrease in serum ferritin per treatment procedure, without a larger decrease in serum hepcidin. This may be clinically relevant and may prevent an increase in intestinal iron uptake and an ensuing vicious circle of more frequent treatment procedures. J. Clin. Apheresis 31:564-570, 2016. © 2015 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  18. Design and modernization of control rooms according to new I and C systems based on HFE principles

    Energy Technology Data Exchange (ETDEWEB)

    Rejas, Luis; Larraz, Javier, E-mail: lrejas@tecnatom.e, E-mail: jlarraz@tecnatom.e [Tecnatom S.A., San Sebastian de los Reyes, Madrid (Spain). New Control Room Design Dept.; Ortega, Fernando, E-mail: fortega@tecnatom.e [Tecnatom S.A., San Sebastian de los Reyes, Madrid (Spain). Control Room and Simulation Dept.

    2011-07-01

    The use of new digital I and C systems in the design of new nuclear power plants, as well as the modernization of existing facilities, implies relevant changes in the control room design. New I and C systems provide new features that affect the control room operating concept. Therefore, a detailed analysis is required to take into consideration all the operating and human factors aspects. Based on Tecnatom experience in the field, this article presents the methodological approach used as well as the most relevant aspects of this kind of project. (author)

  19. Human factors and ergonomics as a patient safety practice

    Science.gov (United States)

    Carayon, Pascale; Xie, Anping; Kianfar, Sarah

    2014-01-01

    Background Human factors and ergonomics (HFE) approaches to patient safety have addressed five different domains: usability of technology; human error and its role in patient safety; the role of healthcare worker performance in patient safety; system resilience; and HFE systems approaches to patient safety. Methods A review of various HFE approaches to patient safety and studies on HFE interventions was conducted. Results This paper describes specific examples of HFE-based interventions for patient safety. Studies show that HFE can be used in a variety of domains. Conclusions HFE is a core element of patient safety improvement. Therefore, every effort should be made to support HFE applications in patient safety. PMID:23813211

  20. Increased iron stores prolong the QT interval - a general population study including 20 261 individuals and meta-analysis of thalassaemia major

    DEFF Research Database (Denmark)

    Henriksen, Lise Fischer; Petri, Anne-Sofie; Hasselbalch, Hans Carl

    2016-01-01

    concentration, transferrin saturation, iron concentration, transferrin concentration and haemochromatosis genotype (C282Y/C282Y). Furthermore, we performed a meta-analysis of case-control studies on thalassaemia major patients and QT interval. Age- and C-reactive protein-adjusted mean corrected QT (QTc......The prolongation of cardiac repolarization (QT interval) has been investigated in studies of patients with secondary iron overload. However, no previous population-based study examining the effect of increased iron stores on QT interval prolongation has previously been undertaken. We tested...... the hypothesis that increased iron stores and haemochromatosis genotype (genetically increased iron stores) are associated with prolongation of the QT interval. We included 20 261 individuals from the Danish General Suburban Population Study and examined differences in QT interval according to ferritin...

  1. First Two Cases of Bloom Syndrome in Russia: Lack of Skin Manifestations in a BLM c.1642C>T (p.Q548X) Homozygote as a Likely Cause of Underdiagnosis.

    Science.gov (United States)

    Suspitsin, Evgeny N; Sibgatullina, Farida I; Lyazina, Lydia V; Imyanitov, Evgeny N

    2017-03-01

    Bloom syndrome (BS) is an exceptionally rare hereditary disease. Typical manifestations of BS usually include growth deficiency, a characteristic facial appearance, skin hypersensitivity to ultraviolet irradiation, and a strong predisposition to early-onset cancers. We have previously described a recurrent BLM c.1642C>T (p.Q548X) mutation, which is present in heterozygous state in 0.2-0.6% of individuals of Slavic origin. Despite the high occurrence of this founder allele, BS has not yet been described in patients of Slavic ethnicity. Here, we present 2 cases of BS, which were missed by standard genetic counseling and were eventually identified entirely due to chance. Our patients show the need for further investigations to confirm whether the atypical appearance of BS is indeed characteristic for biallelic carriers of the c.1642C>T (p.Q548X) allele and whether the absence of skin manifestations contributes to the underdiagnosis of the disease in Russia. Therefore, we suggest that all Slavic patients with only one single clinical feature of BS are to be screened for this allele and subjected to further analysis wherever appropriate. In addition to identifying new BS patients, this effort will help to clarify the frequency of "atypical BS" with incomplete phenotypic manifestations.

  2. An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe(-/-) mice and ameliorates anemia and iron overload in murine β-thalassemia intermedia

    National Research Council Canada - National Science Library

    Schmidt, Paul J; Toudjarska, Iva; Sendamarai, Anoop K; Racie, Tim; Milstein, Stuart; Bettencourt, Brian R; Hettinger, Julia; Bumcrot, David; Fleming, Mark D

    2013-01-01

    .... -thalassemia is a congenital anemia caused by partial or complete loss of -globin synthesis causing ineffective erythropoiesis, anemia, decreased hepcidin production, and secondary iron overload...

  3. Genotyping of single-nucleotide polymorphisms by high-resolution melting of small amplicons.

    Science.gov (United States)

    Liew, Michael; Pryor, Robert; Palais, Robert; Meadows, Cindy; Erali, Maria; Lyon, Elaine; Wittwer, Carl

    2004-07-01

    High-resolution melting of PCR amplicons with the DNA dye LCGreen I was recently introduced as a homogeneous, closed-tube method of genotyping that does not require probes or real-time PCR. We adapted this system to genotype single-nucleotide polymorphisms (SNPs) after rapid-cycle PCR (12 min) of small amplicons (SNP base changes. In addition, clinical protocols for factor V (Leiden) 1691G>A, prothrombin 20210G>A, methylenetetrahydrofolate reductase (MTHFR) 1298A>C, hemochromatosis (HFE) 187C>G, and beta-globin (hemoglobin S) 17A>T were developed. LCGreen I was included in the reaction mixture before PCR, and high-resolution melting was obtained within 2 min after amplification. In all cases, heterozygotes were easily identified because heteroduplexes altered the shape of the melting curves. Approximately 84% of human SNPs involve a base exchange between A::T and G::C base pairs, and the homozygotes are easily genotyped by melting temperatures (T(m)s) that differ by 0.8-1.4 degrees C. However, in approximately 16% of SNPs, the bases only switch strands and preserve the base pair, producing very small T(m) differences between homozygotes (G protocol, but, as predicted from the sequence changes, was not needed for the other four clinical protocols. SNP genotyping by high-resolution melting analysis is simple, rapid, and inexpensive, requiring only PCR, a DNA dye, and melting instrumentation. The method is closed-tube, performed without probes or real-time PCR, and can be completed in less than 2 min after completion of PCR.

  4. Human factors in patient safety as an innovation.

    Science.gov (United States)

    Carayon, Pascale

    2010-09-01

    The use of Human Factors and Ergonomics (HFE) tools, methods, concepts and theories has been advocated by many experts and organizations to improve patient safety. To facilitate and support the spread of HFE knowledge and skills in healthcare and patient safety, we propose to conceptualize HFE as innovations whose diffusion, dissemination, implementation and sustainability need to be understood and specified. Using Greenhalgh et al. (2004) model of innovation, we identified various factors that can either hinder or facilitate the spread of HFE innovations in healthcare organizations. Barriers include lack of systems thinking, complexity of HFE innovations and lack of understanding about the benefits of HFE innovations. Positive impact of HFE interventions on task performance and the presence of local champions can facilitate the adoption, implementation and sustainability of HFE innovations. This analysis concludes with a series of recommendations for HFE professionals, researchers and educators. 2010 Elsevier Ltd. All rights reserved.

  5. Exploring the relationship between maternal iron status and offspring’s blood pressure and adiposity: a Mendelian randomization study

    Directory of Open Access Journals (Sweden)

    Alwan NA

    2012-08-01

    Full Text Available Nisreen A Alwan,1 Debbie A Lawlor,2 Harry J McArdle,3 Darren C Greenwood,4 Janet E Cade11Nutritional Epidemiology Group, School of Food Science and Nutrition, University of Leeds, Leeds, UK; 2MRC Centre for Causal Analyses in Translational Research, University of Bristol, Bristol; 3Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen; 4Biostatistics Unit, Leeds Institute for Health, Genetics and Therapeutics, University of Leeds, Leeds, UKBackground: Iron deficiency is the most common micronutrient deficiency worldwide. Experimental animal studies suggest that mothers deficient in iron during pregnancy are more likely to have offspring who become obese with high blood pressure. C282Y mutation carriers are more likely to have higher iron stores.Methods: We undertook an instrumental variable (IV analysis, using maternal C282Y as an indicator for the mother’s iron status, to examine its association with offspring blood pressure (BP, waist circumference (WC, and body mass index (BMI, and compared the results to that of ordinary least squares (OLS regression. Offspring of a sub-cohort of mothers from the UK Women’s Cohort Study (UKWCS were recruited in 2009–2010 (n = 348, mean age = 41 years. Their blood pressure, height, and weight were measured at their local general medical practice, and they were asked to self-measure their waist circumference. About half were offspring of C282Y carriers. Maternal ferritin was used as a biomarker of maternal iron status.Results: Maternal C282Y was strongly associated with maternal ferritin (mean difference per allele = 84 g/L, 95% confidence interval: 31–137, P = 0.002. Using IV analyses, maternal ferritin was not linked to offspring’s BP, BMI, or WC. The first stage F-statistic for the strength of the instrument was 10 (Kleibergen–Paap rk LM P = 0.009. Maternal ferritin was linked to offspring diastolic BP, WC, and BMI in univariable, but not in multivariable OLS analysis. There

  6. Human Factors Evaluation Mentor Project

    Data.gov (United States)

    National Aeronautics and Space Administration — To obtain valid and reliable data, Human Factors Engineering (HFE) evaluations are currently conducted by people with specialized training and experience in HF. HFE...

  7. Disease: H00211 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available sis is an autosomal recessive iron metabolism disorder characterized by increased intestinal iron absorption, which leads to progress...ive accumulation of iron in the body. Inherited metabolic disease (HFE) HFE [HSA:30

  8. Genetics Home Reference: hereditary hemochromatosis

    Science.gov (United States)

    ... several genes, including HAMP , HFE , HFE2 , SLC40A1 , and TFR2 , can cause hereditary hemochromatosis . Type 1 hemochromatosis results ... the HFE2 or HAMP gene. Mutations in the TFR2 gene cause type 3 hemochromatosis, and mutations in ...

  9. ORF Alignment: NC_002937 [GENIUS II[Archive

    Lifescience Database Archive (English)

    Full Text Available NC_002937 gi|46580180 >1hfeS 1 88 36 123 3e-36 ... ref|YP_010988.1| periplasmic [Fe] ...drogenase small subunit precursor (Fe ... hydrogenlyase small chain) pdb|1HFE...|T Chain T, 1.6 A ... Resolution Structure Of The Fe-Only Hydrogenase From ... Desulfovibrio Desulfuricans pdb|1HFE

  10. Human factors/ergonomics as a systems discipline? "The human use of human beings" revisited

    DEFF Research Database (Denmark)

    Hollnagel, Erik

    2014-01-01

    Discussions of the possible future of Human factors/ergonomics (HFE) usually take the past for granted in the sense that the future of HFE is assumed to be more of the same. This paper argues that the nature of work in the early 2010s is so different from the nature of work when HFE was formulated...

  11. Increased iron stores prolong the QT interval - a general population study including 20 261 individuals and meta-analysis of thalassaemia major.

    Science.gov (United States)

    Henriksen, Lise Fischer; Petri, Anne-Sofie; Hasselbalch, Hans Carl; Kanters, Jørgen Kim; Ellervik, Christina

    2016-09-01

    The prolongation of cardiac repolarization (QT interval) has been investigated in studies of patients with secondary iron overload. However, no previous population-based study examining the effect of increased iron stores on QT interval prolongation has previously been undertaken. We tested the hypothesis that increased iron stores and haemochromatosis genotype (genetically increased iron stores) are associated with prolongation of the QT interval. We included 20 261 individuals from the Danish General Suburban Population Study and examined differences in QT interval according to ferritin concentration, transferrin saturation, iron concentration, transferrin concentration and haemochromatosis genotype (C282Y/C282Y). Furthermore, we performed a meta-analysis of case-control studies on thalassaemia major patients and QT interval. Age- and C-reactive protein-adjusted mean corrected QT (QTc) intervals for ferritin concentration ≥99% vs. ≥25-stores, independent of haemochromatosis genotype and inflammation, are associated with prolongation of the QTc interval in men. This is a novel finding. In addition, the meta-analysis showed prolonged QT interval in thalassaemia major patients compared to healthy controls. © 2016 John Wiley & Sons Ltd.

  12. Human factors and ergonomics for primary care.

    Science.gov (United States)

    Bowie, Paul; Jeffcott, Shelly

    2016-03-01

    In the second paper of this series, we provide a brief overview of the scientific discipline of human factors and ergonomics (HFE). Traditionally the HFE focus in healthcare has been in acute hospital settings which are perceived to exhibit characteristics more similar to other high-risk industries already applying related principles and methods. This paper argues that primary care is an area which could benefit extensively from an HFE approach, specifically in improving the performance and well-being of people and organisations. To this end, we define the purpose of HFE, outline its three specialist sub-domains (physical, cognitive and organisational HFE) and provide examples of guiding HFE principles and practices. Additionally, we describe HFE issues of significance to primary care education, improvement and research and outline early plans for building capacity and capability in this setting.

  13. Human factors engineering plan for reviewing nuclear plant modernization programs

    Energy Technology Data Exchange (ETDEWEB)

    O' Hara, John; Higgins, James [Brookhaven National Laboratory, Upton, NY (United States)

    2004-12-01

    The Swedish Nuclear Power Inspectorate reviews the human factors engineering (HFE) aspects of nuclear power plants (NPPs) involved in the modernization of the plant systems and control rooms. The purpose of a HFE review is to help ensure personnel and public safety by verifying that accepted HFE practices and guidelines are incorporated into the program and nuclear power plant design. Such a review helps to ensure the HFE aspects of an NPP are developed, designed, and evaluated on the basis of a structured top-down system analysis using accepted HFE principles. The review addresses eleven HFE elements: HFE Program Management, Operating Experience Review, Functional Requirements Analysis and Allocation, Task Analysis, Staffing, Human Reliability Analysis, Human-System Interface Design, Procedure Development, Training Program Development, Human Factors Verification and Validation, and Design Implementation.

  14. A strategy for human factors/ergonomics: developing the discipline and profession.

    Science.gov (United States)

    Dul, Jan; Bruder, Ralph; Buckle, Peter; Carayon, Pascale; Falzon, Pierre; Marras, William S; Wilson, John R; van der Doelen, Bas

    2012-01-01

    Human factors/ergonomics (HFE) has great potential to contribute to the design of all kinds of systems with people (work systems, product/service systems), but faces challenges in the readiness of its market and in the supply of high-quality applications. HFE has a unique combination of three fundamental characteristics: (1) it takes a systems approach (2) it is design driven and (3) it focuses on two closely related outcomes: performance and well-being. In order to contribute to future system design, HFE must demonstrate its value more successfully to the main stakeholders of system design. HFE already has a strong value proposition (mainly well-being) and interactivity with the stakeholder group of 'system actors' (employees and product/service users). However, the value proposition (mainly performance) and relationships with the stakeholder groups of 'system experts' (experts fromtechnical and social sciences involved in system design), and 'system decision makers' (managers and other decision makers involved in system design, purchase, implementation and use), who have a strong power to influence system design, need to be developed. Therefore, the first main strategic direction is to strengthen the demand for high-quality HFE by increasing awareness among powerful stakeholders of the value of high-quality HFE by communicating with stakeholders, by building partnerships and by educating stakeholders. The second main strategic direction is to strengthen the application of high-quality HFE by promoting the education of HFE specialists, by ensuring high-quality standards of HFE applications and HFE specialists, and by promoting HFE research excellence at universities and other organisations. This strategy requires cooperation between the HFE community at large, consisting of the International Ergonomics Association (IEA), local (national and regional) HFE societies, and HFE specialists. We propose a joint world-wide HFE development plan, in which the IEA takes a

  15. Homozygotic intronic GAA mutation in three siblings with late-onset Pompe's disease Mutação homozigótica intrônica no gene GAA em três irmãos com doença de Pompe de início tardio

    Directory of Open Access Journals (Sweden)

    Anderson Kuntz Grzesiuk

    2010-04-01

    Full Text Available Pompe's disease (PD is a metabolic myopathy caused by the accumulation of lysosomal glycogen, secondary to acid α-glucosidase (GAA enzyme deficiency. Childhood and late-onset forms are described, differing by the age of onset and symptoms. In this study were analyzed affected siblings with Pompe's disease (PD and their distinct clinical and pathological presentations. METHOD: Diagnosis was performed by the clinical presentation of limb-girdle dystrophies and respiratory compromise. Confirmatory diagnoses were conducted by muscle biopsy, GAA activity measurement and by GAA gene genotyping. RESULTS: The findings suggested muscular involvement due to GAA deficiency. GAA genotyping showed they are homozygous for the c.-32-3C>A mutation. CONCLUSION: Herein we reported a family where three out of five siblings were diagnosed with late-onset PD, although it is a rare metabolic disease inherited in an autossomal recessive manner. We emphasize the importance of including this presentation within the differential diagnoses of the limb-girdle dystrophies once enzyme replacement therapy is available.A doença de Pompe (DP é uma miopatia originada do acúmulo lisossomal de glicogênio, devido à deficiência da enzima α-glicosidase ácida (GAA, sendo descritas formas de inicio precoce e tardio. Neste estudo analisamos retrospectivamente o perfil clinico e patológico de 3 irmãos portadores de doença de Pompe de inicio tardio. MÉTODO: O diagnóstico foi realizado mediante apresentação clinica de distrofia de cinturas associado a comprometimento respiratório, sendo confirmado por biópsia muscular e análise da atividade e genotipagem da GAA. RESULTADOS: Os exames clínicos e laboratoriais demonstram envolvimento muscular devido à deficiência da GAA, com uma mutação c.-32-3C>A em homozigose. CONCLUSÃO: Relatamos os aspectos clínicos e laboratoriais de 3 irmãos afetados por doença de Pompe de início tardio. Enfatizamos a importância de incluir esta patologia no diagnóstico diferencial das distrofias de cinturas, uma vez que para esta patologia específica existe a possibilidade terapêutica através de reposição enzimática.

  16. Absorption of manganese and iron in a mouse model of hemochromatosis.

    Directory of Open Access Journals (Sweden)

    Jonghan Kim

    Full Text Available Hereditary hemochromatosis, an iron overload disease associated with excessive intestinal iron absorption, is commonly caused by loss of HFE gene function. Both iron and manganese absorption are regulated by iron status, but the relationships between the transport pathways of these metals and how they are affected by HFE-associated hemochromatosis remain poorly understood. Loss of HFE function is known to alter the intestinal expression of DMT1 (divalent metal transporter-1 and Fpn (ferroportin, transporters that have been implicated in absorption of both iron and manganese. Although the influence of HFE deficiency on dietary iron absorption has been characterized, potential effects on manganese metabolism have yet to be explored. To investigate the role of HFE in manganese absorption, we characterized the uptake and distribution of the metal in Hfe (-/- knockout mice after intravenous, intragastric, and intranasal administration of (54Mn. These values were compared to intravenous and intragastric administration of (59Fe. Intestinal absorption of (59Fe was increased and clearance of injected (59Fe was also increased in Hfe(-/- mice compared to controls. Hfe (-/- mice displayed greater intestinal absorption of (54Mn compared to wild-type Hfe(+/+ control mice. After intravenous injection, the distribution of (59Fe to heart and liver was greater in Hfe (-/- mice but no remarkable differences were observed for (54Mn. Although olfactory absorption of (54Mn into blood was unchanged in Hfe (-/- mice, higher levels of intranasally-instilled (54Mn were associated with Hfe(-/- brain compared to controls. These results show that manganese transport and metabolism can be modified by HFE deficiency.

  17. Human factors engineering program review model

    Energy Technology Data Exchange (ETDEWEB)

    1994-07-01

    The staff of the Nuclear Regulatory Commission is performing nuclear power plant design certification reviews based on a design process plan that describes the human factors engineering (HFE) program elements that are necessary and sufficient to develop an acceptable detailed design specification and an acceptable implemented design. There are two principal reasons for this approach. First, the initial design certification applications submitted for staff review did not include detailed design information. Second, since human performance literature and industry experiences have shown that many significant human factors issues arise early in the design process, review of the design process activities and results is important to the evaluation of an overall design. However, current regulations and guidance documents do not address the criteria for design process review. Therefore, the HFE Program Review Model (HFE PRM) was developed as a basis for performing design certification reviews that include design process evaluations as well as review of the final design. A central tenet of the HFE PRM is that the HFE aspects of the plant should be developed, designed, and evaluated on the basis of a structured top-down system analysis using accepted HFE principles. The HFE PRM consists of ten component elements. Each element in divided into four sections: Background, Objective, Applicant Submittals, and Review Criteria. This report describes the development of the HFE PRM and gives a detailed description of each HFE review element.

  18. Developing human factors/ergonomics as a design discipline.

    Science.gov (United States)

    Norros, Leena

    2014-01-01

    This paper deals with internal challenges that the human factors/ergonomics (HFE) research faces when wishing to strengthen its contribution to development of work systems. Three established characteristics of high-quality HFE, i.e., HFE takes a systems approach, HFE is design-driven, and HFE focuses on two closely related outcomes, performance and well-being, are taken as a starting point of a methodological discussion, in which conceptual innovations, e.g. adopting the technology-in-use perspective, are proposed to support development of HFE towards the high-quality aims. The feasibility of the proposed conceptual choices is demonstrated by introducing a naturalistic HFE analysis approach including four HFE functions. The gained experience of the use of this approach in a number of complex work domains allows the conclusion that becoming design-driven appears as that most difficult quality target for HFE to reach. Creating an own design discipline identity in a multi-voiced collaboration is the key internal challenge for human factors/ergonomics. Copyright © 2013 Elsevier Ltd and The Ergonomics Society. All rights reserved.

  19. Sepsis and siderosis, Yersinia enterocolitica and hereditary haemochromatosis.

    Science.gov (United States)

    Thwaites, Phoebe A; Woods, Marion L

    2017-01-04

    A 60-year-old woman was admitted with sepsis, relative bradycardia, CT evidence of numerous small liver abscesses and 'skin bronzing' consistent with hereditary haemochromatosis (HH). Yersinia enterocolitica O:9 infection was confirmed by serology specimens taken 10 days apart. Iron overload was detected, and homozygous C282Y gene mutation confirmed HH. Liver biopsy revealed grade IV siderosis with micronodular cirrhosis. Haemochromatosis is a common, inherited disorder leading to iron overload that can produce end-organ damage from excess iron deposition. Haemochromatosis diagnosis allowed aggressive medical management with phlebotomy achieving normalisation of iron stores. Screening for complications of cirrhosis was started that included hepatoma surveillance. Iron overload states are known to increase patient susceptibility to infections caused by lower virulence bacteria lacking sophisticated iron metabolism pathways, for example, Yersinia enterocolitica Although these serious disseminated infections are rare, they may serve as markers for occult iron overload and should prompt haemochromatosis screening. 2017 BMJ Publishing Group Ltd.

  20. Disruption of hemochromatosis protein and transferrin receptor 2 causes iron-induced liver injury in mice.

    Science.gov (United States)

    Delima, Roheeth D; Chua, Anita C G; Tirnitz-Parker, Janina E E; Gan, Eng K; Croft, Kevin D; Graham, Ross M; Olynyk, John K; Trinder, Debbie

    2012-08-01

    Mutations in hemochromatosis protein (HFE) or transferrin receptor 2 (TFR2) cause hereditary hemochromatosis (HH) by impeding production of the liver iron-regulatory hormone, hepcidin (HAMP). This study examined the effects of disruption of Hfe or Tfr2, either alone or together, on liver iron loading and injury in mouse models of HH. Iron status was determined in Hfe knockout (Hfe(-/-)), Tfr2 Y245X mutant (Tfr2(mut)), and double-mutant (Hfe(-/-) ×Tfr2(mut) ) mice by measuring plasma and liver iron levels. Plasma alanine transaminase (ALT) activity, liver histology, and collagen deposition were evaluated to assess liver injury. Hepatic oxidative stress was assessed by measuring superoxide dismutase (SOD) activity and F(2)-isoprostane levels. Gene expression was measured by real-time polymerase chain reaction. Hfe(-/-) ×Tfr2(mut) mice had elevated hepatic iron with a periportal distribution and increased plasma iron, transferrin saturation, and non-transferrin-bound iron, compared with Hfe(-/-), Tfr2(mut), and wild-type (WT) mice. Hamp1 expression was reduced to 40% (Hfe(-/-) and Tfr2(mut) ) and 1% (Hfe(-/-) ×Tfr2(mut)) of WT values. Hfe(-/-) ×Tfr2(mut) mice had elevated plasma ALT activity and mild hepatic inflammation with scattered aggregates of infiltrating inflammatory cluster of differentiation 45 (CD45)-positive cells. Increased hepatic hydoxyproline levels as well as Sirius red and Masson's Trichrome staining demonstrated advanced portal collagen deposition. Hfe(-/-) and Tfr2(mut) mice had less hepatic inflammation and collagen deposition. Liver F(2) -isoprostane levels were elevated, and copper/zinc and manganese SOD activities decreased in Hfe(-/-) ×Tfr2(mut), Tfr2(mut), and Hfe(-/-) mice, compared with WT mice. Disruption of both Hfe and Tfr2 caused more severe hepatic iron overload with more advanced lipid peroxidation, inflammation, and portal fibrosis than was observed with the disruption of either gene alone. The Hfe(-/-) ×Tfr2(mut) mouse model

  1. Intracardiac and intracerebral thrombosis associated with ...

    African Journals Online (AJOL)

    Intracardiac and intracerebral thrombosis associated with methylenetetrahydrofolate reductase A1298C homozygote mutation in paediatric steroidresistant ... The patient was found to have a homozygote mutation in the methylenetetrahydrofolate reductase (MTHFR) gene as an additional risk factor for recurrent thrombosis.

  2. Human factors in industrial systems: 40 years on.

    Science.gov (United States)

    Drury, Colin G

    2008-06-01

    I evaluate the contribution of a pioneering Human Factors special issue on human factors in industrial systems. Papers on the content of the journal's first 10 years showed that industrial human factors/ergonomics (HF/E) in 1969 was quite a rarity in the journal and the society. The 12 papers in the special issue are reviewed briefly and show a wide range of topics, including traditional industrial engineering, physical HF/E, and more mainstream applications of HF/E in this domain similar to those in military and aerospace domains. The evaluation is through citations, later journal content, society technical group membership, and specific influences of Harris's own paper in the issue. The expected direct citation influence of this special issue was not found: Citation counts were in line with all papers in Human Factors. However, other journals have been founded in North America that serve industrial HF/E and provide an outlet for more papers per year than Human Factors. In addition, the industrial domain is well represented in the Human Factors and Ergonomics Society. Finally, Harris's paper has been influential in the specific area of HF/E in inspection. Industrial HF/E is now more accepted within the HF/E community, although largely in the physical ergonomics subspecialty. There is now evidence of use of HF/E techniques more broadly in industry, including service as well manufacturing enterprises.

  3. State of science: human factors and ergonomics in healthcare.

    Science.gov (United States)

    Hignett, Sue; Carayon, Pascale; Buckle, Peter; Catchpole, Ken

    2013-01-01

    The past decade has seen an increase in the application of human factors and ergonomics (HFE) techniques to healthcare delivery in a broad range of contexts (domains, locations and environments). This paper provides a state of science commentary using four examples of HFE in healthcare to review and discuss analytical and implementation challenges and to identify future issues for HFE. The examples include two domain areas (occupational ergonomics and surgical safety) to illustrate a traditional application of HFE and the area that has probably received the most research attention. The other two examples show how systems and design have been addressed in healthcare with theoretical approaches for organisational and socio-technical systems and design for patient safety. Future opportunities are identified to develop and embed HFE systems thinking in healthcare including new theoretical models and long-term collaborative partnerships. HFE can contribute to systems and design initiatives for both patients and clinicians to improve everyday performance and safety, and help to reduce and control spiralling healthcare costs. There has been an increase in the application of HFE techniques to healthcare delivery in the past 10 years. This paper provides a state of science commentary using four illustrative examples (occupational ergonomics, design for patient safety, surgical safety and organisational and socio-technical systems) to review and discuss analytical and implementation challenges and identify future issues for HFE.

  4. Emerging role of human factors and ergonomics in healthcare delivery – A new field of application and influence for the IEA

    Science.gov (United States)

    Carayon, Pascale

    2014-01-01

    Recent developments of research and application of Human Factors and Ergonomics (HFE) are described, in particular the domain of healthcare delivery. HFE activities in this domain are highlighted and challenges for the discipline and the International Ergonomics Association are presented. PMID:22317500

  5. Slow high-frequency effects in mechanics: problems, solutions, potentials

    DEFF Research Database (Denmark)

    Thomsen, Jon Juel

    2005-01-01

    them are introduced first in terms of simple physical examples, and then in generalized form for mathematical models covering broad classes of discrete and continuous mechanical systems. Several application examples are summarized. Three mathematical tools for analyzing HFE effects are described......Strong high-frequency excitation (HFE) may change the ‘slow’ (i.e. effective or average) properties of mechanical systems, e.g. their stiffness, natural frequencies, equilibriums, equilibrium stability, and bifurcation paths. This tutorial describes three general HFE effects: Stiffening...... – an apparent change in the stiffness associated with an equilibrium; Biasing – a tendency for a system to move towards a particular state which does not exist or is unstable without HFE; and Smoothening – a tendency for discontinuities to be apparently smeared out by HFE. The effects and a method for analyzing...

  6. Human factors/ergonomics as a systems discipline? "The human use of human beings" revisited.

    Science.gov (United States)

    Hollnagel, Erik

    2014-01-01

    Discussions of the possible future of Human factors/ergonomics (HFE) usually take the past for granted in the sense that the future of HFE is assumed to be more of the same. This paper argues that the nature of work in the early 2010s is so different from the nature of work when HFE was formulated 60-70 years ago that a critical reassessment of the basis for HFE is needed. If HFE should be a systems discipline, it should be a soft systems rather than a hard systems discipline. It is not enough for HFE to seek to improve performance and well-being through systems design, since any change to the work environment in principle alters the very basis for the change. Instead HFE should try to anticipate how the nature of work will change so that it can both foresee what work will be and propose what work should be. Copyright © 2013 Elsevier Ltd and The Ergonomics Society. All rights reserved.

  7. Human factors engineering in oil and gas--a review of industry guidance.

    Science.gov (United States)

    Robb, Martin; Miller, Gerald

    2012-01-01

    Oil and gas exploration and production activities are carried out in hazardous environments in many parts of the world. Recent events in the Gulf of Mexico highlight those risks and underline the importance of considering human factors during facility design. Ergonomic factors such as machinery design, facility and accommodation layout and the organization of work activities have been systematically considered over the past twenty years on a limited number of offshore facility design projects to a) minimize the occupational risks to personnel, b) support operations and maintenance tasks and c) improve personnel wellbeing. During this period, several regulators and industry bodies such as the American Bureau of Shipping (ABS), the American Society of Testing and Materials (ASTM), the UK's Health and Safety Executive (HSE), Oil and Gas Producers (OGP), and Norway's Petroleum Safety Authority (PSA) have developed specific HFE design standards and guidance documents for the application of Human Factors Engineering (HFE) to the design and operation of Oil and Gas projects. However, despite the existence of these guidance and recommended design practise documents, and documented proof of their value in enhancing crew safety and efficiency, HFE is still not well understood across the industry and application across projects is inconsistent. This paper summarizes the key Oil and Gas industry bodies' HFE guidance documents, identifies recurring themes and current trends in the use of these standards, provides examples of where and how these HFE standards have been used on past major offshore facility design projects, and suggests criteria for selecting the appropriate HFE strategy and tasks for future major oil and gas projects. It also provides a short history of the application of HFE to the offshore industry, beginning with the use of ASTM F 1166 to a major operator's Deepwater Gulf of Mexico facility in 1990 and the application of HFE to diverse world regions. This

  8. Apo-Ferritin as a Therapeutic Treatment for Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    2013-12-01

    HFE H67D allelic variant, present in 30% of ALS patients, and the SOD1 G93A mutation , infusion of aCSF with or without H-ferritin is not...associated with the iron-overload disorder hereditary hemochromatosis. In the human population, genetic variations in the 9 HFE gene, particularly H63D...increase the incidence of ALS (21-24); indeed, the reported prevalence of variations in the HFE gene in ALS is higher than that of SOD1 (25) and to date

  9. Biological Psychiatry Congress 2015

    Directory of Open Access Journals (Sweden)

    H Temmingh

    2015-08-01

    Higgins, B Drogmoller, G Wright, L van der Merwe, N McGregor, B Chiliza, L Asmal, L Koen, D Niehaus, R Emsley, L Warnich 42. Effects of diet, smoking and alcohol consumption on disability (EDSS in people diagnosed with multiple sclerosis S Janse van Rensburg, W Davis, D Geiger, F J Cronje, L Whati, M Kidd, M J Kotze 43. The clinical utility of neuroimaging in an acute adolescnet psychiatric inpatient population Z Khan, A Lachman, J Harvey 44. Relationships between childhood trauma (CT and premorbid adjustment (PA in a highly traumatised sample of patients with first-episode schizophrenia (FES S Kilian, J Burns, S Seedat, L Asmal, B Chiliza, S du Plessis, R Olivier, R Emsley 45. Functional and cognitive outcomes using an mTOR inhibitor in an adolescent with TSC A Lachman, C van der Merwe, P Boyes, P de Vries 46. Perceptions about adolescent body image and eating behaviour K Laxton, A B R Janse van Rensburg 47. Clinical relevance of FTO rs9939609 as a determinant of cardio-metabolic risk in South African patients with major depressive disorder H K Luckhoff, M J Kotze 48. Childhood abuse and neglect as predictors of deficits in verbal auditory memory in non-clinical adolescents with low anxiety proneness L Martin, K Martin, S Seedat 49. The changes of pro-inflammatory cytokines in a prenatally stressed febrile seizure animal model and whether Rhus chirindensis may attenuate these changes A Mohamed, M V Mabandla, L Qulu 50. Influence of TMPRSS6 A736v and HFE C282y on serum iron parameters and age of onset in patients with multiple sclerosis K E Moremi, M J Kotze, H K Luckhoff, L R Fisher, M Kidd, R van Toorn, S Janse van Rensburg 51. Polypharmacy in pregnant women with serious mental illness E Thomas, E du Toit, L Koen, D Niehaus 52. Infant attachment and maternal depression as predictors of neurodevelopmental and behavioural outcomes at follow-up J Nothling, B Laughton, S Seedat 53. Differences in abuse, neglect and exposure to community violence in adolescents with and

  10. Building a Formal Model of a Human-Interactive System: Insights into the Integration of Formal Methods and Human Factors Engineering

    Science.gov (United States)

    Bolton, Matthew L.; Bass, Ellen J.

    2009-01-01

    Both the human factors engineering (HFE) and formal methods communities are concerned with finding and eliminating problems with safety-critical systems. This work discusses a modeling effort that leveraged methods from both fields to use model checking with HFE practices to perform formal verification of a human-interactive system. Despite the use of a seemingly simple target system, a patient controlled analgesia pump, the initial model proved to be difficult for the model checker to verify in a reasonable amount of time. This resulted in a number of model revisions that affected the HFE architectural, representativeness, and understandability goals of the effort. If formal methods are to meet the needs of the HFE community, additional modeling tools and technological developments are necessary.

  11. [Effect of high frequency electrotherapy on caspase-3 and ultra microstructure of hippocampus in rats following cerebral ischemia/reperfusion].

    Science.gov (United States)

    Fan, Yongmei; Wang, Rumi; Zhang, Changjie; Peng, Wenna; Yin, Jing; Hu, Zhiping

    2017-01-28

    To investigate the effect of high frequency electrotherapy (HFE) on rat hippocampus after cerebral ischemia/reperfusion (I/R).
 Methods: A rat model of cerebral I/R injury was established. The rats were randomly divided into a sham group, an I/R group and an HFE group. The HFE group received thearapy daily for different sessions for 1, 3, 7 d. Neuronal deficit score,neuron ultra microstructure in the hippocampus and caspase-3 protein expression were measured on 1 st, 3 th and 7th d.
 Results: Compared with the I/R group, the HFE group showed the decreased neurological deficit scores, with significant differences between the 2 groups (Pelectrotherapy can improve neural function, suppress caspase-3 expression and apoptosis in nerve cells and improve the ultra microstructure of neurons, displaying a protective effect on cerebral I/R injury in rats.

  12. Human factors/ergonomics implications of big data analytics: Chartered Institute of Ergonomics and Human Factors annual lecture.

    Science.gov (United States)

    Drury, Colin G

    2015-01-01

    In recent years, advances in sensor technology, connectedness and computational power have come together to produce huge data-sets. The treatment and analysis of these data-sets is known as big data analytics (BDA), and the somewhat related term data mining. Fields allied to human factors/ergonomics (HFE), e.g. statistics, have developed computational methods to derive meaningful, actionable conclusions from these data bases. This paper examines BDA, often characterised by volume, velocity and variety, giving examples of successful BDA use. This examination provides context by considering examples of using BDA on human data, using BDA in HFE studies, and studies of how people perform BDA. Significant issues for HFE are the reliance of BDA on correlation rather than hypotheses and theory, the ethics of BDA and the use of HFE in data visualisation.

  13. Influence of lead on repetitive behavior and dopamine metabolism in a mouse model of iron overload.

    Science.gov (United States)

    Chang, JuOae; Kueon, Chojin; Kim, Jonghan

    2014-12-01

    Exposures to lead (Pb) are associated with neurological problems including psychiatric disorders and impaired learning and memory. Pb can be absorbed by iron transporters, which are up-regulated in hereditary hemochromatosis, an iron overload disorder in which increased iron deposition in various parenchymal organs promote metal-induced oxidative damage. While dysfunction in HFE (High Fe) gene is the major cause of hemochromatosis, the transport and toxicity of Pb in Hfe-related hemochromatosis are largely unknown. To elucidate the relationship between HFE gene dysfunction and Pb absorption, H67D knock-in Hfe-mutant and wild-type mice were given drinking water containing Pb 1.6 mg/ml ad libitum for 6 weeks and examined for behavioral phenotypes using the nestlet-shredding and marble-burying tests. Latency to nestlet-shredding in Pb-treated wild-type mice was prolonged compared with non-exposed wild-types (p < 0.001), whereas Pb exposure did not alter shredding latency in Hfe-mutant mice. In the marble-burying test, Hfe-mutant mice showed an increased number of marbles buried compared with wild-type mice (p = 0.002), indicating more repetitive behavior upon Hfe mutation. Importantly, Pb-exposed wild-type mice buried more marbles than non-exposed wild-types, whereas the number of marbles buried by Hfe-mutant mice did not change whether or not exposed to Pb. These results suggest that Hfe mutation could normalize Pb-induced behavioral alteration. To explore the mechanism of repetitive behavior caused by Pb, western blot analysis was conducted for proteins involved in brain dopamine metabolism. The levels of tyrosine hydroxylase and dopamine transporter increased upon Pb exposure in both genotypes, whereas Hfe-mutant mice displayed down-regulation of the dopamine transporter and dopamine D1 receptor with D2 receptor elevated. Taken together, our data support the idea that both Pb exposure and Hfe mutation increase repetitive behavior in mice and further suggest that

  14. The Human Factors Engineering in Process Design Modifications CNAT; La Ingenieria de Factores Humanos en el Proceso de Modificaciones de diseno de CNAT

    Energy Technology Data Exchange (ETDEWEB)

    Foronda Delgado, A.; Almeida Parra, P.; Bote Moreno, J.

    2013-07-01

    This contribution presents the process followed at the Almaraz and Trillo Nuclear Power Plants in order to integrate Human Factors Engineering (HFE) in the Design Modifications. This includes the applicable rules and regulations, the classification criteria used to categorize the modification, the activities that are to be carried out in each case, as well as recent examples where the full HFE program model was applied at Almaraz (Alternate Shutdown Panel) and Trillo (Primary Bleed and Feed).

  15. Development of Human Factors Ontology for Business Knowledge Management

    OpenAIRE

    Monica Philippart; Waldemar Karwowski

    2011-01-01

    Employee knowledge and cognitive skills are key assets to achieving business success, yet are often mismanaged. By promoting the human-centered design approach, the discipline of human factors and ergonomics (HF/E) can significantly contribute to optimizing business processes through effective management of employee knowledge. However, a comprehensive methodology is needed to help organizations integrate the HF/E principles across various business processes. This paper introduces a novel meth...

  16. Water Supply and Treatment Equipment

    Science.gov (United States)

    2009-09-15

    CWK will be activated per the TM instructions and the proper warmup time will be allocated. The system will be operated per the TM. Any...8 4.5 Human Factors Engineering (HFE) ................................... 10 4.6 Operational Check Test...in paragraph 4.4, Safety, the noise survey in paragraph 4.5, Human Factors Engineering (HFE), and document any modifications that corrected

  17. Human factors and health information technology: current challenges and future directions.

    Science.gov (United States)

    Patel, V L; Kannampallil, T G

    2014-08-15

    Recent federal mandates and incentives have spurred the rapid growth, development and adoption of health information technology (HIT). While providing significant benefits for better data integration, organization, and availability, recent reports have raised questions regarding their potential to cause medication errors, decreased clinician performance, and lowered efficiency. The goal of this survey article is to (a) examine the theoretical and foundational models of human factors and ergonomics (HFE) that are being advocated for achieving patient safety and quality, and their use in the evaluation of healthcare systems; (b) and the potential for macroergonomic HFE approaches within the context of current research in biomedical informatics. We reviewed literature (2007-2013) on the use of HFE approaches in healthcare settings, from databases such as Pubmed, CINAHL, and Cochran. Based on the review, we discuss the systems-oriented models, their use in the evaluation of HIT, and examples of their use in the evaluation of EHR systems, clinical workflow processes, and medication errors. We also discuss the opportunities for better integrating HFE methods within biomedical informatics research and its potential advantages. The use of HFE methods is still in its infancy - better integration of HFE within the design lifecycle, and quality improvement efforts can further the ability of informatics researchers to address the key concerns regarding the complexity in clinical settings and develop HIT solutions that are designed within the social fabric of the considered setting.

  18. Drug-device combination products in the twenty-first century: epinephrine auto-injector development using human factors engineering.

    Science.gov (United States)

    Edwards, Eric S; Edwards, Evan T; Simons, F Estelle R; North, Robert

    2015-05-01

    The systematic application of human factors engineering (HFE) principles to the development of drug-device combination products, including epinephrine auto-injectors (EAIs), has the potential to improve the effectiveness and safety of drug administration. A PubMed search was performed to assess the role of HFE in the development of drug-device combination products. The following keywords were used in different combinations: 'human factors engineering,' 'human factors,' 'medical products,' 'epinephrine/adrenaline auto-injector,' 'healthcare' and 'patient safety.' This review provides a summary of HFE principles and their application to the development of drug-device combination products as advised by the US FDA. It also describes the HFE process that was applied to the development of Auvi-Q, a novel EAI, highlighting specific steps that occurred during the product-development program. For drug-device combination products, device labeling and usability are critical and have the potential to impact clinical outcomes. Application of HFE principles to the development of drug-delivery devices has the potential to improve product quality and reliability, reduce risk and improve patient safety when applied early in the development process. Additional clinical and real-world studies will confirm whether the application of HFE has helped to develop an EAI that better meets the needs of patients at risk of anaphylaxis.

  19. What do human factors and ergonomics professionals value in research publications? Re-examining the research-practice gap.

    Science.gov (United States)

    Chung, Amy Z Q; Williamson, Ann; Shorrock, Steven T

    2014-01-01

    The research-practice gap is of concern in human factors/ergonomics (HF/E) as there is a belief that HF/E research may not be making an impact on practice in the 'real world'. A potential issue is what researchers and practitioners perceive as important in HF/E journal articles as a primary means of conveying research findings to practitioners. This study examined the characteristics that make scientific journal articles appeal to HF/E researchers and practitioners using a web-based survey. HF/E researchers and practitioners were more similar than expected in judgements of important attributes and the selection of articles. Both practitioners and researchers considered practical significance to be more important than theoretical significance, in direct contrast to professionals from a related discipline--psychology. Well-written articles were appreciated across disciplines. The results signal a strong interest in practical applications in HF/E, but a relative lack of focus on development of theories that should be the basis for practical applications.

  20. The dichotomy of the application of a systems approach in UK healthcare the challenges and priorities for implementation.

    Science.gov (United States)

    Pickup, Laura; Lang, Alexandra; Atkinson, Sarah; Sharples, Sarah

    2018-01-01

    There is increasing demand for a systems approach within national healthcare guidelines to provide a systematic and sustainable framework for improvements in patient safety. Supported by this is the growing body of evidence within Human Factors/Ergonomics (HFE) healthcare literature for the inclusion of this approach in health service design, provision and evaluation. This paper considers the current interpretation of this within UK healthcare systems and the dichotomy which exists in the challenge to implement a systems approach. Three case studies, from primary and secondary care, present a systems approach, offering a novel perspective of primary care and blood sampling. These provide practical illustrations of how HFE methods have been used in collaboration with healthcare staff to understand the system for the purpose of professional education, design and safety of clinical activities. The paper concludes with the challenge for implementation and proposes five roles for systems HFE to support patient safety. Practitioner Summary: healthcare is classified as a complex and dynamic system within this paper and as such HFE system methods are presented as desirable to understand the system, to develop HFE tools, to deliver education and integrate HFE within healthcare systems.

  1. Updating Human Factors Engineering Guidelines for Conducting Safety Reviews of Nuclear Power Plants

    Energy Technology Data Exchange (ETDEWEB)

    O, J.M.; Higgins, J.; Stephen Fleger - NRC

    2011-09-19

    The U.S. Nuclear Regulatory Commission (NRC) reviews the human factors engineering (HFE) programs of applicants for nuclear power plant construction permits, operating licenses, standard design certifications, and combined operating licenses. The purpose of these safety reviews is to help ensure that personnel performance and reliability are appropriately supported. Detailed design review procedures and guidance for the evaluations is provided in three key documents: the Standard Review Plan (NUREG-0800), the HFE Program Review Model (NUREG-0711), and the Human-System Interface Design Review Guidelines (NUREG-0700). These documents were last revised in 2007, 2004 and 2002, respectively. The NRC is committed to the periodic update and improvement of the guidance to ensure that it remains a state-of-the-art design evaluation tool. To this end, the NRC is updating its guidance to stay current with recent research on human performance, advances in HFE methods and tools, and new technology being employed in plant and control room design. This paper describes the role of HFE guidelines in the safety review process and the content of the key HFE guidelines used. Then we will present the methodology used to develop HFE guidance and update these documents, and describe the current status of the update program.

  2. Hemochromatosis enhances tumor progression via upregulation of intracellular iron in head and neck cancer.

    Directory of Open Access Journals (Sweden)

    Michelle Lenarduzzi

    Full Text Available Despite improvements in treatment strategies for head and neck squamous cell carcinoma (HNSCC, outcomes have not significantly improved; highlighting the importance of identifying novel therapeutic approaches to target this disease. To address this challenge, we proceeded to evaluate the role of iron in HNSCC.Expression levels of iron-related genes were evaluated in HNSCC cell lines using quantitative RT-PCR. Cellular phenotypic effects were assessed using viability (MTS, clonogenic survival, BrdU, and tumor formation assays. The prognostic significance of iron-related proteins was determined using immunohistochemistry.In a panel of HNSCC cell lines, hemochromatosis (HFE was one of the most overexpressed genes involved in iron regulation. In vitro knockdown of HFE in HNSCC cell lines significantly decreased hepcidin (HAMP expression and intracellular iron level. This in turn, resulted in a significant decrease in HNSCC cell viability, clonogenicity, DNA synthesis, and Wnt signalling. These cellular changes were reversed by re-introducing iron back into HNSCC cells after HFE knockdown, indicating that iron was mediating this phenotype. Concordantly, treating HNSCC cells with an iron chelator, ciclopirox olamine (CPX, significantly reduced viability and clonogenic survival. Finally, patients with high HFE expression experienced a reduced survival compared to patients with low HFE expression.Our data identify HFE as potentially novel prognostic marker in HNSCC that promotes tumour progression via HAMP and elevated intracellular iron levels, leading to increased cellular proliferation and tumour formation. Hence, these findings suggest that iron chelators might have a therapeutic role in HNSCC management.

  3. Superoxide Dismutase 3 Polymorphism Associated with Reduced Lung Function in Two Large Populations

    DEFF Research Database (Denmark)

    Dahl, Morten; Bowler, Russell P; Juul, Klaus

    2008-01-01

    . Measurements and Main Results: Genotyping the Copenhagen City Heart Study identified 35 E1/I1 homozygotes, 1,050 heterozygotes, and 8,008 noncarriers (Hardy-Weinberg equilibrium: P = 0.93). Using quadruple lung function measurements, we found that E1/I1 homozygotes had 7% lower FVC % predicted (P = 0...

  4. Polymorphism in exon 1 of adiponectin gene and its association with ...

    African Journals Online (AJOL)

    Association analysis indicated that all of these traits had significant population effects except meat colour (P < 0.05) and then the birds with homozygote (CC) had significant lower than homozygotes (DD) for IMF, water holding capacity and abdominal fat (P < 0.05). The research suggested that genotype DD may be an ...

  5. An Integrated Suite of Tools to support Human Factors Engineering

    Energy Technology Data Exchange (ETDEWEB)

    Jacques V Hugo

    2001-08-01

    Human Factors Engineering (HFE) work for the nuclear industry imposes special demands on the practitioner in terms of the scope, complexity and safety requirements for humans in nuclear installations. Unfortunately HFE lags behind other engineering disciplines in the development and use of modern, powerful tools for the full range of analysis and design processes. HFE does not appear to be an attractive market for software and hardware developers and as a result, HFE practitioners usually have to rely on inefficient general-purpose tools like standard office software, or they have to use expensive special-purpose tools that offer only part of the solution they require and which also do not easily integrate with other tools. There have been attempts to develop generic software tools to support the HFE analyst and also to achieve some order and consistency in format and presentation. However, in spite of many years of development, very few tools have emerged that have achieved these goals. This would suggest the need for special tools, but existing commercial products have been found inadequate and to date not a single tool has been developed that adequately supports the special requirements of HFE work for the nuclear industry. This paper describes an integrated suite of generic as well as purpose-built tools that facilitate information solicitation, issues tracking, work domain analysis, functional requirements analysis, function allocation, operational sequence analysis, task analysis and development of HSI design requirements. In combination, this suite of tools supports the analytical as well as the representational aspects of key HFE activities primarily for new NPPs, including capturing information from subject matter experts and various source documents directly into the appropriate tool and then linking, analyzing and extending that information further to represent detailed functional and task information, and ultimately HSI design requirements. The paper

  6. Cleaning and materials compatibility test results for elimination of flammable solvents in wipe applications.

    Energy Technology Data Exchange (ETDEWEB)

    Lopez, Edwin Paul

    2005-06-01

    In recent years, efforts have been made within the nuclear weapons complex (National Nuclear Security Administration) of the Department of Energy (DOE) to replace Resource Conservation and Recovery Act (RCRA) regulated solvents (i.e., flammable, toxic, corrosive, and reactive) and ozone-depleting chemicals (ODC) with more benign alternatives. Within the National Nuclear Security Administration (NNSA) and the Department of Defense (DoD) sectors, these solvents are used for cleaning hardware during routine maintenance operations. A primary goal of this study is to replace flammable solvents used in wiping applications. Two cleaners, including a hydrofluoroether (HFE) and an azeotrope of the HFE and isopropyl alcohol (IPA), have been studied as potential replacements for flammable solvents. Cleaning efficacy, short-term and long-term materials compatibility, corrosion, drying times, flammability, environment, safety and health (ES&H) and accelerated aging issues were among the experiments used to screen candidate solvents by the interagency team performing this work. This report presents cleaning efficacy results as determined by the contact angle Goniometer as well as materials compatibility results of various metal alloys and polymers. The results indicate that IPA (baseline cleaner) and the HFE/IPA azeotrope are roughly equivalent in their ability to remove fluorinated grease, silicone grease, and a simulated finger print contaminant from various metal alloys. All of the ASTM sandwich and immersion corrosion tests with IPA, HFE or the HFE/IPA azeotrope on metal alloys showed no signs of corrosion. Furthermore, no deleterious effects were noted for polymeric materials immersed in IPA, HFE, or the HFE/IPA azeotrope.

  7. SIMULATED HUMAN ERROR PROBABILITY AND ITS APPLICATION TO DYNAMIC HUMAN FAILURE EVENTS

    Energy Technology Data Exchange (ETDEWEB)

    Herberger, Sarah M.; Boring, Ronald L.

    2016-10-01

    Abstract Objectives: Human reliability analysis (HRA) methods typically analyze human failure events (HFEs) at the overall task level. For dynamic HRA, it is important to model human activities at the subtask level. There exists a disconnect between dynamic subtask level and static task level that presents issues when modeling dynamic scenarios. For example, the SPAR-H method is typically used to calculate the human error probability (HEP) at the task level. As demonstrated in this paper, quantification in SPAR-H does not translate to the subtask level. Methods: Two different discrete distributions were generated for each SPAR-H Performance Shaping Factor (PSF) to define the frequency of PSF levels. The first distribution was a uniform, or uninformed distribution that assumed the frequency of each PSF level was equally likely. The second non-continuous distribution took the frequency of PSF level as identified from an assessment of the HERA database. These two different approaches were created to identify the resulting distribution of the HEP. The resulting HEP that appears closer to the known distribution, a log-normal centered on 1E-3, is the more desirable. Each approach then has median, average and maximum HFE calculations applied. To calculate these three values, three events, A, B and C are generated from the PSF level frequencies comprised of subtasks. The median HFE selects the median PSF level from each PSF and calculates HEP. The average HFE takes the mean PSF level, and the maximum takes the maximum PSF level. The same data set of subtask HEPs yields starkly different HEPs when aggregated to the HFE level in SPAR-H. Results: Assuming that each PSF level in each HFE is equally likely creates an unrealistic distribution of the HEP that is centered at 1. Next the observed frequency of PSF levels was applied with the resulting HEP behaving log-normally with a majority of the values under 2.5% HEP. The median, average and maximum HFE calculations did yield

  8. Racial and ethnic differences in the home food environment explain disparities in dietary practices of middle school children in Texas.

    Science.gov (United States)

    Ranjit, Nalini; Evans, Alexandra E; Springer, Andrew E; Hoelscher, Deanna M; Kelder, Steve H

    2015-01-01

    To examine racial and ethnic differences among middle school children in the home food environment (HFE) and the extent to which associations of healthy and unhealthy eating with the HFE differ by race and ethnicity. Cross-sectional secondary analyses of baseline data from Coordinated Approach to Child Health Middle School, a school-based intervention targeting obesity and obesogenic behaviors among middle school children in Austin, TX. A total of 2,502 children (mean age, 13.9 years; 58% Hispanic, 28% white, and 14% black). Availability and accessibility of healthy foods, and parental support of healthy eating, and family meals. Consumption of both healthy and unhealthy foods was examined. Differences across racial and ethnic groups in aspects of HFE were estimated using linear regression. Models also examined racial and ethnic differences in consumption of healthy and unhealthy foods. If adjusting for HFE, such differences were accounted for. White children had significantly better HFEs than Hispanic and black children with greater availability and accessibility of healthy foods (P foods but not in consumption of unhealthy foods. Improved HFE may increase healthy eating among ethnic minorities but is unlikely to reduce unhealthy eating. Copyright © 2015 Society for Nutrition Education and Behavior. Published by Elsevier Inc. All rights reserved.

  9. Association of Transition Readiness to Intentional Self-Regulation and Hopeful Future Expectations in Youth With Illness.

    Science.gov (United States)

    Hart, Laura C; Pollock, McLean; Hill, Sherika; Maslow, Gary

    Little is known about how transition readiness relates to other developmental skills of adolescence in youth with chronic illness. Better understanding of how transition readiness relates to these other developmental skills could lead to a broader array of tools to improve transition readiness. Intentional self-regulation (ISR) and hopeful future expectations (HFE) are 2 developmental skills of adolescence that improve with participation in developmental programming and thus are modifiable. We explored associations between transition readiness, as measured by the Transition Readiness Assessment Questionnaire 29 (TRAQ-29) and ISR and HFE in youth with chronic illness recruited from a variety of subspecialty clinics from a major southeast medical center. A total of 71 adolescents with chronic illness were included in the analysis. The TRAQ-29 Self-Advocacy domain showed positive associations to both ISR (P = .03) and HFE (P = .009). In addition, the TRAQ-29 overall had positive associations to HFE (P = .04). The significant associations between TRAQ-29 Self-Advocacy domain scores and ISR and HFE suggest that transition readiness is developing within the context of other developmental areas in adolescence. More work is needed to see if the programming that improves these other developmental skills might also improve transition readiness. Copyright © 2016 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.

  10. A human factors engineering evaluation of the Multi-Function Waste Tank Facility. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Donohoo, D.T. [Pacific Northwest Lab., Richland, WA (United States); Sarver, T.L. [ARES Corp., San Francisco, CA (United States)

    1995-06-05

    This report documents the methods and results of a human factors engineering (HFE) review conducted on the Multi-Function Waste Tank Facility (MWTF), Westinghouse Hanford Company (WHC) Project 236A, to be constructed at the U.S. Department of Energy (DOE) facility at Hanford, Washington. This HFE analysis of the MWTF was initiated by WHC to assess how well the current facility and equipment design satisfies the needs of its operations and maintenance staff and other potential occupants, and to identify areas of the design that could benefit from improving the human interfaces at the facility. Safe and effective operations, including maintenance, is a primary goal for the MWTF. Realization of this goal requires that the MWTF facility, equipment, and operations be designed in a manner that is consistent with the abilities and limitations of its operating personnel. As a consequence, HFE principles should be applied to the MWTF design, construction, its operating procedures, and its training. The HFE review was focused on the 200-West Area facility as the design is further along than that of the 200-East Area. The review captured, to the greatest extent feasible at this stage of design, all aspects of the facility activities and included the major topics generally associated with HFE (e.g., communication, working environment). Lessons learned from the review of the 200 West facility will be extrapolated to the 200-East Area, as well as generalized to the Hanford Site.

  11. Building Secure Public Key Encryption Scheme from Hidden Field Equations

    Directory of Open Access Journals (Sweden)

    Yuan Ping

    2017-01-01

    Full Text Available Multivariate public key cryptography is a set of cryptographic schemes built from the NP-hardness of solving quadratic equations over finite fields, amongst which the hidden field equations (HFE family of schemes remain the most famous. However, the original HFE scheme was insecure, and the follow-up modifications were shown to be still vulnerable to attacks. In this paper, we propose a new variant of the HFE scheme by considering the special equation x2=x defined over the finite field F3 when x=0,1. We observe that the equation can be used to further destroy the special structure of the underlying central map of the HFE scheme. It is shown that the proposed public key encryption scheme is secure against known attacks including the MinRank attack, the algebraic attacks, and the linearization equations attacks. The proposal gains some advantages over the original HFE scheme with respect to the encryption speed and public key size.

  12. The perceptual significance of high-frequency energy in the human voice

    Directory of Open Access Journals (Sweden)

    Brian B. Monson

    2014-06-01

    Full Text Available While human vocalizations generate acoustical energy at frequencies up to (and beyond 20 kHz, the energy at frequencies above about 5 kHz has traditionally been neglected in speech perception research. The intent of this paper is to review (1 the historical reasons for this research trend and (2 the work that continues to elucidate the perceptual significance of high-frequency energy (HFE in speech and singing. The historical and physical factors reveal that, while HFE was believed to be unnecessary and/or impractical for applications of interest, it was never shown to be perceptually insignificant. Rather, the main causes for focus on low-frequency energy appear to be because the low-frequency portion of the speech spectrum was seen to be sufficient (from a perceptual standpoint, or the difficulty of HFE research was too great to be justifiable (from a technological standpoint. The advancement of technology continues to overcome concerns stemming from the latter reason. Likewise, advances in our understanding of the perceptual effects of HFE now cast doubt on the first cause. Emerging evidence indicates that HFE plays a more significant role than previously believed, and should thus be considered in speech and voice perception research, especially in research involving children and the hearing impaired.

  13. The perceptual significance of high-frequency energy in the human voice

    Science.gov (United States)

    Monson, Brian B.; Hunter, Eric J.; Lotto, Andrew J.; Story, Brad H.

    2014-01-01

    While human vocalizations generate acoustical energy at frequencies up to (and beyond) 20 kHz, the energy at frequencies above about 5 kHz has traditionally been neglected in speech perception research. The intent of this paper is to review (1) the historical reasons for this research trend and (2) the work that continues to elucidate the perceptual significance of high-frequency energy (HFE) in speech and singing. The historical and physical factors reveal that, while HFE was believed to be unnecessary and/or impractical for applications of interest, it was never shown to be perceptually insignificant. Rather, the main causes for focus on low-frequency energy appear to be because the low-frequency portion of the speech spectrum was seen to be sufficient (from a perceptual standpoint), or the difficulty of HFE research was too great to be justifiable (from a technological standpoint). The advancement of technology continues to overcome concerns stemming from the latter reason. Likewise, advances in our understanding of the perceptual effects of HFE now cast doubt on the first cause. Emerging evidence indicates that HFE plays a more significant role than previously believed, and should thus be considered in speech and voice perception research, especially in research involving children and the hearing impaired. PMID:24982643

  14. Erythrocyte reference values in Emirati people with and without α+ thalassemia.

    Science.gov (United States)

    Denic, Srdjan; Souid, Abdul-Kader; Nagelkerke, Nicolaas; Showqi, Saad; Balhaj, Ghazala

    2011-02-24

    Interpreting the erythroid lineage in populations with high frequency of α+ thalassemia allele is challenging due to the high prevalence of α+ thalassemia homozygotes. For such populations, separate reference values for normal and α+ thalassemia homozygotes are needed. We studied the erythroid lineage in 1,079 citizens of United Arab Emirates (UAE). Subjects with abnormal hemoglobin (39), iron deficiency (136) or erroneous entries (8) were excluded. MCV distribution in the remaining individuals (896) was visibly bimodal. Statistical mixture analysis with Normix program was used to separate subpopulations with normal and small red cells. Hardy-Weinberg equation was used to estimate genotype frequencies. MCV of 78.0 fl separated phenotype-derived normal homozygotes (715) from phenotype-derived α+ thalassemia homozygotes (181). The erythrocyte indices were significantly different between the two groups (p < 0.0001). The overall prevalence of phenotype-derived α+ thalassemia homozygotes (-α/-α) was 0.20 and markedly varied among tribes, 0 to 0.31 (Mean = 0.15). The frequency of phenotype-derived α+ thalassemia allele was 0.44; when accounting for tribal population structure and inbreeding, the calculated frequency was 0.34. These values were very similar to those found in the same population by genotyping and other phenotyping methods. The erythrocyte reference values for phenotype-derived normal homozygotes in Emiratis closely overlapped with those for Caucasians and normal homozygotes defined by genotyping. The reference values for phenotype-derived α+ thalassemia homozygotes in Emiratis also closely overlapped with those for α+ thalassemia homozygotes defined by genotyping. In populations with frequent α+ thalassemia mutations, two sets of erythrocyte reference values could be determined without genotyping.

  15. Erythrocyte reference values in Emirati people with and without α+ thalassemia

    Directory of Open Access Journals (Sweden)

    Showqi Saad

    2011-02-01

    Full Text Available Abstract Background Interpreting the erythroid lineage in populations with high frequency of α+ thalassemia allele is challenging due to the high prevalence of α+ thalassemia homozygotes. For such populations, separate reference values for normal and α+ thalassemia homozygotes are needed. Methods We studied the erythroid lineage in 1,079 citizens of United Arab Emirates (UAE. Subjects with abnormal hemoglobin (39, iron deficiency (136 or erroneous entries (8 were excluded. MCV distribution in the remaining individuals (896 was visibly bimodal. Statistical mixture analysis with Normix program was used to separate subpopulations with normal and small red cells. Hardy-Weinberg equation was used to estimate genotype frequencies. Results MCV of 78.0 fl separated phenotype-derived normal homozygotes (715 from phenotype-derived α+ thalassemia homozygotes (181. The erythrocyte indices were significantly different between the two groups (p + thalassemia homozygotes (-α/-α was 0.20 and markedly varied among tribes, 0 to 0.31 (Mean = 0.15. The frequency of phenotype-derived α+ thalassemia allele was 0.44; when accounting for tribal population structure and inbreeding, the calculated frequency was 0.34. These values were very similar to those found in the same population by genotyping and other phenotyping methods. The erythrocyte reference values for phenotype-derived normal homozygotes in Emiratis closely overlapped with those for Caucasians and normal homozygotes defined by genotyping. The reference values for phenotype-derived α+ thalassemia homozygotes in Emiratis also closely overlapped with those for α+ thalassemia homozygotes defined by genotyping. Conclusion In populations with frequent α+ thalassemia mutations, two sets of erythrocyte reference values could be determined without genotyping.

  16. Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice.

    Science.gov (United States)

    Ramos, Emilio; Kautz, Léon; Rodriguez, Richard; Hansen, Michael; Gabayan, Victoria; Ginzburg, Yelena; Roth, Marie-Paule; Nemeth, Elizabeta; Ganz, Tomas

    2011-04-01

    In response to iron loading, hepcidin synthesis is homeostatically increased to limit further absorption of dietary iron and its release from stores. Mutations in HFE, transferrin receptor 2 (Tfr2), hemojuvelin (HJV), or bone morphogenetic protein 6 (BMP6) prevent appropriate hepcidin response to iron, allowing increased absorption of dietary iron, and eventually iron overload. To understand the role each of these proteins plays in hepcidin regulation by iron, we analyzed hepcidin messenger RNA (mRNA) responsiveness to short and long-term iron challenge in iron-depleted Hfe, Tfr2, Hjv, and Bmp6 mutant mice. After 1-day (acute) iron challenge, Hfe(-/-) mice showed a smaller hepcidin increase than their wild-type strain-matched controls, Bmp6(-/-) mice showed nearly no increase, and Tfr2 and Hjv mutant mice showed no increase in hepcidin expression, indicating that all four proteins participate in hepcidin regulation by acute iron changes. After a 21-day (chronic) iron challenge, Hfe and Tfr2 mutant mice increased hepcidin expression to nearly wild-type levels, but a blunted increase of hepcidin was seen in Bmp6(-/-) and Hjv(-/-) mice. BMP6, whose expression is also regulated by iron, may mediate hepcidin regulation by iron stores. None of the mutant strains (except Bmp6(-/-) mice) had impaired BMP6 mRNA response to chronic iron loading. TfR2, HJV, BMP6, and, to a lesser extent, HFE are required for the hepcidin response to acute iron loading, but are partially redundant for hepcidin regulation during chronic iron loading and are not involved in the regulation of BMP6 expression. Our findings support a model in which acute increases in holotransferrin concentrations transmitted through HFE, TfR2, and HJV augment BMP receptor sensitivity to BMPs. A distinct regulatory mechanism that senses hepatic iron may modulate hepcidin response to chronic iron loading. 2011 American Association for the Study of Liver Diseases.

  17. Stoichiometries of transferrin receptors 1 and 2 in human liver.

    Science.gov (United States)

    Chloupková, Maja; Zhang, An-Sheng; Enns, Caroline A

    2010-01-15

    Mutations in either the hereditary hemochromatosis protein, HFE, or transferrin receptor 2, TfR2, result in a similarly severe form of the most common type of iron overload disease called hereditary hemochromatosis. Models of the interactions between HFE, TfR1, and TfR2 imply that these proteins are present in different molar concentrations in the liver, where they control expression of the iron regulatory hormone, hepcidin, in response to body iron loading. The aim of this study was to determine in vivo levels of mRNA by quantitative RT-PCR and concentrations of these proteins by quantitative immunoblotting in human liver tissues. The level of TfR2 mRNA was 21- and 63-fold higher than that of TfR1 and HFE, respectively. Molar concentration of TfR2 protein was the highest and determined to be 1.95 nmol/g protein in whole cell lysates and 10.89 nmol/g protein in microsomal membranes. Molar concentration of TfR1 protein was 4.5- and 6.1-fold lower than that of TfR2 in whole cell lysates and membranes, respectively. The level of HFE protein was below 0.53 nmol/g of total protein. HFE is thus present in substoichiometric concentrations with respect to both TfR1 and TfR2 in human liver tissue. This finding supports a model, in which availability of HFE is limiting for formation of complexes with TfR1 or TfR2. Copyright 2009 Elsevier Inc. All rights reserved.

  18. Using strong nonlinearity and high-frequency vibrations to control effective mechanical stiffness

    DEFF Research Database (Denmark)

    Thomsen, Jon Juel

    2008-01-01

    High-frequency excitation (HFE) can be used to change the effective stiffness of an elastic structure, and related quanti-ties such as resonance frequencies, wave speed, buckling loads, and equilibrium states. There are basically two ways to do this: By using parametrical HFE (with or without non...... the method of direct separation of motions with results of a modified multiple scales ap-proach, valid also for strong nonlinearity, the stiffening ef-fect is predicted for a generic 1-dof system, and results are tested against numerical simulation and ((it is planned)) laboratory experiments....

  19. Circulating Gastrin is Increased in Hemochromatosis.

    Science.gov (United States)

    Smith, Kelly A.; Kovac, Suzana; Anderson, Gregory J.; Shulkes, Arthur; Baldwin, Graham S.

    2006-01-01

    Gastric acid production is important in intestinal iron absorption. The peptide hormone gastrin exists in both amidated and non-amidated forms, which stimulate and potentiate gastric acid secretion, respectively. Since non-amidated gastrins require ferric ions for biological activity in vitro, this study investigated the connection between iron status and gastrin by measurement of circulating gastrin concentrations in mice and humans with hemochromatosis. Gastrin concentrations are increased in the plasma and gastric mucosa of Hfe-/- mice, and in the sera of humans with HFE-related hemochromatosis. The discovery of a relationship between iron status and circulating gastrin concentrations opens a new perspective on the mechanisms of iron homeostasis. PMID:17064691

  20. MIDAS-FAST: Design and Validation of a Model-Based Tool to Predict Operator Performance with Robotic Arm Automation

    Science.gov (United States)

    Sebok, Angelia (Principal Investigator); Wickens, Christopher; Gacy, Marc; Brehon, Mark; Scott-Nash, Shelly; Sarter, Nadine; Li, Huiyang; Gore, Brian; Hooey, Becky

    2017-01-01

    The Coalition for Aerospace and Science (CAS) is hosting an exhibition on Capitol Hill on June 14, 2017, to highlight the contributions of CAS members to NASAs portfolio of activities. This exhibition represents an opportunity for an HFES members ground breaking work to be displayed and to build on support within Congress for NASAs human research program including in those areas that are of specific interest to the HFE community. The intent of this poster presentation is to demonstrate the positive outcome that comes from funding HFE related research on a project like the one exemplified by MIDAS-FAST.

  1. Stoichiometries of Transferrin Receptors 1 and 2 in Human Liver

    OpenAIRE

    Chloupková, Maja; Zhang, An-Sheng; Enns, Caroline A.

    2009-01-01

    Mutations in either the hereditary hemochromatosis protein, HFE, or transferrin receptor 2, TfR2, result in a similarly severe form of the most common type of iron overload disease called hereditary hemochromatosis. Models of the interactions between HFE, TfR1, and TfR2 imply that these proteins are present in different molar concentrations in the liver, where they control expression of the iron regulatory hormone, hepcidin, in response to body iron loading. The aim of this study was to deter...

  2. Development of an electronic Human Factor Management Program (e HFMP)

    Energy Technology Data Exchange (ETDEWEB)

    Sung, Chan Ho; Kim, Young Gab; Jung, Yeon Sub [KHNP Central Research Institute, Daejeon (Korea, Republic of)

    2012-10-15

    Human error is one of main contributors of reactor trip in nuclear power plants. Therefore, HFE application is essential in every field of nuclear power plants such as operating, maintenance, and plant design. However, HFE is an unfamiliar term and field for plant staffs. Lots of activities has been carried out to reduce human error and to enhance human performance. During these efforts, it is frequently asked where human factor guidelines are, and how the guidelines are applied to their usual activities. This paper explains e HFMP for this purpose.

  3. Neolithic and Bronze Age migration to Ireland and establishment of the insular Atlantic genome.

    Science.gov (United States)

    Cassidy, Lara M; Martiniano, Rui; Murphy, Eileen M; Teasdale, Matthew D; Mallory, James; Hartwell, Barrie; Bradley, Daniel G

    2016-01-12

    The Neolithic and Bronze Age transitions were profound cultural shifts catalyzed in parts of Europe by migrations, first of early farmers from the Near East and then Bronze Age herders from the Pontic Steppe. However, a decades-long, unresolved controversy is whether population change or cultural adoption occurred at the Atlantic edge, within the British Isles. We address this issue by using the first whole genome data from prehistoric Irish individuals. A Neolithic woman (3343-3020 cal BC) from a megalithic burial (10.3× coverage) possessed a genome of predominantly Near Eastern origin. She had some hunter-gatherer ancestry but belonged to a population of large effective size, suggesting a substantial influx of early farmers to the island. Three Bronze Age individuals from Rathlin Island (2026-1534 cal BC), including one high coverage (10.5×) genome, showed substantial Steppe genetic heritage indicating that the European population upheavals of the third millennium manifested all of the way from southern Siberia to the western ocean. This turnover invites the possibility of accompanying introduction of Indo-European, perhaps early Celtic, language. Irish Bronze Age haplotypic similarity is strongest within modern Irish, Scottish, and Welsh populations, and several important genetic variants that today show maximal or very high frequencies in Ireland appear at this horizon. These include those coding for lactase persistence, blue eye color, Y chromosome R1b haplotypes, and the hemochromatosis C282Y allele; to our knowledge, the first detection of a known Mendelian disease variant in prehistory. These findings together suggest the establishment of central attributes of the Irish genome 4,000 y ago.

  4. Excised radicle tips as a source of genomic DNA for PCR-based ...

    Indian Academy of Sciences (India)

    -tip-excised seedlings retain viability because of the formation of adventitious roots. We demonstrate the utility of this method in distinguishing homozygotes from heterozygotes in a cotton breeding population and in hybrid seed purity testing.

  5. Dietary Iron Intake and Serum Ferritin Concentration in 213 Patients Homozygous for the HFEC282Y Hemochromatosis Mutation

    Directory of Open Access Journals (Sweden)

    Victor R Gordeuk

    2012-01-01

    Full Text Available BACKGROUND: HFEC282Y homozygotes have an increased risk for developing increased iron stores and related disorders. It is controversial whether dietary iron restrictions should be recommended to such individuals.

  6. Variation de la calcémie et de la magnésémie chez les ...

    African Journals Online (AJOL)

    Objectif: Déterminer la variation de la calcémie et de la magnésémie chez les drépanocytaires majeurs homozygotes SS. Méthodologie: Il s'agit d'une étude cas - témoin sur une population de 140 sujets répartis en 2 groupes. Un premier groupe de 70 drépanocytaires homozygotes SS constitué d'hommes et de femmes, ...

  7. The Frequent 5,10-Methylenetetrahydrofolate Reductase C677T Polymorphism Is Associated with a Common Haplotype in Whites, Japanese, and Africans

    OpenAIRE

    Rosenberg, Nurit; Murata, Mitsuru; Ikeda, Yasuo; Opare-Sem, Ohene; Zivelin, Ariella; Geffen, Eli; Seligsohn, Uri

    2002-01-01

    The common 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism causes decreased activity of this enzyme and can be associated with mild-to-moderate hyperhomocysteinemia in homozygotes, particularly when there is folic acid deficiency, as well as with vascular dementia, arterial thrombosis, venous thrombosis, neural-tube defects, and fetal loss. When folic acid intake is sufficient, homozygotes for MTHFR 677T appear to be protected against colon cancer and acute lymphatic leuke...

  8. Human Factors Engineering and Ergonomics Analysis for the Canister Storage Building (CSB) Results and Findings

    Energy Technology Data Exchange (ETDEWEB)

    GARVIN, L.J.

    1999-09-20

    The purpose for this supplemental report is to follow-up and update the information in SNF-3907, Human Factors Engineering (HFE) Analysis: Results and Findings. This supplemental report responds to applicable U.S. Department of Energy Safety Analysis Report review team comments and questions. This Human Factors Engineering and Ergonomics (HFE/Erg) analysis was conducted from April 1999 to July 1999; SNF-3907 was based on analyses accomplished in October 1998. The HFE/Erg findings presented in this report and SNF-3907, along with the results of HNF-3553, Spent Nuclear Fuel Project, Final Safety Analysis Report, Annex A, ''Canister Storage Building Final Safety Analysis Report,'' Chapter A3.0, ''Hazards and Accidents Analyses,'' provide the technical basis for preparing or updating HNF-3553. Annex A, Chaptex A13.0, ''Human Factors Engineering.'' The findings presented in this report allow the HNF-3553 Chapter 13.0, ''Human Factors,'' to respond fully to the HFE requirements established in DOE Order 5480.23, Nuclear Safety Analysis Reports.

  9. Restoration of the Apollo 15 Heat Flow Experiment Data from 1975 to 1977

    Science.gov (United States)

    Nagihara, S.; Nakamura, Y.; Taylor, P. T.; Williams, D. R.; Kiefer, W. S.

    2017-01-01

    The Apollo 15 Heat Flow Experiment (HFE) was conducted from July 1971 through January 1977. Two heat flow probes were deployed roughly 8.5 meters apart. Probe 1 and Probe 2 penetrated to 1.4-meters and 1-meter depths into the lunar regolith, respectively. Temperatures at different depths and the surface were logged with 7.25-minute intervals and transmitted to Earth. At the conclusion of the experiment, only data obtained from July 1971 through December 1974 were processed and archived at the National Space Science Data Center (NSSDC) by the principal investigator of the experiment, Marcus Langseth of Columbia University. Langseth died in 1997. It is not known what happened to the HFE data tapes he used. Current researchers have strong interests in re-examining the HFE data for the full duration of the experiment. We have recovered and processed large portions of the Apollo 15 HFE data from 1975 through 1977 by assembling data and metadata from various sources.

  10. Structural basis of urea-induced unfolding: Unraveling the folding pathway of hemochromatosis factor E.

    Science.gov (United States)

    Khan, Parvez; Prakash, Amresh; Haque, Md Anzarul; Islam, Asimul; Hassan, Md Imtaiyaz; Ahmad, Faizan

    2016-10-01

    Hereditary hemochromatosis factor E (HFE) is a type 1 transmembrane protein, and acts as a negative regulator of iron-uptake. The equilibrium unfolding and conformational stability of the HFE protein was examined in the presence of urea. The folding and unfolding transitions were monitored with the help of circular dichroism (CD), intrinsic fluorescence and absorption spectroscopy. Analysis of transition curves revealed that the folding of HFE is not a two-state process. However, it involved stable intermediates. Transition curves (plot of fluorescence (F346) and CD signal at 222nm (θ222) versus [Urea], the molar urea concentration) revealed a biphasic transition with midpoint (Cm) values at 2.88M and 4.95M urea. Whereas, absorption analysis shows one two-state transition centered at 2.96M. To estimate the protein stability, denaturation curves were analyzed for Gibbs free energy change in the absence of urea (ΔGD(0)) associated with the equilibrium of denaturation exist between native state↔denatured state. The intermediate state was further characterized by hydrophobic probe, 1-anilinonaphthalene-8-sulfonic acid (ANS-binding). For seeing the effect of urea on the structure and dynamics of HFE, molecular dynamics simulation for 60ns was also performed. A clear correspondence was established between the in vitro and in silico studies. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Human factors engineering report for the cold vacuum drying facility

    Energy Technology Data Exchange (ETDEWEB)

    IMKER, F.W.

    1999-06-30

    The purpose of this report is to present the results and findings of the final Human Factors Engineering (HFE) technical analysis and evaluation of the Cold Vacuum Drying Facility (CVDF). Ergonomics issues are also addressed in this report, as appropriate. This report follows up and completes the preliminary work accomplished and reported by the Preliminary HFE Analysis report (SNF-2825, Spent Nuclear Fuel Project Cold Vacuum Drying Facility Human Factors Engineering Analysis: Results and Findings). This analysis avoids redundancy of effort except for ensuring that previously recommended HFE design changes have not affected other parts of the system. Changes in one part of the system may affect other parts of the system where those changes were not applied. The final HFE analysis and evaluation of the CVDF human-machine interactions (HMI) was expanded to include: the physical work environment, human-computer interface (HCI) including workstation and software, operator tasks, tools, maintainability, communications, staffing, training, and the overall ability of humans to accomplish their responsibilities, as appropriate. Key focal areas for this report are the process bay operations, process water conditioning (PWC) skid, tank room, and Central Control Room operations. These key areas contain the system safety-class components and are the foundation for the human factors design basis of the CVDF.

  12. Effective properties of mechanical systems under high-frequency excitation at multiple frequencies

    DEFF Research Database (Denmark)

    Thomsen, Jon Juel

    2008-01-01

    Effects of strong high-frequency excitation at multiple frequencies (multi-HFE) are analyzed for a class of generally nonlinear systems. The effects are illustrated for a simple pendulum system with a vibrating support, and for a parametrically excited flexible beam. For the latter, theoretical...

  13. Computing effective properties of nonlinear structures exposed to strong high-frequency loading at multiple frequencies

    DEFF Research Database (Denmark)

    Thomsen, Jon Juel

    2006-01-01

    Effects of strong high-frequency excitation at multiple frequencies (multi-HFE) are analyzed for a class of generally nonlinear systems. The effects are illustrated for a simple pendulum system with a vibrating support, and for a parametrically excited flexible beam. For the latter, theoretical...

  14. Author Details

    African Journals Online (AJOL)

    Wilson, MM. Vol 16, No 2 (2015) - Articles Study of the effect of HFE gene mutations on iron overload in Egyptian thalassemia patients. Abstract PDF. ISSN: 1110-8630. AJOL African Journals Online. HOW TO USE AJOL... for Researchers · for Librarians · for Authors · FAQ's · More about AJOL · AJOL's Partners · Terms and ...

  15. Egyptian Journal of Medical Human Genetics - Vol 16, No 2 (2015)

    African Journals Online (AJOL)

    Study of the effect of HFE gene mutations on iron overload in Egyptian thalassemia patients · EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT. MM Wilson, H Al-Wakeel, F Said, M El-Ghamrawy, M Assaad, A El-Beshlawy, 129-133.

  16. Recent advance in the molecular genetics of Wilson disease and hereditary hemochromatosis.

    Science.gov (United States)

    Lv, Tingxia; Li, Xiaojin; Zhang, Wei; Zhao, Xinyan; Ou, Xiaojuan; Huang, Jian

    2016-10-01

    Metabolic liver diseases such as Wilson disease (WD) and hereditary hemochromatosis (HH) possess complicated pathogenesis and typical hereditary characteristics with the hallmarks of a deficiency in metal metabolism. Mutations in genes encoding ATPase, Cu + transporting, beta polypeptide (ATP7B) and hemochromatosis (HFE) or several non-HFE genes are considered to be causative for WD and HH, respectively. Although the identification of novel mutations in ATP7B for WD and HFE or the non-HFE genes for HH has increased, especially with the application of whole genome sequencing technology in recent years, the biological function of the identified mutations, as well as genotype-phenotype correlations remain to be explored. Further analysis of the causative gene mutation would be critical to clarify the mechanisms underlying specific disease phenotypes. In this review, we therefore summarize the recent advances in the molecular genetics of WD and HH including the updated mutation spectrums and the correlation between genotype and phenotype, with an emphasis on biological functional studies of the individual mutations identified in WD and HH. The weakness of the current functional studies and analysis for the clinical association of the individual mutation was also discussed. These works are essential for the understanding of the association between genotypes and phenotypes of these inherited metabolic liver diseases. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  17. Development of a draft of human factors safety review procedures for the Korean next generation reactor

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jung Woon; Moon, B. S.; Park, J. C.; Lee, Y. H.; Oh, I. S.; Lee, H. C. [Korea Atomic Energy Research Institute, Taejeon (Korea)

    2000-02-01

    In this study, a draft of human factors engineering (HFE) safety review procedures (SRP) was developed for the safety review of KNGR based on HFE Safety and Regulatory Requirements and Guidelines (SRRG). This draft includes acceptance criteria, review procedure, and evaluation findings for the areas of review including HFE Program Management, Human Factors Analyses, Human Factors Design, and HFE Verification and Validation, based on Section 15.1 'Human Factors Engineering Design Process' and 15.2 'Control Room Human Factors Engineering' of KNGR Specific Safety Requirements and Chapter 15 'Human Factors Engineering' of KNGR Safety Regulatory Guides. For the effective review, human factors concerns or issues related to advanced HSI design that have been reported so far should be extensively examined. In this study, a total of 384 human factors issues related to the advanced HSI design were collected through our review of a total of 145 documents. A summary of each issue was described and the issues were identified by specific features of HSI design. These results were implemented into a database system. 8 refs., 2 figs. (Author)

  18. A Virtual Campus Based on Human Factor Engineering

    Science.gov (United States)

    Yang, Yuting; Kang, Houliang

    2014-01-01

    Three Dimensional or 3D virtual reality has become increasingly popular in many areas, especially in building a digital campus. This paper introduces a virtual campus, which is based on a 3D model of The Tourism and Culture College of Yunnan University (TCYU). Production of the virtual campus was aided by Human Factor and Ergonomics (HF&E), an…

  19. A Systematic Review of Mixed Methods Research on Human Factors and Ergonomics in Health Care

    Science.gov (United States)

    Carayon, Pascale; Kianfar, Sarah; Li, Yaqiong; Xie, Anping; Alyousef, Bashar; Wooldridge, Abigail

    2016-01-01

    This systematic literature review provides information on the use of mixed methods research in human factors and ergonomics (HFE) research in health care. Using the PRISMA methodology, we searched four databases (PubMed, PsycInfo, Web of Science, and Engineering Village) for studies that met the following inclusion criteria: (1) field study in health care, (2) mixing of qualitative and quantitative data, (3) HFE issues, and (4) empirical evidence. Using an iterative and collaborative process supported by a structured data collection form, the six authors identified a total of 58 studies that primarily address HFE issues in health information technology (e.g., usability) and in the work of healthcare workers. About two-thirds of the mixed methods studies used the convergent parallel study design where quantitative and qualitative data were collected simultaneously. A variety of methods were used for collecting data, including interview, survey and observation. The most frequent combination involved interview for qualitative data and survey for quantitative data. The use of mixed methods in healthcare HFE research has increased over time. However, increasing attention should be paid to the formal literature on mixed methods research to enhance the depth and breadth of this research. PMID:26154228

  20. Genetic predisposition to Parkinson's disease

    DEFF Research Database (Denmark)

    Halling, Jónrit; Petersen, Maria Skaalum; Grandjean, Philippe

    2008-01-01

    OBJECTIVE: To investigate whether the genetic variants of CYP2D6 and HFE are more frequent in Parkinson's disease (PD) patients compared with controls in a population where the prevalence of these variants and PD are increased. METHODS: Blood samples were collected from 79 PD patients and 154...

  1. Human Factors and Ergonomics in the Design of Health Information Technology: Trends and Progress in 2014.

    Science.gov (United States)

    Pelayo, S; Ong, Ms

    2015-08-13

    To summarize significant contributions to the research on human factors and organizational issues in medical informatics. An extensive search using PubMed/Medline and Web of Science® was conducted to identify the scientific contributions, published in 2014, to human factors and organizational issues in medical informatics, with a focus on health information technology (HIT) usability. The selection process comprised three steps: (i) 15 candidate best papers were selected by the two section editors, (ii) external reviewers from a pool of international experts reviewed each candidate best paper, and (iii) the final selection of three best papers was made by the editorial board of the IMIA Yearbook. Noteworthy papers published in 2014 describe an efficient, easy to implement, and useful process for detecting and mitigating human factors and ergonomics (HFE) issues of HIT. They contribute to promote the HFE approach with interventions based on rigorous and well-conducted methods when designing and implementing HIT. The application of HFE in the design and implementation of HIT remains limited, and the impact of incorporating HFE principles on patient safety is understudied. Future works should be conducted to advance this field of research, so that the safety and quality of patient care are not compromised by the increasing adoption of HIT.

  2. Parallels in Computer-Aided Design Framework and Software Development Environment Efforts.

    Science.gov (United States)

    1992-05-01

    Civil Rights Act of 1964 Title IX of th. Educational Amenrimeirts of 1972? and Sect Jr S04 of !hfe Reoahcrl,ton Art of 1973 or other fedlerl sate, or...is similar to many efforts in the SDE community for defining reference models for IPSEs. Research Systems Commercial Systems Many mechanisms I Concepto

  3. Expression of iron-related genes in human brain and brain tumors

    Directory of Open Access Journals (Sweden)

    Britton Robert S

    2009-04-01

    Full Text Available Abstract Background Defective iron homeostasis may be involved in the development of some diseases within the central nervous system. Although the expression of genes involved in normal iron balance has been intensively studied in other tissues, little is known about their expression in the brain. We investigated the mRNA levels of hepcidin (HAMP, HFE, neogenin (NEO1, transferrin receptor 1 (TFRC, transferrin receptor 2 (TFR2, and hemojuvelin (HFE2 in normal human brain, brain tumors, and astrocytoma cell lines. The specimens included 5 normal brain tissue samples, 4 meningiomas, one medulloblastoma, 3 oligodendrocytic gliomas, 2 oligoastrocytic gliomas, 8 astrocytic gliomas, and 3 astrocytoma cell lines. Results Except for hemojuvelin, all genes studied had detectable levels of mRNA. In most tumor types, the pattern of gene expression was diverse. Notable findings include high expression of transferrin receptor 1 in the hippocampus and medulla oblongata compared to other brain regions, low expression of HFE in normal brain with elevated HFE expression in meningiomas, and absence of hepcidin mRNA in astrocytoma cell lines despite expression in normal brain and tumor specimens. Conclusion These results indicate that several iron-related genes are expressed in normal brain, and that their expression may be dysregulated in brain tumors.

  4. Molecular basis of the structural stability of hemochromatosis factor E: A combined molecular dynamic simulation and GdmCl-induced denaturation study.

    Science.gov (United States)

    Khan, Parvez; Parkash, Amresh; Islam, Asimul; Ahmad, Faizan; Hassan, Md Imtaiyaz

    2016-03-01

    Hemochromatosis factor E (HFE) is a member of class I MHC family and plays a significant role in the iron homeostasis. Denaturation of HFE induced by guanidinium chloride (GdmCl) was measured by monitoring changes in [θ]222 (mean residue ellipticity at 222 nm), intrinsic fluorescence emission intensity at 346 nm (F346 ) and the difference absorption coefficient at 287 nm (Δε287) at pH 8.0 and 25°C. Coincidence of denaturation curves of these optical properties suggests that GdmCl-induced denaturation (native (N) state ↔ denatured (D) state) is a two-state process. The GdmCl-induced denaturation was found reversible in the entire concentration range of the denaturant. All denaturation curves were analyzed for ΔGD0, Gibbs free energy change associated with the denaturation equilibrium (N state ↔ D state) in the absence of GdmCl, which is a measure of HFE stability. We further performed molecular dynamics simulation for 40 ns to see the effect of GdmCl on the structural stability of HFE. A well defined correlation was established between in vitro and in silico studies. © 2015 Wiley Periodicals, Inc.

  5. Main Control Room Upgrade for Kori Unit 1 in Korea

    Energy Technology Data Exchange (ETDEWEB)

    Ha, Jae Taeg; Choi, Moon Jae [KEPCO, Daejeon (Korea, Republic of)

    2014-08-15

    Kori Unit 1 is a 30 years old nuclear power plant and its MCR and MCB was upgraded based on the latest Human Factors Engineering (HFE) principles. The objectives of applying the Human Factors Engineering (HFE) principles are to minimize the human errors and to enhance the safe operation of the plant. In order to systematically incorporate the HFE design principles into the Human System Interface (HSI) design, HFE Program Plan (HFEPP) for Kori Unit 1 was developed and the plan provided an overview of the HSI design process along with detailed methods and results. The upgrade includes addition of Bypassed and Inoperable Status Indication System (BISI) and the replacement of the conventional MMI devices such as hardwired hand switches, recorders and indicators with new advanced control and display devices using VDUs (Video Display Units). The VDUs significantly improve the effectiveness and efficiency of the monitoring function. Plant Monitoring System (PMS) and Plant Annunciator System (PAS) were upgraded also by replacing the outdated systems with advanced digital systems with future expansion capability. In addition, the MCR related equipment and/or facilities were replaced or improved. Some of these include the enhancement of MCR interior designs for better working environment, dimmable ceiling lighting, aesthetically pleasing decor of ceiling, wall and floor as well as ergonomically improved operator consoles.

  6. Self-assembly synthesis of 3D graphene-encapsulated hierarchical Fe3O4 nano-flower architecture with high lithium storage capacity and excellent rate capability

    Science.gov (United States)

    Ma, Yating; Huang, Jian; Lin, Liang; Xie, Qingshui; Yan, Mengyu; Qu, Baihua; Wang, Laisen; Mai, Liqiang; Peng, Dong-Liang

    2017-10-01

    Graphene-encapsulated hierarchical metal oxides architectures can efficiently combine the merits of graphene and hierarchical metal oxides, which are deemed as the potential anode material candidates for the next-generation lithium-ion batteries due to the synergistic effect between them. Herein, a cationic surfactant induced self-assembly method is developed to construct 3D Fe3O4@reduction graphene oxide (H-Fe3O4@RGO) hybrid architecture in which hierarchical Fe3O4 nano-flowers (H-Fe3O4) are intimately encapsulated by 3D graphene network. Each H-Fe3O4 particle is constituted of rod-shaped skeletons surrounded by petal-like nano-flakes that are made up of enormous nanoparticles. When tested as the anode material in lithium-ion batteries, a high reversible capacity of 2270 mA h g-1 after 460 cycles is achieved under a current density of 0.5 A g-1. More impressively, even tested at a large current density of 10 A g-1, a decent reversible capacity of 490 mA h g-1 can be retained, which is still higher than the theoretical capacity of traditional graphite anode, demonstrating the remarkable lithium storage properties. The reasons for the excellent electrochemical performance of H-Fe3O4@RGO electrode have been discussed in detail.

  7. Gully monitoring at two locations in the Grand Canyon National Park, Arizona, 1996-2010, with emphasis on documenting effects of the March 2008 high-flow experiment

    Science.gov (United States)

    Schott, Nathan D.; Hazel, Joseph E.; Fairley, Helen C.; Kaplinski, Matt; Parnell, Roderic A.

    2014-01-01

    Many archeological sites in the Grand Canyon are being impacted by gully incision. In March 2008, a high-flow experiment (2008 HFE) was conducted with the intention of redistributing fine sediment (sand, silt, and clay) from the bed of the Colorado River to higher elevations along the channel margin. Deposition of fine sediment in gully mouths has been hypothesized to slow gully erosion rates and lessen impacts to archeological sites. The effects of the 2008 HFE on gullies were evaluated by comparing the topographic changes of three gullies at two study sites before and after the 2008 HFE. Comparison results indicated that sediment was deposited in gully mouths during the 2008 HFE, and that the inundated areas nearest to the river can be extensively altered by mainstream flow during high-flow events. Additionally, the history of gully evolution at the two study sites was examined between 1996 and 2010 and indicated that gullies have been subjected to thalweg incision and gully widening processes over a decadal timescale. Although the small sample size precludes extrapolating the results to other gullies, the findings contribute to the understanding of gully erosion in archeologically significant areas and have implications for future monitoring of gully erosion and evaluating the effectiveness of check dams intended to mitigate that erosion at archaeological sites in the Grand Canyon National Park.

  8. Total mortality by elevated transferrin saturation in patients with diabetes

    DEFF Research Database (Denmark)

    Ellervik, Christina; Andersen, Henrik Ullits; Tybjærg-Hansen, Anne

    2013-01-01

    It is not known to what extent iron overload predicts prognosis in patients with diabetes after diagnosis or whether iron overload is a risk factor independent of the HFE genotype. We investigated total and cause-specific mortality according to increased transferrin saturation (≥ 50 vs....

  9. GenBank blastx search result: AK058436 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  10. GenBank blastx search result: AK062355 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  11. GenBank blastn search result: AK058686 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  12. GenBank blastn search result: AK059019 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  13. GenBank blastn search result: AK241145 [KOME

    Lifescience Database Archive (English)

    Full Text Available chromosome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members

  14. GenBank blastn search result: AK119240 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  15. GenBank blastn search result: AK105816 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  16. GenBank blastx search result: AK059019 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  17. GenBank blastn search result: AK058436 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  18. GenBank blastn search result: AK059098 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  19. GenBank blastn search result: AK059159 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  20. GenBank blastn search result: AK058913 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  1. GenBank blastn search result: AK058741 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  2. GenBank blastx search result: AK059159 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  3. GenBank blastx search result: AK058741 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  4. GenBank blastx search result: AK059098 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  5. GenBank blastx search result: AK058686 [KOME

    Lifescience Database Archive (English)

    Full Text Available ome 6 Contains the 3' part of the HFE gene for haemochromatosis protein, two genes for novel histone 4 family members..., two genes for novel histone 1 family members, three genes for novel histone 2B family members, a

  6. Liquid-liquid extraction of iron (III) from Ouenza iron ore leach liquor ...

    African Journals Online (AJOL)

    The stoichiometry of the extracted species was determined by using the method of slope analysis. The number of moles of H+, Cl- and TBP associated with the extracted species was determined and the extracted species was found to be HFeCl4 (TBP)2. Keywords: solvent extraction; iron (III); Tributylphosphate; leach liquor; ...

  7. Firefighting to Innovation: Using Human Factors and Ergonomics to Tackle Slip, Trip, and Fall Risks in Hospitals.

    Science.gov (United States)

    Hignett, Sue; Wolf, Laurie; Taylor, Ellen; Griffiths, Paula

    2015-11-01

    The aim of this study was to use a theoretical model (bench) for human factors and ergonomics (HFE) and a comparison with occupational slips, trips, and falls (STFs) risk management to discuss patient STF interventions (bedside). Risk factors for patient STFs have been identified and reported since the 1950s and are mostly unchanged in the 2010s. The prevailing clinical view has been that STF events indicate underlying frailty or illness, and so many of the interventions over the past 60 years have focused on assessing and treating physiological factors (dizziness, illness, vision/hearing, medicines) rather than designing interventions to reduce risk factors at the time of the STF. Three case studies are used to discuss how HFE has been, or could be, applied to STF risk management as (a) a design-based (building) approach to embed safety into the built environment, (b) a staff- (and organization-) based approach, and (c) a patient behavior-based approach to explore and understand patient perspectives of STF events. The results from the case studies suggest taking a similar HFE integration approach to other industries, that is, a sustainable design intervention for the person who experiences the STF event-the patient. This paper offers a proactive problem-solving approach to reduce STFs by patients in acute hospitals. Authors of the three case studies use HFE principles (bench/book) to understand the complex systems for facility and equipment design and include the perspective of all stakeholders (bedside). © 2015, Human Factors and Ergonomics Society.

  8. A systematic review of mixed methods research on human factors and ergonomics in health care.

    Science.gov (United States)

    Carayon, Pascale; Kianfar, Sarah; Li, Yaqiong; Xie, Anping; Alyousef, Bashar; Wooldridge, Abigail

    2015-11-01

    This systematic literature review provides information on the use of mixed methods research in human factors and ergonomics (HFE) research in health care. Using the PRISMA methodology, we searched four databases (PubMed, PsycInfo, Web of Science, and Engineering Village) for studies that met the following inclusion criteria: (1) field study in health care, (2) mixing of qualitative and quantitative data, (3) HFE issues, and (4) empirical evidence. Using an iterative and collaborative process supported by a structured data collection form, the six authors identified a total of 58 studies that primarily address HFE issues in health information technology (e.g., usability) and in the work of healthcare workers. About two-thirds of the mixed methods studies used the convergent parallel study design where quantitative and qualitative data were collected simultaneously. A variety of methods were used for collecting data, including interview, survey and observation. The most frequent combination involved interview for qualitative data and survey for quantitative data. The use of mixed methods in healthcare HFE research has increased over time. However, increasing attention should be paid to the formal literature on mixed methods research to enhance the depth and breadth of this research. Copyright © 2015. Published by Elsevier Ltd.

  9. No Association between Variation in Longevity Candidate Genes and Aging-related Phenotypes in Oldest-old Danes

    DEFF Research Database (Denmark)

    Sørensen, Mette; Nygaard, Marianne; Debrabant, Birgit

    2016-01-01

    additional genes repeatedly considered as candidates for human longevity: APOE, APOA4, APOC3, ACE, CETP, HFE, IL6, IL6R, MTHFR, TGFB1, SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. Altogether, 1,049 single nucleotide polymorphisms (SNPs) were genotyped in 1,088 oldest-old (age 92-93 years) Danes and analysed...

  10. Enhanced ergonomics approaches for product design: a user experience ecosystem perspective and case studies.

    Science.gov (United States)

    Xu, Wei

    2014-01-01

    This paper first discusses the major inefficiencies faced in current human factors and ergonomics (HFE) approaches: (1) delivering an optimal end-to-end user experience (UX) to users of a solution across its solution lifecycle stages; (2) strategically influencing the product business and technology capability roadmaps from a UX perspective and (3) proactively identifying new market opportunities and influencing the platform architecture capabilities on which the UX of end products relies. In response to these challenges, three case studies are presented to demonstrate how enhanced ergonomics design approaches have effectively addressed the challenges faced in current HFE approaches. Then, the enhanced ergonomics design approaches are conceptualised by a user-experience ecosystem (UXE) framework, from a UX ecosystem perspective. Finally, evidence supporting the UXE, the advantage and the formalised process for executing UXE and methodological considerations are discussed. Practitioner Summary: This paper presents enhanced ergonomics approaches to product design via three case studies to effectively address current HFE challenges by leveraging a systematic end-to-end UX approach, UX roadmaps and emerging UX associated with prioritised user needs and usages. Thus, HFE professionals can be more strategic, creative and influential.

  11. A question of our marketing or our preconceptions: commentary on the paper 'a strategy for human factors/ergonomics: developing the discipline and profession'.

    Science.gov (United States)

    Nathanael, Dimitris; Marmaras, Nicolas

    2012-01-01

    The present paper is a commentary on the recently published IEA strategy for human factors/ergonomics (Dul, J., et al. (2012), A strategy for human factors/ergonomics: developing the discipline and profession. Ergonomics, 55(4), 377-395). Two main issues that demand attention are: (i) the way others understand our profession and discipline, and (ii) the way we understand our profession and added value to industry. First, it is advocated that the discussion on the future of human factors/ergonomics (HFE) should be focused more on the quality of the delivered value of HFE and less on its visibility and marketing. Second, the three fundamental characteristics of HFE, as proposed in the report, are discussed and the consequences of this proposal are further developed. Arguments are put forward on the endemic epistemological vagueness within the discipline and on the optimistic definition of its aim. Finally, a proposal is made at the epistemological level, which challenges some established convictions of the discipline. It is advocated that such an epistemological evolution may be necessary if HFE is to make progress towards contributing to system performance. The paper is a commentary on the IEA strategy for human factors/ergonomics. Issues discussed are, the way others understand our profession and the way we understand our profession and added value to industry. Some of the established convictions of the discipline are challenged and proposals are made to overcome these.

  12. Defense of Defense Human Factors Engineering Technical Advisory Group Meeting Summary

    Science.gov (United States)

    2012-07-01

    Williamson, D; Internet Relay Chat (IRC) Coordinate Extractor (ICE) 11 Meeting Agenda DoD HFE TAG Distribution A: Cleared for public release...the grass roots connection – Explore the joint mission space – Create new metrics to measure human performance and effectiveness – Need-driven

  13. Hereditary hemochromatosis: genetic complexity and new diagnostic approaches.

    NARCIS (Netherlands)

    Swinkels, D.W.; Janssen, M.C.H.; Bergmans, J.; Marx, J.J.M.

    2006-01-01

    Since the discovery of the hemochromatosis gene (HFE) in 1996, several novel gene defects have been detected, explaining the mechanism and diversity of iron-overload diseases. At least 4 main types of hereditary hemochromatosis (HH) have been identified. Surprisingly, genes involved in HH encode for

  14. RNA-Seq Analysis of Abdominal Fat Reveals Differences between Modern Commercial Broiler Chickens with High and Low Feed Efficiencies.

    Directory of Open Access Journals (Sweden)

    Zhu Zhuo

    Full Text Available For economic and environmental reasons, chickens with superior feed efficiency (FE are preferred in the broiler chicken industry. High FE (HFE chickens typically have reduced abdominal fat, the major adipose tissue in chickens. In addition to its function of energy storage, adipose tissue is a metabolically active organ that also possesses endocrine and immune regulatory functions. It plays a central role in maintaining energy homeostasis. Comprehensive understanding of the gene expression in the adipose tissue and the biological basis of FE are of significance to optimize selection and breeding strategies. Through gene expression profiling of abdominal fat from high and low FE (LFE commercial broiler chickens, the present study aimed to characterize the differences of gene expression between HFE and LFE chickens. mRNA-seq analysis was carried out on the total RNA of abdominal fat from 10 HFE and 12 LFE commercial broiler chickens, and 1.48 billion of 75-base sequence reads were generated in total. On average, 11,565 genes were expressed (>5 reads/gene/sample in the abdominal fat tissue, of which 286 genes were differentially expressed (DE at q (False Discover Rate 1.3 between HFE and LFE chickens. Expression levels from RNA-seq were confirmed with the NanoString nCounter analysis system. Functional analysis showed that the DE genes were significantly (p < 0.01 enriched in lipid metabolism, coagulation, and immune regulation pathways. Specifically, the LFE chickens had higher expression of lipid synthesis genes and lower expression of triglyceride hydrolysis and cholesterol transport genes. In conclusion, our study reveals the overall differences of gene expression in the abdominal fat from HFE and LFE chickens, and the results suggest that the divergent expression of lipid metabolism genes represents the major differences.

  15. Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading

    Science.gov (United States)

    Ramos, Emilio; Kautz, Léon; Rodriguez, Richard; Hansen, Michael; Gabayan, Victoria; Ginzburg, Yelena; Roth, Marie-Paule; Nemeth, Elizabeta; Ganz, Tomas

    2011-01-01

    In response to iron loading, hepcidin synthesis is homeostatically increased to limit further absorption of dietary iron and its release from stores. Mutations in HFE, transferrin receptor 2 (Tfr2), hemojuvelin (HJV) or bone morphogenetic protein 6 (BMP6) prevent appropriate hepcidin response to iron, allowing increased absorption of dietary iron, and eventually iron overload. To understand the role each of these proteins plays in hepcidin regulation by iron, we analyzed hepcidin mRNA responsiveness to short and long-term iron challenge in iron-depleted Hfe, Tfr2, Hjv and Bmp6 mutant mice. After 1-day (acute) iron challenge, Hfe−/− showed a smaller hepcidin increase than their wild-type strain-matched controls, Bmp6−/− nearly no increase, and Tfr2 and Hjv mutants no increase in hepcidin expression, indicating that all four proteins participate in hepcidin regulation by acute iron changes. After a 21-day (chronic) iron challenge, Hfe and Tfr2 mutants increased hepcidin expression to nearly wild-type levels but a blunted increase of hepcidin was seen in Bmp6−/− and Hjv−/− mice. BMP6, whose expression is also regulated by iron, may mediate hepcidin regulation by iron stores. None of the mutant strains (excepting Bmp6−/− mice) had impaired BMP6 mRNA response to chronic iron loading. Conclusion: TfR2, HJV and BMP6 and, to a lesser extent, HFE, are required for the hepcidin response to acute iron loading, but are partially redundant for hepcidin regulation during chronic iron loading, and are not involved in the regulation of BMP6 expression. Our findings support a model in which acute increases in holotransferrin concentrations transmitted through HFE, TfR2 and HJV augment BMP receptor sensitivity to BMPs. A distinct regulatory mechanism that senses hepatic iron may modulate hepcidin response to chronic iron loading. PMID:21480335

  16. Short-Term Effects of the 2008 High-Flow Experiment on Macroinvertebrates in Colorado River Below Glen Canyon Dam, Arizona

    Science.gov (United States)

    Rosi-Marshall, Emma J.; Kennedy, Theodore A.; Kincaid, Dustin W.; Cross, Wyatt F.; Kelly, Holly A.W.; Behn, Kathrine A.; White, Tyler; Hall, Robert O.; Baxter, Colden V.

    2010-01-01

    Glen Canyon Dam has dramatically altered the physical environment (especially discharge regime, water temperatures, and sediment inputs) of the Colorado River. High-flow experiments (HFE) that mimic one aspect of the natural hydrograph (floods) were implemented in 1996, 2004, and 2008. The primary goal of these experiments was to increase the size and total area of sandbar habitats that provide both camping sites for recreational users and create backwaters (areas of stagnant flow in the lee of return-current eddies) that may be important as rearing habitat for native fish. Experimental flows might also positively or negatively alter the rainbow trout (Oncorhynchus mykiss) sport fishery in the clear tailwater reach below Glen Canyon Dam, Ariz., and native fish populations in downstream reaches (for example, endangered humpback chub, Gila cypha) through changes in available food resources. We examined the short-term response of benthic macroinvertebrates to the March 2008 HFE at three sites [river mile 0 (RM 0, 15.7 miles downriver from the dam), RM 62, and RM 225] along the Colorado River downstream from Glen Canyon Dam by sampling immediately before and then 1, 7, 14, and 30 days after the HFE. We selected these sites because of their importance to management; RM 0 has a valuable trout fishery, and RM 62 is the location of the largest population of the endangered humpback chub in the Grand Canyon. In addition to the short-term collection of samples, as part of parallel investigations, we collected 3 years of monthly (quarterly for RM 62) benthic macroinvertebrate samples that included 15 months of post-HFE data for all three sites, but processing of the samples is only complete for one site (RM 0). At RM 0, the HFE caused an immediate 1.75 g AFDM/m2 (expressed as grams ash-free dry mass, or AFDM) reduction of macroinvertebrate biomass that was driven by significant reductions in the biomass of the two dominant taxa in this reach-Potamopyrgus antipodarum (New

  17. Fast estimation of Colles' fracture load of the distal section of the radius by homogenized finite element analysis based on HR-pQCT.

    Science.gov (United States)

    Hosseini, Hadi S; Dünki, Andreas; Fabech, Jonas; Stauber, Martin; Vilayphiou, Nicolas; Pahr, Dieter; Pretterklieber, Michael; Wandel, Jasmin; Rietbergen, Bert van; Zysset, Philippe K

    2017-04-01

    Fractures of the distal section of the radius (Colles' fractures) occur earlier in life than other osteoporotic fractures. Therefore, they can be interpreted as a warning signal for later, more deleterious fractures of vertebral bodies or the femoral neck. In the past decade, the advent of HR-pQCT allowed a detailed architectural analysis of the distal radius and an automated but time-consuming estimation of its strength with linear micro-finite element (μFE) analysis. Recently, a second generation of HR-pQCT scanner (XtremeCT II, SCANCO Medical, Switzerland) with a resolution beyond 61 μm became available for even more refined biomechanical investigations in vivo. This raises the question how biomechanical outcome variables compare between the original (LR) and the new (HR) scanner resolution. Accordingly, the aim of this work was to validate experimentally a patient-specific homogenized finite element (hFE) analysis of the distal section of the human radius for the fast prediction of Colles' fracture load based on the last generation HR-pQCT. Fourteen pairs of fresh frozen forearms (mean age = 77.5±9) were scanned intact using the high (61 μm) and the low (82 μm) resolution protocols that correspond to the new and original HR-pQCT systems. From each forearm, the 20mm most distal section of the radius were dissected out, scanned with μCT at 16.4 μm and tested experimentally under compression up to failure for assessment of stiffness and ultimate load. Linear and nonlinear hFE models together with linear micro finite element (μFE) models were then generated based on the μCT and HR-pQCT reconstructions to predict the aforementioned mechanical properties of 24 sections. Precision errors of the short term reproducibility of the FE analyses were measured based on the repeated scans of 12 sections. The calculated failure loads correlated strongly with those measured in the experiments: accounting for donor as a random factor, the nonlinear hFE provided a

  18. Human Factors Engineering as a System in the Vision for Exploration

    Science.gov (United States)

    Whitmore, Mihriban; Smith, Danielle; Holden, Kritina

    2006-01-01

    In order to accomplish NASA's Vision for Exploration, while assuring crew safety and productivity, human performance issues must be well integrated into system design from mission conception. To that end, a two-year Technology Development Project (TDP) was funded by NASA Headquarters to develop a systematic method for including the human as a system in NASA's Vision for Exploration. The specific goals of this project are to review current Human Systems Integration (HSI) standards (i.e., industry, military, NASA) and tailor them to selected NASA Exploration activities. Once the methods are proven in the selected domains, a plan will be developed to expand the effort to a wider scope of Exploration activities. The methods will be documented for inclusion in NASA-specific documents (such as the Human Systems Integration Standards, NASA-STD-3000) to be used in future space systems. The current project builds on a previous TDP dealing with Human Factors Engineering processes. That project identified the key phases of the current NASA design lifecycle, and outlined the recommended HFE activities that should be incorporated at each phase. The project also resulted in a prototype of a webbased HFE process tool that could be used to support an ideal HFE development process at NASA. This will help to augment the limited human factors resources available by providing a web-based tool that explains the importance of human factors, teaches a recommended process, and then provides the instructions, templates and examples to carry out the process steps. The HFE activities identified by the previous TDP are being tested in situ for the current effort through support to a specific NASA Exploration activity. Currently, HFE personnel are working with systems engineering personnel to identify HSI impacts for lunar exploration by facilitating the generation of systemlevel Concepts of Operations (ConOps). For example, medical operations scenarios have been generated for lunar habitation

  19. Financial Analysis of Experimental Releases Conducted at Glen Canyon Dam during Water Year 2015

    Energy Technology Data Exchange (ETDEWEB)

    Graziano, D. J. [Argonne National Lab. (ANL), Argonne, IL (United States); Poch, L. A. [Argonne National Lab. (ANL), Argonne, IL (United States); Veselka, T. D. [Argonne National Lab. (ANL), Argonne, IL (United States)

    2016-11-01

    This report examines the financial implications of experimental flows conducted at the Glen Canyon Dam (GCD) in water year (WY) 2015. It is the seventh report in a series examining the financial implications of experimental flows conducted since the Record of Decision (ROD) was adopted in February 1997 (Reclamation 1996). A report released in January 2011 examined WYs 1997 to 2005 (Veselka et al. 2011); a report released in August 2011 examined WYs 2006 to 2010 (Poch et al. 2011); a report released June 2012 examined WY 2011 (Poch et al. 2012); a report released April 2013 examined WY 2012 (Poch et al. 2013); a report released June 2014 examined WY 2013 (Graziano et al. 2014); and a report released September 2015 examined WY 2014 (Graziano et al. 2015). An experimental release may have either a positive or negative impact on the financial value of energy production. Only one experimental release was conducted at GCD in WY 2015; specifically, a high flow experimental (HFE) release conducted in November 2014. For this experimental release, financial costs of approximately $2.1 million were incurred because the HFE required sustained water releases that exceeded the powerplant’s maximum flow rate. In addition, during the month of the experiment, operators were not allowed to shape GCD power production to either follow firm power customer loads or to respond to market prices. This study identifies the main factors that contribute to HFE costs and examines the interdependencies among these factors. It applies an integrated set of tools to estimate financial impacts by simulating the GCD operations under two scenarios: (1) a baseline scenario that mimics both HFE operations during the experiment and during the rest of the year when it complies with the 1996 ROD operating criteria, and (2) a “without experiments” scenario that is identical to the baseline except it assumes that the HFE did not occur. The Generation and Transmission Maximization (GTMax) model was the

  20. TRAF1 Gene Polymorphism Correlates with the Titre of Gp210 Antibody in Patients with Primary Biliary Cirrhosis

    Directory of Open Access Journals (Sweden)

    Agnieszka Kempinska-Podhorodecka

    2012-01-01

    Full Text Available Background. Polymorphisms of TRAF1 (Tumor necrosis factor receptor-associated factor 1 are associated with rheumatoid arthritis (RA. Whether TRAF1 polymorphisms confer increased risk for primary biliary cirrhosis (PBC, an autoimmune liver disease which can co-exist with RA, is unknown. Aim of the Study. To assess the frequency of the RA-conferring susceptibility TRAF1 polymorphisms rs3761847 and rs2900180 in a cohort of PBC patients. The association of TRAF1 polymorphisms with clinical features and autoantibody markers was also analyzed. Methods. We studied 179 PBC patients and 300 controls. Samples were genotyped for TRAF1 gene polymorphisms by real-time PCR. Autoantibodies were tested by ELISA. Results. The frequency of rs3761847 and rs2900180 polymorphisms did not differ between patients and controls. Laboratory or clinical features were not associated with specific polymorphisms. Gp210 autoantibody titres were conspicuously higher among GG homozygotes of rs3761847 as compared with AA homozygotes (P=0.02. In contrast, antichromatin titers were higher in AA compared to GG rs3761847 homozygotes (P=0.04. Rheumatoid factor IgG titres were significantly higher in rs2900180 TT homozygotes than CC homozygotes (P=0.02. Conclusions. TRAF1 polymorphisms occur with the similar frequency in PBC patients and in the general population, but their presence is probably involved in the regulation of specific PBC-related autoantibodies.

  1. Consanguinity analysis in Israeli mental retardates.

    Science.gov (United States)

    Costeff, H; Cohen, B E; Weller, L; Rahman, D

    1977-01-01

    Consanguinity rates were analyzed in 904 families of retardates studied in 11 Israeli Jewish ethnic groups. It was estimated that the representative recessive gene frequency is .00518, implying that a gene equilibrium maintained by mutation alone is improbable and that some other hypothesis should be considered. The proportions of homozygotes among the following idiopathic subgroups are estimated as follows: 18%-19% homozygotes among severe idiopathic retardates with nonconsanguineous parents and no affected siblings; 74%-76% homozygotes among severe idiopathic retardates with first-cousin parents and no affected siblings; 5% homozygotes among mild idiopathic and idiopathic-familial retardates with nonconsanguineous parents; and 41% homozygotes among mild idiopathic and idiopathic-familial retardates with first-cousin parents. The estimated number of major gene loci within ethnic groups is 17-21 for severe idiopathic retardation and 43-61 for mild idiopathic retardation. These findings provide a basis for genetic counseling of families with single retardates of unknown cause. They can also be useful in epidemiologic studies of nongenetic factors. The great prevalence of common gene defects causing retardation, coupled with the rarity of disorders of amino acid metabolism in the same series, seem to indicate that further emphasis on amino acid metabolism may be nonproductive in the scientific study of retardation and that other biochemical approaches should be encouraged. PMID:879167

  2. [Detection of cytochrome P450 3A4 gene polymorphism guides for labor analgesia with sufentanil medication].

    Science.gov (United States)

    Chi, Li-qun; Lu, Xin; Wang, Lei; Liu, Shu-ping; Ding, Nan; Zhang, Hong-ying; E, Wen

    2015-08-18

    To investigate the relationship between single nucleotide polymorphisms (SNPs) of cytochrome P450 (CYP450) 3A4 rs2242480 and inter-individual differences of sufentanil consumption in accouchement sans douleur. A total of 131 parturient women were collected. According to the distribution of genotypes and allele frequencies of rs2242480, the doses of sufentanil were individually designed. CC homozygotes were given the standard analgesia dose, CT heterozygotes and TT homozygotes were given 87.6% of standard sufentanil dose. Visual analogue score (VAS) between CC group and CT/TT group were 3.67±1.2 and 3.44±1.5, consistent with the expected analgesic standards. The difference was not statistically significant. The parturient women carrying CT heterozygotes and TT homozygotes of CYP3A4 rs2242480 required less sufentanil in accouchement sans douleur.

  3. Deficiency in the regulation of testicular galactolipid sulphotransferase in rats carrying the growth-and-reproduction-complex (grc) gene.

    Science.gov (United States)

    Lingwood, C; Kunz, H W; Gill, T J

    1985-01-01

    The regulation of the activity of testicular germ-cell galactolipid sulphotransferase was investigated in rats homozygous for the grc (growth and reproductive complex) gene. In the adult grc homozygotes, the activity was elevated relative to that in the wild-type animals, and a concomitant deficiency of a developmentally regulated sulphotransferase inhibitor was found. Spermatogenesis in the grc homozygotes is blocked at a stage that correlates temporally with the earliest detection of this inhibitor in the wild-type animal. In addition, there was a similar increase in the specific activity of the kidney galactolipid sulphotransferase in the grc homozygotes. This biochemical abnormality is the first to be associated with a genetically regulated, developmental defect linked to the major histocompatibility complex, and it is related to the pathogenesis of one of the major lesions controlled by the grc. Images Fig. 1. Fig. 2. PMID:3864441

  4. A Theoretical Framework for Association Studies in F2 Family Pools Using Allele Frequencies from Genotyping-By-Sequencing

    DEFF Research Database (Denmark)

    Janss, Luc L; Ashraf, Bilal H; Greve-Pedersen, Morten

    In Perennial ryegrass breeding, F2's derived from parental crosses are sown in plots and phenotypes and genotypes are obtained as single measurements for the whole F2 family pool. For genotypes this means that quantitative assays must be used to obtain allele frequencies. For this purpose...... a sequencing approach to obtain Single Nucleotide Polymorphisms (SNPs) frequencies is considered here. In this work we develop the theoretical framework to perform association studies using allele frequencies from such F2 family pools. We show that expected allele frequencies in the F2 families will have...... individuals. This effect is caused by extreme families (homozygote x homozygote) being less frequent than extreme (homozygote) individuals. We finally consider the effects of using sequencing to obtain allele frequencies, which will cause inaccuracy in the frequency estimate due to obtaining a limited number...

  5. Suitability of virtual prototypes to support human factors/ergonomics evaluation during the design.

    Science.gov (United States)

    Aromaa, Susanna; Väänänen, Kaisa

    2016-09-01

    In recent years, the use of virtual prototyping has increased in product development processes, especially in the assessment of complex systems targeted at end-users. The purpose of this study was to evaluate the suitability of virtual prototyping to support human factors/ergonomics evaluation (HFE) during the design phase. Two different virtual prototypes were used: augmented reality (AR) and virtual environment (VE) prototypes of a maintenance platform of a rock crushing machine. Nineteen designers and other stakeholders were asked to assess the suitability of the prototype for HFE evaluation. Results indicate that the system model characteristics and user interface affect the experienced suitability. The VE system was valued as being more suitable to support the assessment of visibility, reach, and the use of tools than the AR system. The findings of this study can be used as a guidance for the implementing virtual prototypes in the product development process. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Social and personal normative influences on healthcare professionals to use information technology: Towards a more robust social ergonomics.

    Science.gov (United States)

    Holden, Richard J

    2012-09-01

    Social structures and processes are increasingly acknowledged and studied within the human factors/ergonomics (HFE) discipline. At the same time, social phenomena are rarely the focus of HFE work, leaving a knowledge gap. The present study directly addresses social and personal normative forces that influence technology use and performance. Social and personal normative influence to use electronic health records (EHR) were investigated using semi-structured qualitative interviews with 20 attending physicians at two US hospitals. Analyses used a comprehensive framework based on leading social scientific theories and revealed numerous sources of influence, including hospital administration, colleagues, patients, clinical and professional groups, government, and one's self. Influence was achieved through different means and invoked different psychological processes. Findings motivate a new view of professionals' technology use as a highly social process occurring in a social context, with implications for research, policy, design, and in general the development of a robust social ergonomics.

  7. Investigation of irradiation effect on npn BJT electrical properties

    Science.gov (United States)

    Assaf, J.

    2016-10-01

    The irradiation effects of neutrons and gamma rays on a commercial type of npn Bipolar Junction Transistors (BJTs) are reported. The decrease of the current gain factor hFE for increasing dose was analyzed. Reduction ratio for hFE between 84% and 98% at the saturated reduction level have been obtained. This is due to a small decreasing in the collector current IC and a large increasing in the base current IB, where hFE=IC/IB. Reduction ratio per dose indicates the higher influence of the neutrons than that of gamma for the same equivalent dose. Moreover, the voltage gain as a function of the frequency decremented after irradiation, and the collector saturated voltage (VCEsat) was increased. These effects illustrate the damage in the function of BJTs.

  8. Hereditary hemochromatosis

    Directory of Open Access Journals (Sweden)

    Stephen A. Geller

    2015-03-01

    Full Text Available Hereditary hemochromatosis (HH is the most commonly identified autosomal recessive genetic disorder in the white population, characterized by increased intestinal iron absorption and secondary abnormal accumulation in parenchymal organs, not infrequently accompanied by functional impairment. This entity is associated with mutations of the HFE gene (located on the short arm of chromosome 6 at location 6p22.2; closely linked to the HLA-A3 locus, which encodes the HFE protein, a membrane protein thought to regulate iron absorption by affecting the interaction between transferrin receptor and transferrin.

  9. IDHEAS – A NEW APPROACH FOR HUMAN RELIABILITY ANALYSIS

    Energy Technology Data Exchange (ETDEWEB)

    G. W. Parry; J.A Forester; V.N. Dang; S. M. L. Hendrickson; M. Presley; E. Lois; J. Xing

    2013-09-01

    This paper describes a method, IDHEAS (Integrated Decision-Tree Human Event Analysis System) that has been developed jointly by the US NRC and EPRI as an improved approach to Human Reliability Analysis (HRA) that is based on an understanding of the cognitive mechanisms and performance influencing factors (PIFs) that affect operator responses. The paper describes the various elements of the method, namely the performance of a detailed cognitive task analysis that is documented in a crew response tree (CRT), and the development of the associated time-line to identify the critical tasks, i.e. those whose failure results in a human failure event (HFE), and an approach to quantification that is based on explanations of why the HFE might occur.

  10. Hype, harmony and human factors: applying user-centered design to achieve sustainable telehealth program adoption and growth.

    Science.gov (United States)

    Rossos, P G; St-Cyr, O; Purdy, B; Toenjes, C; Masino, C; Chmelnitsky, D

    2015-01-01

    Despite decades of international experience with the use of information and communication technologies in healthcare delivery, widespread telehealth adoption remains limited and progress slow. Escalating health system challenges related to access, cost and quality currently coincide with rapid advancement of affordable and reliable internet based communication technologies creating unprecedented opportunities and incentives for telehealth. In this paper, we will describe how Human Factors Engineering (HFE) and user-centric elements have been incorporated into the establishment of telehealth within a large academic medical center to increase acceptance and sustainability. Through examples and lessons learned we wish to increase awareness of HFE and its importance in the successful implementation, innovation and growth of telehealth programs.

  11. Towards a sustainable world through human factors and ergonomics: it is all about values.

    Science.gov (United States)

    Lange-Morales, Karen; Thatcher, Andrew; García-Acosta, Gabriel

    2014-01-01

    In this paper, we analyse two approaches that attempt to address how a human factors and ergonomics (HFE) perspective can contribute to the sustainability of the human race. We outline the principles, purposes and fields of application of ergoecology and green ergonomics, and thereafter deal with their context of emergence, and the overlaps in purpose, and principles. Shared values are deduced and related to socio-technical principles for systems' design. Social responsibility and environmental/ecospheric responsibility are the leading threads of ergoecology and green ergonomics, giving rise to the values of: respect for human rights, respect for the Earth, respect for ethical decision-making, appreciation of complexity, respect for transparency and openness, and respect for diversity. We discuss the consequences of considering these values in HFE theory and practice.

  12. Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features.

    Science.gov (United States)

    Heidari, M; Johnstone, D M; Bassett, B; Graham, R M; Chua, A C G; House, M J; Collingwood, J F; Bettencourt, C; Houlden, H; Ryten, M; Olynyk, J K; Trinder, D; Milward, E A

    2016-11-01

    The 'neurodegeneration with brain iron accumulation' (NBIA) disease family entails movement or cognitive impairment, often with psychiatric features. To understand how iron loading affects the brain, we studied mice with disruption of two iron regulatory genes, hemochromatosis (Hfe) and transferrin receptor 2 (Tfr2). Inductively coupled plasma atomic emission spectroscopy demonstrated increased iron in the Hfe-/- × Tfr2mut brain (P=0.002, n ≥5/group), primarily localized by Perls' staining to myelinated structures. Western immunoblotting showed increases of the iron storage protein ferritin light polypeptide and microarray and real-time reverse transcription-PCR revealed decreased transcript levels (P0.05). Overlap (P0.05). These results implicate myelin-related systems involved in NBIA neuropathogenesis in early responses to iron loading. This may contribute to behavioral symptoms in NBIA and hemochromatosis and is relevant to patients with abnormal iron status and psychiatric disorders involving myelin abnormalities or resistant to conventional treatments.

  13. On the application of motivation theory to human factors/ergonomics: motivational design principles for human-technology interaction.

    Science.gov (United States)

    Szalma, James L

    2014-12-01

    Motivation is a driving force in human-technology interaction. This paper represents an effort to (a) describe a theoretical model of motivation in human technology interaction, (b) provide design principles and guidelines based on this theory, and (c) describe a sequence of steps for the. evaluation of motivational factors in human-technology interaction. Motivation theory has been relatively neglected in human factors/ergonomics (HF/E). In both research and practice, the (implicit) assumption has been that the operator is already motivated or that motivation is an organizational concern and beyond the purview of HF/E. However, technology can induce task-related boredom (e.g., automation) that can be stressful and also increase system vulnerability to performance failures. A theoretical model of motivation in human-technology interaction is proposed, based on extension of the self-determination theory of motivation to HF/E. This model provides the basis for both future research and for development of practical recommendations for design. General principles and guidelines for motivational design are described as well as a sequence of steps for the design process. Human motivation is an important concern for HF/E research and practice. Procedures in the design of both simple and complex technologies can, and should, include the evaluation of motivational characteristics of the task, interface, or system. In addition, researchers should investigate these factors in specific human-technology domains. The theory, principles, and guidelines described here can be incorporated into existing techniques for task analysis and for interface and system design.

  14. A Summary of Crew Workload and Situational Awareness Ratings for U.S. Army Aviation Aircraft

    Science.gov (United States)

    2014-06-01

    58F BHIVE 2 Human Factors Engineering (HFE) #1, 2, 3 Design Assessment RAH-66 CPC, EDS Force Development Test and Experimentation (FDT&E) 1...1188 Operate ASE/transponder 1184 Respond to IMC Conditions 1194 Perform Refueling /Rearming Operations 1404 Perform Electronic...Portable Cockpit EDS Engineering Development Simulator EUD Early User Demonstration FDT&E Force Development Test and Evaluation FLIR Forward-Looking

  15. Demands on new reactor concepts from the of view of organizational psychology and ergonomics. Anforderungen an neue Reaktorkonzepte aus organisationspsychologischer und ergonomischer Sicht

    Energy Technology Data Exchange (ETDEWEB)

    Wilpert, B. (Technische Univ. Berlin (Germany). Forschungsstelle Systemsicherheit); Becker, G. (TUEV Rheinland e.V., Inst. fuer Kerntechnik und Strahlenschutz, Koeln (Germany))

    1994-04-01

    The paper is intended to define the most important aspects of Human Factor Engineering (HFE) which from the points of view of organizational psychology and ergonomics right now have to be made a subject of the discussion about safety criteria and design principles. Room and time only allow to identify the most important principles related to demands on the manufacturers, but not to represent detailed acceptance criteria which, in the first place, will have to be specified by licensing authorities. (orig./DG)

  16. Design Development and Implementation of the Human-System Interface for Lungmen Nuclear Project

    Science.gov (United States)

    Chuang, Chang-Fu; Chou, Hwai-Pwu

    2008-10-01

    The Lungmen Nuclear Power Project (LMNPP), under construction in Taiwan, consists of two GE Advanced Boiling Water Reactor (ABWR) units, each with 1350 MW electrical output. Major Human-System Interfaces (HSIs) of LMNPP are different from traditional operating BWRs or ABWRs. Video display units (VDUs) are the main human-system interface for operators to manipulate and to know the status of the equipment and plant information. Based upon NUREG-0711, the applicable human factors engineering (HFE) guideline in the design of HSIs has been adopted. An important aspect of the Lungmen HFE program has been the direct involvement of the end user, Taiwan Power Company (TPC), throughout the design development and implementation to ensure that the process for the design is compliant with the HFE principles, and that the necessary displays, control, and alarms are provided to support the identified personnel tasks. This paper reviews the applicable HFE principles and the HSI design process including verification and validation (V&V) process in the design of HSIs for the LMNPP. This paper also presents three topics of interest in the LMNPP HSI design development and implementation process-validation with simulator, alarm auto reset, and VDU operational configuration strategy. The objective for developing the VDU operational configuration strategy was, after appropriate V&V, to reinforce operation discipline and optimize operator crew task assignments and workload during typical operations, and to confirm the need for an intensive training program that addresses the knowledge and skill requirements of the operators to meet the task characteristics and the responses of the plant processes. The results to date and implications for going forward from this process are also presented.

  17. Development and Application of a Clinical Microsystem Simulation Methodology for Human Factors-Based Research of Alarm Fatigue.

    Science.gov (United States)

    Kobayashi, Leo; Gosbee, John W; Merck, Derek L

    2017-07-01

    (1) To develop a clinical microsystem simulation methodology for alarm fatigue research with a human factors engineering (HFE) assessment framework and (2) to explore its application to the comparative examination of different approaches to patient monitoring and provider notification. Problems with the design, implementation, and real-world use of patient monitoring systems result in alarm fatigue. A multidisciplinary team is developing an open-source tool kit to promote bedside informatics research and mitigate alarm fatigue. Simulation, HFE, and computer science experts created a novel simulation methodology to study alarm fatigue. Featuring multiple interconnected simulated patient scenarios with scripted timeline, "distractor" patient care tasks, and triggered true and false alarms, the methodology incorporated objective metrics to assess provider and system performance. Developed materials were implemented during institutional review board-approved study sessions that assessed and compared an experimental multiparametric alerting system with a standard monitor telemetry system for subject response, use characteristics, and end-user feedback. A four-patient simulation setup featuring objective metrics for participant task-related performance and response to alarms was developed along with accompanying structured HFE assessment (questionnaire and interview) for monitor systems use testing. Two pilot and four study sessions with individual nurse subjects elicited true alarm and false alarm responses (including diversion from assigned tasks) as well as nonresponses to true alarms. In-simulation observation and subject questionnaires were used to test the experimental system's approach to suppressing false alarms and alerting providers. A novel investigative methodology applied simulation and HFE techniques to replicate and study alarm fatigue in controlled settings for systems assessment and experimental research purposes.

  18. Evaluating the Effects of Clothing and Individual Equipment on Marksmanship Performance Using a Novel Five Target Methodology

    Science.gov (United States)

    2016-11-01

    NUMBER 13-137, 15-025 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION...Reprint of a paper presented at Proceedings of the Human Factors and Ergonomics Society (HFE) Annual Meeting 2016. 19-23 September, 2016. Washington...provide insight into how a product will perform in an operational environment (Johnson, McMenemy & Dauphinee, 1990; Johnson & Kobrick, 1997; Bensel

  19. The obese Göttingen minipig as a model of the metabolic syndrome

    DEFF Research Database (Denmark)

    Johansen, T.; Malmlöf, K.; Hansen, Harald S.

    2001-01-01

    The objective of the study reported here was to induce obesity in the female Göttingen minipig to establish a model of the human metabolic syndrome. Nine- to ten-month-old female Göttingen minipigs received a high-fat high-energy (HFE) diet or a low-fat, low-energy (LFE) diet. The energy contents...... of the metabolic impairments seen in obese humans, and may thus serve as a model of the metabolic syndrome....

  20. Review of the IEEE Standard for Computerized Operating Procedure Systems

    Energy Technology Data Exchange (ETDEWEB)

    O' Hara, J.; Higgins, J.

    2010-02-26

    Increasingly nuclear power plant procedures, such as emergency operating procedures, are being presented in computer form with functionality to support operator use and management of the procedures. The U.S. Nuclear Regulatory Commission (NRC) currently has guidance for the review of computer-based procedures (CBPs); however, there remain CBP functions and human performance issues for which up-to-date guidance is lacking. The Institute of Electrical and Electronics Engineers (IEEE) has initiated a standard development effort to address the human factors engineering (HFE) aspects of CBP systems. When completed, it may provide guidance to supplement the NRC staff's review criteria. The purpose of our study was to evaluate the suitability of the IEEE Standard for use in the NRC's HFE safety reviews of CBP systems and to ensure that the guidance meets the NRC's standard for scientific and engineering rigor used in its own guidance development efforts. We established the following criteria with which to evaluate the Standard: (1) it should meet an existing need of NRC reviewers, (2) it should be based in sound HFE principles, (3) it should be thoroughly peer-reviewed, and (4) it should address CBP-related human performance issues identified in the literature. This report describes the methodology we used to evaluate each criterion. Our evaluation concluded that the Standard generally does meet these criteria, however several areas were identified for which additional clarifications are needed. Thus consideration of the Standard's use by the NRC is supported. The standard evaluation methodology developed in this study can be generally applied to the review of other HFE standards being considered for possible use or endorsement by the NRC.

  1. An Evaluation of the Effects of Human Factors and Ergonomics on Health Care and Patient Safety Practices: A Systematic Review.

    Science.gov (United States)

    Mao, Xuanyue; Jia, Pengli; Zhang, Longhao; Zhao, Pujing; Chen, Ying; Zhang, Mingming

    2015-01-01

    From the viewpoint of human factors and ergonomics (HFE), errors often occur because of the mismatch between the system, technique and characteristics of the human body. HFE is a scientific discipline concerned with understanding interactions between human behavior, system design and safety. To evaluate the effectiveness of HFE interventions in improving health care workers' outcomes and patient safety and to assess the quality of the available evidence. We searched databases, including MEDLINE, EMBASE, BIOSIS Previews and the CBM (Chinese BioMedical Literature Database), for articles published from 1996 to Mar.2015. The quality assessment tool was based on the risk of bias criteria developed by the Cochrane Effective Practice and Organization of Care (EPOC) Group. The interventions of the included studies were categorized into four relevant domains, as defined by the International Ergonomics Association. For this descriptive study, we identified 8, 949 studies based on our initial search. Finally, 28 studies with 3,227 participants were included. Among the 28 included studies, 20 studies were controlled studies, two of which were randomized controlled trials. The other eight studies were before/after surveys, without controls. Most of the studies were of moderate or low quality. Five broad categories of outcomes were identified in this study: 1) medical errors or patient safety, 2) health care workers' quality of working life (e.g. reduced fatigue, discomfort, workload, pain and injury), 3) user performance (e.g., efficiency or accuracy), 4) health care workers' attitudes towards the interventions(e.g., satisfaction and preference), and 5) economic evaluations. The results showed that the interventions positively affected the outcomes of health care workers. Few studies considered the financial merits of these interventions. Most of the included studies were of moderate quality. This review highlights the need for scientific and standardized guidelines regarding

  2. Lessons from the Army’s Future Combat Systems Program

    Science.gov (United States)

    2012-01-01

    commercial use only. Unauthorized posting of RAND electronic documents to a non-RAND website is prohibited . RAND electronic documents are protected under... prohibited . RAND documents are protected under copyright law. For information on reprint and linking permissions, please visit the R AND permissions...Terror HAS Hit Avoidance Suite HBCT Heavy Brigade Combat Team HEMP High-Altitude Electromagnetic Pulse HFE Heavy Fuel Engine HMMWV High Mobility

  3. Boiling heat transfer in narrow channels with offset strip fins: Application to electronic chipsets cooling

    OpenAIRE

    Pulvirenti, B.; Matalone, A.; Barucca, U.

    2010-01-01

    Abstract An experimental study on saturated flow boiling heat transfer of HFE-7100 in vertical rectangular channels with offset strip fins is presented. The experiments have been carried out at atmospheric pressure, over a wide range of vapour quality and heat fluxes up to 1.8?105 W/m2. The local boiling heat transfer coefficient has been obtained from experiments and analysed by means of Chen superposition method. Some correlations for convective boiling and nucleate boiling heat ...

  4. Homozygosity for a single base-pair mutation in the oocyte-specific GDF9 gene results in sterility in Thoka sheep

    DEFF Research Database (Denmark)

    Nicel, Linda; Bishop, Stephen; Pong-Wong, Richardo

    2009-01-01

    ovulation rate, although in some cases homozygous ewes are infertile. In the present study we present a detailed characterisation of a novel mutation in growth differentiation factor 9 (GDF9), found in Icelandic Thoka sheep. This mutation is a single base change (A1279C) resulting in a non...... and infertility in homozygotes. Analysis of homozygote ovarian morphology and a number of genes normally activated in growing follicles showed that GDF9 was not involved in oocyte activation, but in subsequent development of the follicle. This study highlights the importance of oocyte factors in regulating...

  5. Allelic Imbalance of mRNA Associated with α2-HS Glycoprotein (Fetuin-A) Polymorphism

    OpenAIRE

    Inaoka, Yoshihiko; Osawa, Motoki; Mukasa, Nahoko; Miyashita, Keiko; Satoh, Fumiko; Kakimoto, Yu

    2015-01-01

    Alpha 2-HS glycoprotein (AHSG), also designated as fetuin-A, exhibits polymorphism in population genetics consisting of two major alleles of AHSG ? 1 and AHSG ? 2. The serum level in the AHSG ? 1 homozygote is significantly higher than that of the AHSG ? 2 homozygote. This study examined the molecular mechanism for the cis-regulatory expression. To quantitate allele-specific mRNA in intra-assays of the heterozygote, RT-PCR method employing primers that were incorporated to the two closely loc...

  6. Human-system interface design review guideline -- Reviewer`s checklist: Final report. Revision 1, Volume 2

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-06-01

    NUREG-0700, Revision 1, provides human factors engineering (HFE) guidance to the US Nuclear Regulatory Commission staff for its: (1) review of the human system interface (HSI) design submittals prepared by licensees or applications for a license or design certification of commercial nuclear power plants, and (2) performance of HSI reviews that could be undertaken as part of an inspection or other type of regulatory review involving HSI design or incidents involving human performance. The guidance consists of a review process and HFE guidelines. The document describes those aspects of the HSI design review process that are important to the identification and resolution of human engineering discrepancies that could adversely affect plant safety. Guidance is provided that could be used by the staff to review an applicant`s HSI design review process or to guide the development of an HSI design review plan, e.g., as part of an inspection activity. The document also provides detailed HFE guidelines for the assessment of HSI design implementations. NUREG-0700, Revision 1, consists of three stand-alone volumes. Volume 2 is a complete set of the guidelines contained in Volume 1, Part 2, but in a checklist format that can be used by reviewers to assemble sets of individual guidelines for use in specific design reviews. The checklist provides space for reviewers to enter guidelines evaluations and comments.

  7. Anti-inflammatory activity of a honey flavonoid extract on lipopolysaccharide-activated N13 microglial cells.

    Science.gov (United States)

    Candiracci, Manila; Piatti, Elena; Dominguez-Barragán, María; García-Antrás, Daniel; Morgado, Bruno; Ruano, Diego; Gutiérrez, Juan F; Parrado, Juan; Castaño, Angélica

    2012-12-19

    Neuroinflammation is an important contributor to pathogenesis of age-related neurodegenerative disorders such as Alzheimer's or Parkinson's disease. Accumulating evidence indicates that inhibition of microglia-mediated neuroinflammation may become a reliable protective strategy for neurodegenerative processes. Flavonoids, widely distributed in the vegetable kingdom and in foods such as honey, have been suggested as novel therapeutic agents for the reduction of the deleterious effects of neuroinflammation. The present study investigated the potential protective effect of a honey flavonoid extract (HFE) on the production of pro-inflammatory mediators by lipopolysaccharide-stimulated N13 microglia. The results show that HFE significantly inhibited the release of pro-inflammatory cytokines such as TNF-α and IL-1β. The expressions of iNOS and the production of reactive oxygen intermediates (ROS) were also significantly inhibited. Accordingly, the present study demonstrates that HFE is a potent inhibitor of microglial activation and thus a potential preventive-therapeutic agent for neurodegenerative diseases involving neuroinflammation.

  8. Mathematical Approach in Rheological Characterizing of Asphalt Emulsion Residues

    Directory of Open Access Journals (Sweden)

    Seong Hwan Cho

    2015-01-01

    Full Text Available Three different emulsion residues, such as SS1HP, HFE90, and SS-1VH (trackless, and a base asphalt binder (PG 64-22 are compared to characterize rheological properties by using DSR test. In order to capture the emulsion properties, different frequencies (from 1 to 100 rad/sec at a 10% constant shear rate and temperatures (from −45°C to 75°C with 15°C increments were applied. Then, a master curve for shear modulus was plotted for each emulsion. The transition of the HFE90 emulsion from viscous to elastic behavior occurs at lower temperatures, compared to the other materials. This emulsion is known for performing in a wider temperature range as shown in the results. The trackless emulsion presents an elastic behavior at intermediate temperatures. This product is known as having very fast setting and high resistance to shear stresses. The trackless emulsion presents the highest viscous and elastic modulus, followed by the PG 64-22 binder, SS1HP, and HFE90 emulsion. Shear strength test results show a behavior between trackless emulsion and SS1HP similar to the frequency sweep test results performed by DSR.

  9. A HUMAN FACTORS META MODEL FOR U.S. NUCLEAR POWER PLANT CONTROL ROOM MODERNIZATION

    Energy Technology Data Exchange (ETDEWEB)

    Joe, Jeffrey C.

    2017-03-01

    Over the last several years, the United States (U.S.) Department of Energy (DOE) has sponsored human factors research and development (R&D) and human factors engineering (HFE) activities through its Light Water Reactor Sustainability (LWRS) program to modernize the main control rooms (MCR) of commercial nuclear power plants (NPP). Idaho National Laboratory (INL), in partnership with numerous commercial nuclear utilities, has conducted some of this R&D to enable the life extension of NPPs (i.e., provide the technical basis for the long-term reliability, productivity, safety, and security of U.S. NPPs). From these activities performed to date, a human factors meta model for U.S. NPP control room modernization can now be formulated. This paper discusses this emergent HFE meta model for NPP control room modernization, with the goal of providing an integrated high level roadmap and guidance on how to perform human factors R&D and HFE for those in the U.S. nuclear industry that are engaging in the process of upgrading their MCRs.

  10. Predictive models of safety based on audit findings: Part 2: Measurement of model validity.

    Science.gov (United States)

    Hsiao, Yu-Lin; Drury, Colin; Wu, Changxu; Paquet, Victor

    2013-07-01

    Part 1 of this study sequence developed a human factors/ergonomics (HF/E) based classification system (termed HFACS-MA) for safety audit findings and proved its measurement reliability. In Part 2, we used the human error categories of HFACS-MA as predictors of future safety performance. Audit records and monthly safety incident reports from two airlines submitted to their regulatory authority were available for analysis, covering over 6.5 years. Two participants derived consensus results of HF/E errors from the audit reports using HFACS-MA. We adopted Neural Network and Poisson regression methods to establish nonlinear and linear prediction models respectively. These models were tested for the validity of prediction of the safety data, and only Neural Network method resulted in substantially significant predictive ability for each airline. Alternative predictions from counting of audit findings and from time sequence of safety data produced some significant results, but of much smaller magnitude than HFACS-MA. The use of HF/E analysis of audit findings provided proactive predictors of future safety performance in the aviation maintenance field. Copyright © 2013 Elsevier Ltd and The Ergonomics Society. All rights reserved.

  11. Human factors in general practice - early thoughts on the educational focus for specialty training and beyond.

    Science.gov (United States)

    McKay, John; Pickup, Laura; Atkinson, Sarah; McNab, Duncan; Bowie, Paul

    2016-05-01

    In the third article in the series, we describe the outputs from a series of roundtable discussions by Human Factors experts and General Practice (GP) Educational Supervisors tasked with examining the GP (family medicine) training and work environments through the lens of the systems and designed-centred discipline of Human Factors and Ergonomics (HFE). A prominent issue agreed upon proposes that the GP setting should be viewed as a complex sociotechnical system from a care service and specialty training perspective. Additionally, while the existing GP specialty training curriculum in the United Kingdom (UK) touches on some important HFE concepts, we argue that there are also significant educational gaps that could be addressed (e.g. physical workplace design, work organisation, the design of procedures, decision-making and human reliability) to increase knowledge and skills that are key to understanding workplace complexity and interactions, and supporting everyday efforts to improve the performance and wellbeing of people and organisations. Altogether we propose and illustrate how future HFE content could be enhanced, contexualised and integrated within existing training arrangements, which also serves as a tentative guide in this area for continuing professional development for the wider GP and primary care teams.

  12. A haplotype and linkage disequilibrium analysis of the hereditary hemochromatosis gene region.

    Science.gov (United States)

    Thomas, W; Fullan, A; Loeb, D B; McClelland, E E; Bacon, B R; Wolff, R K

    1998-05-01

    Hereditary hemochromatosis is a recessive disease of iron metabolism widely distributed among people of European descent. Most patients have inherited the causative mutation from a single ancestor. In the course of cloning the hemochromatosis gene, genotypes were generated for these samples at 43 microsatellite repeat markers that span the 6.5-Mb hemochromatosis gene region. The data used to reconstruct the ancestral haplotype across the hemochromatosis gene region are presented in this paper. Portions of the ancestral haplotype were present on 85% of patient chromosomes in this sample and ranged in size from approximately 500 kb to greater than 6.5 Mb. Only one marker, D6S2239, was identical by descent on all of the patient chromosomes containing the ancestral mutation. In contrast, only 3 of the 128 control chromosomes, or 2.3%, carried the ancestral mutation and the surrounding ancestral haplotype. To test new methods for gene finding using linkage disequilibrium we analyzed the genotypic data with a multilocus maximum likelihood method (DISMULT) and a single point method (DISLAMB), both written to analyze data generated from multi-allelic markers. The maximum value from DISLAMB analysis occurred at marker D6S2239, which is less than 20 kb from the hemochromatosis gene HFE, consistent with the haplotype analysis. The peak of the multi-point analysis was 700 kb from HFE, possibly due to the nonuniform recombination rates within this large region. The recombination rate appears to be lower than expected centromeric of the HFE gene.

  13. Vibrational properties of organic donor-acceptor molecular crystals: Anthracene-pyromellitic-dianhydride (PMDA) as a case study

    KAUST Repository

    Fonari, A.

    2015-12-10

    We establish a reliable quantum-mechanical approach to evaluate the vibrational properties of donor-acceptor molecular crystals. The anthracene-PMDA (PMDA = pyromellitic dianhydride) crystal, where anthracene acts as the electron donor and PMDA as the electron acceptor, is taken as a representative system for which experimental non-resonance Raman spectra are also reported. We first investigate the impact that the amount of nonlocal Hartree-Fock exchange (HFE) included in a hybrid density functional has on the geometry, normal vibrational modes, electronic coupling, and electron-vibrational (phonon) couplings. The comparison between experimental and theoreticalRaman spectra indicates that the results based on the αPBE functional with 25%-35% HFE are in better agreement with the experimental results compared to those obtained with the pure PBE functional. Then, taking αPBE with 25% HFE, we assign the vibrational modes and examine their contributions to the relaxation energy related to the nonlocal electron-vibration interactions. The results show that the largest contribution (about 90%) is due to electron interactions with low-frequency vibrational modes. The relaxation energy in anthracene-PMDA is found to be about five times smaller than the electronic coupling.

  14. Improving Safety through Human Factors Engineering.

    Science.gov (United States)

    Siewert, Bettina; Hochman, Mary G

    2015-10-01

    Human factors engineering (HFE) focuses on the design and analysis of interactive systems that involve people, technical equipment, and work environment. HFE is informed by knowledge of human characteristics. It complements existing patient safety efforts by specifically taking into consideration that, as humans, frontline staff will inevitably make mistakes. Therefore, the systems with which they interact should be designed for the anticipation and mitigation of human errors. The goal of HFE is to optimize the interaction of humans with their work environment and technical equipment to maximize safety and efficiency. Special safeguards include usability testing, standardization of processes, and use of checklists and forcing functions. However, the effectiveness of the safety program and resiliency of the organization depend on timely reporting of all safety events independent of patient harm, including perceived potential risks, bad outcomes that occur even when proper protocols have been followed, and episodes of "improvisation" when formal guidelines are found not to exist. Therefore, an institution must adopt a robust culture of safety, where the focus is shifted from blaming individuals for errors to preventing future errors, and where barriers to speaking up-including barriers introduced by steep authority gradients-are minimized. This requires creation of formal guidelines to address safety concerns, establishment of unified teams with open communication and shared responsibility for patient safety, and education of managers and senior physicians to perceive the reporting of safety concerns as a benefit rather than a threat. © RSNA, 2015.

  15. UPDATING THE NRC GUIDANCE FOR HUMAN FACTORS ENGINEERING REVIEWS.

    Energy Technology Data Exchange (ETDEWEB)

    O HARA,J.M.; BROWN,W.S.; HIGGINS,J.C.; PERSENSKY,J.J.; LEWIS,P.M.; BONGARRA,J.

    2002-09-15

    The U.S. Nuclear Regulatory Commission (NRC) reviews the human factors engineering (HFE) aspects of nuclear plants. NUREG-0800 (Standard Review Plan), Chapter 18, ''Human Factors Engineering,'' is the principal NRC staff guidance document. Two main documents provide the review criteria to support the evaluations. The HFE Program Review Model (NUREG-0711) addresses the design process from planning to verification and validation to design implementation. The Human-System Interface Design Review Guidelines (NUREG-0700) provides the guidelines for the review of the HFE aspects of human-system interface technology, such as alarms, information systems, controls, and control room design. Since these documents were published in 1994 and 1996 respectively, they have been used by NRC staff, contractors, nuclear industry organizations, as well as by numerous organizations outside the nuclear industry. Using feedback from users and NRC research conducted in recent years, both documents have been revised and updated. This was done to ensure that they remain state-of-the-art evaluation tools for changing nuclear industry issues and emerging technologies. This paper describes the methodology used to revise and update the documents and summarizes the changes made to each and their current contents. Index Terms for this report are: Control system human factors, Ergonomics, Human factors, Nuclear power generation safety.

  16. Electrical activity of external oblique and multifidus muscles during the hip flexion-extension exercise performed in the Cadillac with different adjustments of springs and individual positions.

    Science.gov (United States)

    Loss, Jefferson F; Melo, Monica O; Rosa, Cristina H; Santos, Artur B; La Torre, Marcelo; Silva, Yumie O

    2010-01-01

    Despite of the widepread use of Pilates in Physical Therapy, there are few studies that have assessed the muscle electrical activation during Pilates exercises. Verify the influence of different spring adjustments and individual positions on the electrical activation of multifidus (MU) and oblique external (OE) muscles during hip flexion-extension (HFE) exercise on the Cadillac. Eight women practicing Pilates exercises for at least six months performed 10 repetitions of HFE in the following situations: Lower Spring, spring fixed at 30 cm in relation to level which the individuals were positioned. Higher Spring, spring fixed at 90 cm in relation to level which the individuals were positioned. Near Position, distance of 10 cm from the fixed spring. Distant Position, distance of 30 cm from the fixed spring. Kinematic and eletromyographic data (EMG) were collected simultaneously and the MU and OE muscles were monitored. Each movement of HFE was splitted in two phases (extension and flexion). The EMG signal was calculated and normalized using the maximal voluntary contraction (MVC). The Wilcoxon test was used to investigate differences between the situations (p MVC, and the highest muscle activation in the lower spring and in the near position. OE muscles presented muscle activation values ranging from 20 to 45% MVC, and the highest values in the higher spring and in the distant position. MU and OE muscles presented a distinct electrical activation during different available spring adjustments and individual positions.

  17. Human-system interface design review guideline -- Review software and user`s guide: Final report. Revision 1, Volume 3

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-06-01

    NUREG-0700, Revision 1, provides human factors engineering (HFE) guidance to the US Nuclear Regulatory Commission staff for its: (1) review of the human system interface (HSI) design submittals prepared by licensees or applications for a license or design certification of commercial nuclear power plants, and (2) performance of HSI reviews that could be undertaken as part of an inspection or other type of regulatory review involving HSI design or incidents involving human performance. The guidance consists of a review process and HFE guidelines. The document describes those aspects of the HSI design review process that are important to the identification and resolution of human engineering discrepancies that could adversely affect plant safety. Guidance is provided that could be used by the staff to review an applicant`s HSI design review process or to guide the development of an HSI design review plan, e.g., as part of an inspection activity. The document also provides detailed HFE guidelines for the assessment of HSI design implementations. NUREG-0700, Revision 1, consists of three stand-alone volumes. Volume 3 contains an interactive software application of the NUREG-0700, Revision 1 guidance and a user`s guide for this software. The software supports reviewers during review preparation, evaluation design using the human factors engineering guidelines, and in report preparation. The user`s guide provides system requirements and installation instructions, detailed explanations of the software`s functions and features, and a tutorial on using the software.

  18. Vibrational properties of organic donor-acceptor molecular crystals: Anthracene-pyromellitic-dianhydride (PMDA) as a case study

    Energy Technology Data Exchange (ETDEWEB)

    Fonari, A.; Corbin, N. S.; Coropceanu, V., E-mail: jean-luc.bredas@kaust.edu.sa, E-mail: coropceanu@gatech.edu [School of Chemistry and Biochemistry and Center for Organic Photonics and Electronics, Georgia Institute of Technology, Atlanta, Georgia 30332-0400 (United States); Vermeulen, D.; McNeil, L. E. [Department of Physics and Astronomy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3255 (United States); Goetz, K. P.; Jurchescu, O. D. [Department of Physics, Wake Forest University, Winston-Salem, North Carolina 27109-7507 (United States); Bredas, J. L., E-mail: jean-luc.bredas@kaust.edu.sa, E-mail: coropceanu@gatech.edu [School of Chemistry and Biochemistry and Center for Organic Photonics and Electronics, Georgia Institute of Technology, Atlanta, Georgia 30332-0400 (United States); Solar and Photovoltaics Engineering Research Center, Division of Physical Science and Engineering, King Abdullah University of Science and Technology, Thuwal 23955-6900 (Saudi Arabia)

    2015-12-14

    We establish a reliable quantum-mechanical approach to evaluate the vibrational properties of donor-acceptor molecular crystals. The anthracene-PMDA (PMDA = pyromellitic dianhydride) crystal, where anthracene acts as the electron donor and PMDA as the electron acceptor, is taken as a representative system for which experimental non-resonance Raman spectra are also reported. We first investigate the impact that the amount of nonlocal Hartree-Fock exchange (HFE) included in a hybrid density functional has on the geometry, normal vibrational modes, electronic coupling, and electron-vibrational (phonon) couplings. The comparison between experimental and theoretical Raman spectra indicates that the results based on the αPBE functional with 25%-35% HFE are in better agreement with the experimental results compared to those obtained with the pure PBE functional. Then, taking αPBE with 25% HFE, we assign the vibrational modes and examine their contributions to the relaxation energy related to the nonlocal electron-vibration interactions. The results show that the largest contribution (about 90%) is due to electron interactions with low-frequency vibrational modes. The relaxation energy in anthracene-PMDA is found to be about five times smaller than the electronic coupling.

  19. Molecular Diagnostic and Pathogenesis of Hereditary Hemochromatosis

    Science.gov (United States)

    Santos, Paulo C. J. L.; Krieger, Jose E.; Pereira, Alexandre C.

    2012-01-01

    Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by enhanced intestinal absorption of dietary iron. Without therapeutic intervention, iron overload leads to multiple organ damage such as liver cirrhosis, cardiomyopathy, diabetes, arthritis, hypogonadism and skin pigmentation. Most HH patients carry HFE mutant genotypes: homozygosity for p.Cys282Tyr or p.Cys282Tyr/p.His63Asp compound heterozygosity. In addition to HFE gene, mutations in the genes that encode hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin (SLC40A1) have been associated with regulation of iron homeostasis and development of HH. The aim of this review was to identify the main gene mutations involved in the pathogenesis of type 1, 2, 3 and 4 HH and their genetic testing indication. HFE testing for the two main mutations (p.Cys282Tyr and p.His63Asp) should be performed in all patients with primary iron overload and unexplained increased transferrin saturation and/or serum ferritin values. The evaluation of the HJV p.Gly320Val mutation must be the molecular test of choice in suspected patients with juvenile hemochromatosis with less than 30 years and cardiac or endocrine manifestations. In conclusion, HH is an example that genetic testing can, in addition to performing the differential diagnostic with secondary iron overload, lead to more adequate and faster treatment. PMID:22408404

  20. Molecular Diagnostic and Pathogenesis of Hereditary Hemochromatosis

    Directory of Open Access Journals (Sweden)

    Paulo C. J. L. Santos

    2012-02-01

    Full Text Available Hereditary hemochromatosis (HH is an autosomal recessive disorder characterized by enhanced intestinal absorption of dietary iron. Without therapeutic intervention, iron overload leads to multiple organ damage such as liver cirrhosis, cardiomyopathy, diabetes, arthritis, hypogonadism and skin pigmentation. Most HH patients carry HFE mutant genotypes: homozygosity for p.Cys282Tyr or p.Cys282Tyr/p.His63Asp compound heterozygosity. In addition to HFE gene, mutations in the genes that encode hemojuvelin (HJV, hepcidin (HAMP, transferrin receptor 2 (TFR2 and ferroportin (SLC40A1 have been associated with regulation of iron homeostasis and development of HH. The aim of this review was to identify the main gene mutations involved in the pathogenesis of type 1, 2, 3 and 4 HH and their genetic testing indication. HFE testing for the two main mutations (p.Cys282Tyr and p.His63Asp should be performed in all patients with primary iron overload and unexplained increased transferrin saturation and/or serum ferritin values. The evaluation of the HJV p.Gly320Val mutation must be the molecular test of choice in suspected patients with juvenile hemochromatosis with less than 30 years and cardiac or endocrine manifestations. In conclusion, HH is an example that genetic testing can, in addition to performing the differential diagnostic with secondary iron overload, lead to more adequate and faster treatment.

  1. Human Factors Engineering Program Review Model (NUREG-0711)Revision 3: Update Methodology and Key Revisions

    Energy Technology Data Exchange (ETDEWEB)

    OHara J. M.; Higgins, J.; Fleger, S.

    2012-07-22

    The U.S. Nuclear Regulatory Commission (NRC) reviews the human factors engineering (HFE) programs of applicants for nuclear power plant construction permits, operating licenses, standard design certifications, and combined operating licenses. The purpose of these safety reviews is to help ensure that personnel performance and reliability are appropriately supported. Detailed design review procedures and guidance for the evaluations is provided in three key documents: the Standard Review Plan (NUREG-0800), the HFE Program Review Model (NUREG-0711), and the Human-System Interface Design Review Guidelines (NUREG-0700). These documents were last revised in 2007, 2004 and 2002, respectively. The NRC is committed to the periodic update and improvement of the guidance to ensure that it remains a state-of-the-art design evaluation tool. To this end, the NRC is updating its guidance to stay current with recent research on human performance, advances in HFE methods and tools, and new technology being employed in plant and control room design. NUREG-0711 is the first document to be addressed. We present the methodology used to update NUREG-0711 and summarize the main changes made. Finally, we discuss the current status of the update program and the future plans.

  2. Human-system interface design review guideline -- Process and guidelines: Final report. Revision 1, Volume 1

    Energy Technology Data Exchange (ETDEWEB)

    None

    1996-06-01

    NUREG-0700, Revision 1, provides human factors engineering (HFE) guidance to the US Nuclear Regulatory Commission staff for its: (1) review of the human system interface (HSI) design submittals prepared by licensees or applications for a license or design certification of commercial nuclear power plants, and (2) performance of HSI reviews that could be undertaken as part of an inspection or other type of regulatory review involving HSI design or incidents involving human performance. The guidance consists of a review process and HFE guidelines. The document describes those aspects of the HSI design review process that are important to the identification and resolution of human engineering discrepancies that could adversely affect plant safety. Guidance is provided that could be used by the staff to review an applicant`s HSI design review process or to guide the development of an HSI design review plan, e.g., as part of an inspection activity. The document also provides detailed HFE guidelines for the assessment of HSI design implementations. NUREG-0700, Revision 1, consists of three stand-alone volumes. Volume 1 consists of two major parts. Part 1 describes those aspects of the review process of the HSI design that are important to identifying and resolving human engineering discrepancies. Part 2 contains detailed guidelines for a human factors engineering review which identify criteria for assessing the implementation of an applicant`s or licensee`s HSI design.

  3. Effect of the Hydrofluoroether Cosolvent Structure in Acetonitrile-Based Solvate Electrolytes on the Li+ Solvation Structure and Li-S Battery Performance.

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Minjeong; Wu, Heng-Liang; Narayanan, Badri; See, Kimberly A.; Assary, Rajeev S.; Zhu, Lingyang; Haasch, Richard T.; Zhang, Shuo; Zhang, Zhengcheng; Curtiss, Larry A.; Gewirth, Andrew A.

    2017-11-15

    We evaluate hydrofluoroether (HFE) cosolvents with varying degrees of fluorination in the acetonitrile-based solvate electrolyte to determine the effect of the HFE structure on the electrochemical performance of the Li-S battery. Solvates or sparingly solvating electrolytes are an interesting electrolyte choice for the Li-S battery due to their low polysulfide solubility. The solvate electrolyte with a stoichiometric ratio of LiTFSI salt in acetonitrile, (MeCN)(2)-LiTFSI, exhibits limited polysulfide solubility due to the high concentration of LiTFSI. We demonstrate that the addition of highly fluorinated HFEs to the solvate yields better capacity retention compared to that of less fluorinated HFE cosolvents. Raman and NMR spectroscopy coupled with ab initio molecular dynamics simulations show that HFEs exhibiting a higher degree of fluorination coordinate to Li+ at the expense of MeCN coordination, resulting in higher free MeCN content in solution. However, the polysulfide solubility remains low, and no crossover of polysulfides from the S cathode to the Li anode is observed.

  4. The demands and benefits of ergonomics in Sri Lankan apparel industry: A case study at MAS holdings.

    Science.gov (United States)

    Abeysekera, John; Illankoon, Prasanna

    2016-10-17

    Apparel exports bring in sizeable foreign income to Sri Lanka. To protect and promote this industry is a paramount need. This can be carried out by applying Human Factors/Ergonomics (HFE) which has proved to control negative effects at work places. This paper reports a case study which describes the demands and benefits of HFE in MAS Holdings which owns a large share of the apparel industry in Sri Lanka. The study consisted of walk through observation survey, a questionnaire survey and ergonomic work place analysis followed by a training programme to selected employees in three companies. Positive responses to questionnaires revealed good ergonomic practices in the work places surveyed. Ergonomically unfit chairs and potential hazards e.g. exposure to noise and hot environment were detected. It is seen that MAS have introduced strategies originated by Toyota Production System viz. 5S, Kaizen, six sigma etc., which are in fact ergonomic methods. A progressive project MAS boast of viz. 'MAS Operating System' (MOS) empowers training and development to employees. MAS Holdings has adequately realized the benefits of applying HFE as evident by the number of awards received. Relevant companies were advised to take appropriate corrective measures to control the potential hazards.

  5. The Human Factors and Ergonomics of P300-Based Brain-Computer Interfaces.

    Science.gov (United States)

    Powers, J Clark; Bieliaieva, Kateryna; Wu, Shuohao; Nam, Chang S

    2015-08-10

    Individuals with severe neuromuscular impairments face many challenges in communication and manipulation of the environment. Brain-computer interfaces (BCIs) show promise in presenting real-world applications that can provide such individuals with the means to interact with the world using only brain waves. Although there has been a growing body of research in recent years, much relates only to technology, and not to technology in use-i.e., real-world assistive technology employed by users. This review examined the literature to highlight studies that implicate the human factors and ergonomics (HFE) of P300-based BCIs. We assessed 21 studies on three topics to speak directly to improving the HFE of these systems: (1) alternative signal evocation methods within the oddball paradigm; (2) environmental interventions to improve user performance and satisfaction within the constraints of current BCI systems; and (3) measures and methods of measuring user acceptance. We found that HFE is central to the performance of P300-based BCI systems, although researchers do not often make explicit this connection. Incorporation of measures of user acceptance and rigorous usability evaluations, increased engagement of disabled users as test participants, and greater realism in testing will help progress the advancement of P300-based BCI systems in assistive applications.

  6. The Human Factors and Ergonomics of P300-Based Brain-Computer Interfaces

    Directory of Open Access Journals (Sweden)

    J. Clark Powers

    2015-08-01

    Full Text Available Individuals with severe neuromuscular impairments face many challenges in communication and manipulation of the environment. Brain-computer interfaces (BCIs show promise in presenting real-world applications that can provide such individuals with the means to interact with the world using only brain waves. Although there has been a growing body of research in recent years, much relates only to technology, and not to technology in use—i.e., real-world assistive technology employed by users. This review examined the literature to highlight studies that implicate the human factors and ergonomics (HFE of P300-based BCIs. We assessed 21 studies on three topics to speak directly to improving the HFE of these systems: (1 alternative signal evocation methods within the oddball paradigm; (2 environmental interventions to improve user performance and satisfaction within the constraints of current BCI systems; and (3 measures and methods of measuring user acceptance. We found that HFE is central to the performance of P300-based BCI systems, although researchers do not often make explicit this connection. Incorporation of measures of user acceptance and rigorous usability evaluations, increased engagement of disabled users as test participants, and greater realism in testing will help progress the advancement of P300-based BCI systems in assistive applications.

  7. Dietary iron concentration influences serum concentrations of manganese in rats consuming organic or inorganic sources of manganese.

    Science.gov (United States)

    Zhang, Huaiyong; Gilbert, Elizabeth R; Pan, Shuqin; Zhang, Keying; Ding, Xuemei; Wang, Jianping; Zeng, Qiufeng; Bai, Shiping

    2016-02-28

    To determine the effects of dietary Fe concentration on Mn bioavailability in rats fed inorganic or organic Mn sources, fifty-four 22-d-old male rats were randomly assigned and fed a basal diet (2·63 mg Fe/kg) supplemented with 0 (low Fe (L-Fe)), 35 (adequate Fe (A-Fe)) or 175 (high Fe (H-Fe)) mg Fe/kg with 10 mg Mn/kg from MnSO4 or Mn-lysine chelate (MnLys). Tissues were harvested after 21 d of feeding. Serum Mn was greater (P<0·05) in MnLys rats than in MnSO4 rats, and in L-Fe rats than in A-Fe or H-Fe rats. Duodenal divalent metal transporter-1 (DMT1) mRNA was lower (P<0·05) in H-Fe rats than in A-Fe rats for the MnSO4 treatment; however, no significant difference was observed between them for MnLys. Liver DMT1 mRNA abundance was greater (P<0·05) in MnSO4 than in the MnLys group for H-Fe rats. The DMT1 protein in duodenum and liver and ferroportin 1 (FPN1) protein in liver was greater (P<0·05) in the MnSO4 group than in the MnLys group, and in L-Fe rats than in H-Fe rats. Duodenal FPN1 protein was greater (P<0·05) in L-Fe rats than in A-Fe rats for the MnLys treatment, but it was not different between them for the MnSO4 treatment. Results suggest that MnLys increased serum Mn concentration as compared with MnSO4 in rats irrespective of dietary Fe concentration, which was not because of the difference in DMT1 and FPN1 expression in the intestine and liver.

  8. Browse Title Index

    African Journals Online (AJOL)

    RK Alinyoh-Fotter. Vol 4, No 1 (2000), Mesure automatique de la longueur de racines sur des images numérisées, Abstract. S. M. Farssi, G. Sissoko, D. Annerose. Vol 13, No 2 (2011): Series D, Metabolisme du fer chez les drepanocytaires homozygotes au centre hospitalier universitaire campus de Lome (Togo), Abstract.

  9. Common SNP rs6564851 in the BCO1 Gene Affects the Circulating Levels of β-Carotene and the Daily Intake of Carotenoids in Healthy Japanese Women.

    Directory of Open Access Journals (Sweden)

    Suemi Yabuta

    Full Text Available The circulating levels of β-carotene are modulated not only by sex, but also by autosomal gene variations and fruit intake. The aim of this study was to investigate the interactions between β-carotene metabolism-related gene single nucleotide polymorphisms (SNPs; genetic factors and nutrient intake (environmental factors relating to their effects on circulating β-carotene. The serum concentrations of β-carotene and the habitual food intake of 92 healthy Japanese adults were examined. All subjects were genotyped for three common SNPs: rs6564851 in the β-carotene 15,15'-oxygenase 1 (BCO1 gene, rs2278986 in the scavenger receptor class B member 1 (SCARB1 gene and rs362090 in the intestine-specific homeobox (ISX gene. Univariate analysis revealed that the circulating β-carotene levels were significantly higher in rs6564851 GG homozygotes (p = 0.003. Additionally, the daily intake of β-cryptoxanthin was positively associated with the circulating β-carotene levels in female GG homozygotes of rs6564851 (p = 0.023, and the daily intake of α- and β-carotenes, and β-cryptoxanthin was significantly lower in female rs6564851 T allele carries than in female GG homozygotes (p = 0.009, 0.008, 0.009, respectively. The present study apparently indicates that higher circulating β-carotene levels in female rs6564851 GG homozygotes depend on carotenoid intake.

  10. Impact of cystic fibrosis disease on archaea and bacteria composition of gut microbiota.

    Science.gov (United States)

    Miragoli, Francesco; Federici, Sara; Ferrari, Susanna; Minuti, Andrea; Rebecchi, Annalisa; Bruzzese, Eugenia; Buccigrossi, Vittoria; Guarino, Alfredo; Callegari, Maria Luisa

    2017-02-01

    Cystic fibrosis is often associated with intestinal inflammation due to several factors, including altered gut microbiota composition. In this study, we analyzed the fecal microbiota among patients with cystic fibrosis of 10-22 years of age, and compared the findings with age-matched healthy subjects. The participating patients included 14 homozygotes and 14 heterozygotes with the delF508 mutation, and 2 heterozygotes presenting non-delF508 mutations. We used PCR-DGGE and qPCR to analyze the presence of bacteria, archaea and sulfate-reducing bacteria. Overall, our findings confirmed disruption of the cystic fibrosis gut microbiota. Principal component analysis of the qPCR data revealed no differences between homozygotes and heterozygotes, while both groups were distinct from healthy subjects who showed higher biodiversity. Archaea were under the detection limit in all homozygotes subjects, whereas methanogens were detected in 62% of both cystic fibrosis heterozygotes and healthy subjects. Our qPCR results revealed a low frequency of sulfate-reducing bacteria in the homozygote (13%) and heterozygote (13%) patients with cystic fibrosis compared with healthy subjects (87.5%). This is a pioneer study showing that patients with cystic fibrosis exhibit significant reduction of H 2 -consuming microorganisms, which could increase hydrogen accumulation in the colon and the expulsion of this gas through non-microbial routes. © FEMS 2016.

  11. Metabolic rate changes proportionally to circadian frequency in tau mutant Syrian hamsters

    NARCIS (Netherlands)

    Oklejewicz, M; Hut, RA; Daan, S; Loudon, ASI; Stirland, AJ; Loudon, Andrew S.I.; Stirland, Anne J.

    1997-01-01

    The tau mutation in Syrian hamsters (Mesocricetus auratus) is phenotypically expressed in a period of the circadian rhythm of about 20 h in homozygotes (SS) and about 22 h in heterozygotes (S+). The authors investigate whether this well-defined model for variation in circadian period exhibits

  12. Interleukin 6 -174(G>C) gene polymorphism is related to celiac disease and autoimmune thyroiditis coincidence in diabetes type 1 children.

    Science.gov (United States)

    Myśliwiec, Małgorzata; Myśliwska, Jolanta; Zorena, Katarzyna; Balcerska, Anna; Malinowska, Ewa; Wiśniewski, Piotr

    2008-10-01

    The aim of the study was to assess the relationship between IL-6 gene polymorphism at -174(G>C) and the coincidence of celiac and autoimmune thyroid diseases with type 1 diabetes mellitus (DM1) in children. 200 children with DM1 aged 13.23+/-3.54 years and 172 healthy controls were analyzed. The IL-6 gene -174(G>C) polymorphism at the promoter region of the gene was analyzed by the PCR-RFLP method. The genotype distribution was significantly different in diabetic children as compared to the healthy controls (p=0.01). In DM1 patients GC heterozygotes were the most common (52.5%), while CC homozygotes accuted for 29% and GG homozygotes only for 18% of cases. In contrast, GG homozygotes were much more frequent among healthy children (31%). Besides, the GG homozygotes were significantly more frequent among diabetic children with celiac disease (p=0.04) in relation to those without autoimmune complications. In children with autoimmune thyroiditis, the distribution of the IL-6 genotypes was similar to that seen in diabetic patients without autoimmune complications (p=0.24). The results of our study suggest that the diabetic children, who have IL-6 gene -174GG genotype may have an increased risk for celiac disease development.

  13. Efflux and atherosclerosis - The clinical and biochemical impact of variations in the ABCA1 gene

    NARCIS (Netherlands)

    Singaraja, Roshni R.; Brunham, Liam R.; Visscher, Henk; Kastelein, John J. P.; Hayden, Michael R.

    2003-01-01

    Approximately 50 mutations and many single nucleotide polymorphisms have been described in the ABCA1 gene, with mutations leading to Tangier disease and familial hypoalphalipoproteinemia. Homozygotes and heterozygotes for mutations in ABCA1 display a wide range of phenotypes. Identification of ABCA1

  14. Docosahexaenoic acid (DHA) supplementation in pregnancy differentially modulates arachidonic acid and DHA status across FADS genotypes in pregnancy1–3

    Science.gov (United States)

    Scholtz, SA; Kerling, EH; Shaddy, DJ; Li, S; Thodosoff, JM; Colombo, J; Carlson, SE

    2014-01-01

    Some FADS alleles are associated with lower DHA and ARA status assessed by the relative amount of arachidonic acid (ARA) and docosahexaenoic acid (DHA) in plasma and red blood cell (RBC) phospholipids (PL). We determined two FADS single nucleotide polymorphisms (SNPs) in a cohort of pregnant women and examined the relationship of FADS1rs174533 and FADS2rs174575 to DHA and ARA status before and after supplementation with 600 mg per day of DHA. The 205 pregnant women studied were randomly assigned to placebo (mixed soy and corn oil) (n= 96) or 600 mg algal DHA (n=109) in 3 capsules per day for the last two trimesters of pregnancy. Women homozygous for the minor allele of FADS1rs174533 (but not FADS2rs174575) had lower DHA and ARA status at baseline. At delivery, minor allele homozygotes of FADS1rs174533 in the placebo group had lower RBC-DHA compared to major-allele carriers (P = 0.031), while in the DHA-supplemented group, all genotypes had higher DHA status compared to baseline (P = 0.001) and status did not differ by genotype (P = 0.941). Surprisingly, DHA but not the placebo decreased ARA status of minor allele homozygotes of both FADS SNPs but not major allele homozygotes at delivery. Any physiological effects of changing the DHA to ARA ratio by increasing DHA intake appears to be greater in minor allele homozygotes of some FADS SNPs. PMID:25500337

  15. Docosahexaenoic acid (DHA) supplementation in pregnancy differentially modulates arachidonic acid and DHA status across FADS genotypes in pregnancy.

    Science.gov (United States)

    Scholtz, S A; Kerling, E H; Shaddy, D J; Li, S; Thodosoff, J M; Colombo, J; Carlson, S E

    2015-03-01

    Some FADS alleles are associated with lower DHA and ARA status assessed by the relative amount of arachidonic acid (ARA) and docosahexaenoic acid (DHA) in plasma and red blood cell (RBC) phospholipids (PL). We determined two FADS single nucleotide polymorphisms (SNPs) in a cohort of pregnant women and examined the relationship of FADS1rs174533 and FADS2rs174575 to DHA and ARA status before and after supplementation with 600mg per day of DHA. The 205 pregnant women studied were randomly assigned to placebo (mixed soy and corn oil) (n=96) or 600mg algal DHA (n=109) in 3 capsules per day for the last two trimesters of pregnancy. Women homozygous for the minor allele of FADS1rs174533 (but not FADS2rs174575) had lower DHA and ARA status at baseline. At delivery, minor allele homozygotes of FADS1rs174533 in the placebo group had lower RBC-DHA compared to major-allele carriers (P=0.031), while in the DHA-supplemented group, all genotypes had higher DHA status compared to baseline (P=0.001) and status did not differ by genotype (P=0.941). Surprisingly, DHA but not the placebo decreased ARA status of minor allele homozygotes of both FADS SNPs but not major allele homozygotes at delivery. Any physiological effects of changing the DHA to ARA ratio by increasing DHA intake appears to be greater in minor allele homozygotes of some FADS SNPs. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Association of tumor necrosis factor genetic polymorphism with chronic atrophic gastritis and gastric adenocarcinoma in Chinese Han population.

    NARCIS (Netherlands)

    Fei, BY; Xia, B; Deng, CS; Xia, XQ; Xie, M.; Crusius, J.B.A.; Pena, A.S.

    2004-01-01

    0.05). However, TNF-beta Ncol*1/2 and d2/d6 genotypes did not relate to age, gender, grade of differentiation and clinicopathologic stage in patients with gastric adenocarcinoma. The frequency of TNFa6b5c1 haplotype homozygote was significantly lower in patients with gastric adenocarcinoma than in

  17. HLA-DPB1 typing with polymerase chain reaction and restriction fragment length polymorphism technique in Danes

    DEFF Research Database (Denmark)

    Hviid, T V; Madsen, H O; Morling, N

    1992-01-01

    endonucleases: RsaI, FokI, ApaI, SacI, BstUI, EcoNI, and DdeI, and the DNA fragments were separated by electrophoresis in agarose gels. Altogether, 71 individuals were investigated and 16 different HLA-DPB1 types were observed in 26 different heterozygotic combinations, as well as five possible homozygotes...

  18. Intrapopulation and Interpopulation Genetic Variation ofQuercus in Denmark in Denmark

    DEFF Research Database (Denmark)

    Siegismund, Hans Redlef; Jensen, Jan Svejgaard

    2001-01-01

    . The genotypic proportions at two (Pgm and Mnr) . and 0.26 for the hybrid stands. The genotypic proportions at two (and ) of the six loci showed many signi. cant deviations from Hardy-Weinberg expectations, always with an excess of homozygotes, whereas the remaining four loci accorded to Hardy-Weinberg...

  19. A combined DNA-microsatellite and isozyme analysis of the population structure of the harbour porpoise in Danish waters and west Greenland

    DEFF Research Database (Denmark)

    Andersen, L W; Holm, L E; Siegismund, Hans Redlef

    1997-01-01

    deviations from the expected Hardy-Weinberg distribution were only observed in the total sample and at a single locus in the North Sea-summer sample and at two loci in the West Greenland sample. Whenever this occurred a surplus of homozygotes was observed, suggesting a Wahlund effect, a null allele...

  20. Searching for a stock structure in Sardina pilchardus from the Adriatic and Ionian seas using a microsatellite DNA-based approach

    DEFF Research Database (Denmark)

    Ruggeri, Paolo; Splendiani, Andrea; Bonanomi, Sara

    2013-01-01

    of homozygote individuals higher than expected at Hardy-Weinberg equilibrium. The inter-population differentiation level estimated by AMOVA, qST and rRST and Bayesian descriptors detected no signs of population differentiation between the samples analysed. These results are consistent with previous studies...

  1. Detecting low frequent loss-of-function alleles in genome wide association studies with red hair color as example

    NARCIS (Netherlands)

    F. Liu (Fan); M.V. Struchalin (Maksim); K. van Duijn (Kate); A. Hofman (Albert); A.G. Uitterlinden (André); Y.S. Aulchenko (Yurii); M.H. Kayser (Manfred)

    2011-01-01

    textabstractMultiple loss-of-function (LOF) alleles at the same gene may influence a phenotype not only in the homozygote state when alleles are considered individually, but also in the compound heterozygote (CH) state. Such LOF alleles typically have low frequencies and moderate to large effects.

  2. numb one

    African Journals Online (AJOL)

    PROPRIETAIRE

    molecular genetic disorder and is quite frequent around the world, especially in Sub-Saharian Africa, North,. Central and South America and in the Near-East. KEY-WORDS : Sickle cell anemia ... les homozygotes, par contre pour le biochimiste, elle est dominante, car l'hémoglobine S est présente chez les hétérozygotes ...

  3. The Integrative Studies of Genetic and Environmental Factors in Systemic Sclerosis

    Science.gov (United States)

    2010-05-01

    Jin , Christopher Amos. Gene and Pathway-Based Analysis - Second Wave of Genome-wide Association Studies. European Journal of Human Genetics. 2009...had lower expression in homozygote than that in heterozygote. It is somewhat similar to CTGF behavior in mink lung epithelial Mv1Lu cells that the

  4. numb one

    African Journals Online (AJOL)

    PROPRIETAIRE

    dence certaines anomalies cardiaques parfaite- ment inapparentes en radiologie standard. ... RÉSUMÉ. La drépanocytose homozygote SS entraîne chez l'enfant le développement d'une anémie chronique qui s'accompagne d'anomalie .... V - CONCLUSION. La prise en charge efficace des patients drépanocytaires passe ...

  5. Endothelial-derived tissue factor pathway inhibitor regulates arterial thrombosis but is not required for development or hemostasis.

    NARCIS (Netherlands)

    White, T.A.; Johnson, T.; Zarzhevsky, N.; Tom, C.; Delacroix, S.; Holroyd, E.W.; Maroney, S.A.; Singh, R.; Pan, S.; Fay, W.P.; Deursen, J.M.A. van; Mast, A.E.; Sandhu, G.S.; Simari, R.D.

    2010-01-01

    The antithrombotic surface of endothelium is regulated in a coordinated manner. Tissue factor pathway inhibitor (TFPI) localized at the endothelial cell surface regulates the production of FXa by inhibiting the TF/VIIa complex. Systemic homozygotic deletion of the first Kunitz (K1) domain of TFPI

  6. Mapping of the multifoliate pinna (mfp) leaf-blade morphology ...

    Indian Academy of Sciences (India)

    The multifoliate pinna (mfp) mutation alters the leaf-blade architecture of pea, such that simple tendril pinnae of distal domain are replaced by compound pinna blades of tendrilled leaflets in mfp homozygotes. The MFP locus was mapped with reference to DNA markers using F2 and F2:5 RIL as mapping populations.

  7. Differential bitterness in capsaicin, piperine, and ethanol associates with polymorphisms in multiple bitter taste receptor genes

    Science.gov (United States)

    Nolden, Alissa A.; McGeary, John E.; Hayes, John E.

    2016-01-01

    To date, the majority of research exploring associations with genetic variability in bitter taste receptors has understandably focused on compounds and foods that are predominantly or solely perceived as bitter. However, other chemosensory stimuli are also known to elicit bitterness as a secondary sensation. Here we investigated whether TAS2R variation explains individual differences in bitterness elicited by chemesthetic stimuli, including capsaicin, piperine and ethanol. We confirmed that capsaicin, piperine and ethanol elicit bitterness in addition to burning/stinging sensations. Variability in perceived bitterness of capsaicin and ethanol were significantly associated with TAS2R38 and TAS2R3/4/5 diplotypes. For TAS2R38, PAV homozygotes perceived greater bitterness from capsaicin and ethanol presented on circumvallate papillae, compared to heterozygotes and AVI homozygotes. For TAS2R3/4/5, CCCAGT homozygotes rated the greatest bitterness, compared to heterozygotes and TTGGAG homozygotes, for both ethanol and capsaicin when presented on circumvallate papillae. Additional work is needed to determine how these and other chemesthetic stimuli differ in bitterness perception across concentrations and presentation methods. Furthermore, it would be beneficial to determine which TAS2R receptors are activated in vitro by chemesthetic compounds. PMID:26785164

  8. Profil biochimique et hématologique des patients drépanocytaires ...

    African Journals Online (AJOL)

    Profil biochimique et hématologique des patients drépanocytaires homozygotes en phase stationnaire au centre National de Transfusion Sanguine de Dakar. Dominique Doupa, Moustapha Djite, Pape Madieye Gueye, Moussa Seck, Blaise Felix Faye, Sidy Mohamed Seck, Fatou Diallo, Arame Ndiaye, Abdourahmane ...

  9. Development of a Transgenic Mouse with R124H Human TGFBI Mutation Associated with Granular Corneal Dystrophy Type 2.

    Science.gov (United States)

    Yamazoe, Katsuya; Yoshida, Satoru; Yasuda, Miyuki; Hatou, Shin; Inagaki, Emi; Ogawa, Yoko; Tsubota, Kazuo; Shimmura, Shigeto

    2015-01-01

    To investigate the phenotype and predisposing factors of a granular corneal dystrophy type 2 transgenic mouse model. Human TGFBI cDNA with R124H mutation was used to make a transgenic mouse expressing human protein (TGFBIR124H mouse). Reverse transcription PCR (RT-PCR) was performed to analyze TGFBIR124H expression. A total of 226 mice including 23 homozygotes, 106 heterozygotes and 97 wild-type mice were examined for phenotype. Affected mice were also examined by histology, immunohistochemistry and electron microcopy. RT-PCR confirmed the expression of TGFBIR124H in transgenic mice. Corneal opacity defined as granular and lattice deposits was observed in 45.0% of homozygotes, 19.4% of heterozygotes. The incidence of corneal opacity was significantly higher in homozygotes than in heterozygotes (p = 0.02). Histology of affected mice was similar to histology of human disease. Lesions were Congo red and Masson Trichrome positive, and were observed as a deposit of amorphous material by electron microscopy. Subepithelial stroma was also stained with thioflavin T and LC3, a marker of autophagy activation. The incidence of corneal opacity was higher in aged mice in each group. Homozygotes were not necessarily more severe than heterozygotes, which deffers from human cases. We established a granular corneal dystrophy type 2 mouse model caused by R124H mutation of human TGFBI. Although the phenotype of this mouse model is not equivalent to that in humans, further studies using this model may help elucidate the pathophysiology of this disease.

  10. Epigenetics of dominance for enzyme activity

    Indian Academy of Sciences (India)

    We have isolated and purified two parental homodimers and a unique heterodimer of acid phosphatase [coded by Acph-11.05() and Acph-10.95()] from isogenic homozygotes and heterozygotes of Drosophila malerkotliana. and produce qualitatively different allozymes and the two alleles are expressed equally ...

  11. Genetic variation in Rhabdomys pumilio (Sparrman 1784) - an ...

    African Journals Online (AJOL)

    genetic differentiation (F st) of 0.459 and the low mean value for the effective number of migrants (Nm) of 0.179 indicated low levels of gene flow between the different localities of R. pummo. The negative, near zero F,S value of -0.01 indicated a balance between heterozygotes and homozygotes. Rogers (1972) genetic ...

  12. RFLP's in de plantenveredeling: het gebruik van RFLP's (Restrictie Fragment Lengte Polymorfismen) voor de constructie van genenkaarten

    NARCIS (Netherlands)

    Wagenvoort, M.; Nijs, den A.P.M.

    1988-01-01

    Recente ontwikkelingen in de moleculaire biologie hebben het mogelijk gemaakt de variatie in het DNA op moleculair niveau zichtbaar te maken, RFLP's. Met behulp van RFLP's zijn in korte tijd zeer gedetailleerde moleculaire kaarten geconstrueerd, vooral in zelfbevruchtende (homozygote) gewassen zoals

  13. D allele of the angiotensin-converting enzyme gene is a risk factor for secondary cardiac events after myocardial infarction.

    Science.gov (United States)

    Yoshida, M; Iwai, N; Ohmichi, N; Izumi, M; Nakamura, Y; Kinoshita, M

    1999-07-31

    We retrospectively examined the relationship between the genotype of the angiotensin-converting enzyme (ACE) gene or the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, and the secondary cardiac events after myocardial infarction. The study population consisted of 176 patients (ACE genotype: deletion homozygote (DD)=20, insertion/deletion heterozygote (ID)=91, insertion homozygote (II)=65; MTHFR genotype: valine homozygote (VV)=37, valine/alanine heterozygote (VA)=71, alanine homozygote (AA)=68) with acute or recent myocardial infarction at the start of the follow-up. We defined the occurrence of cardiac death, recurrent myocardial infarction, or admission due to unstable angina as the endpoint. Cardiac events related coronary intervention were excluded from the endpoints. During the follow-up (1903+/-1414 days), four patients had cardiac death, 12 patients had recurrent myocardial infarction and 13 patients had admission due to unstable angina. A Cox analysis revealed that the endpoints were significantly associated with diabetes mellitus (RR=4.423), total cholesterol level (RR=1.025) and the genotype of the ACE gene (RR=4.490). The ID or DD genotype of the ACE gene was associated with higher occurrence of the endopoints. The MTFHR gene was not associated with the endopoint. The present results suggest that the presence of the deletion allele of the ACE gene may be a risk factor for secondary cardiac events after myocardial infarction.

  14. Development of sequence-tagged site markers linked to the pillar growth type in peach (Prunus persica)

    Science.gov (United States)

    In peach [Prunus persica (L.) Batsch], trees showing columnar [also termed pillar or broomy] growth habit are of interest for high density production systems. While the selection of the columnar homozygote (pillar) phenotype (brbr) can be carried out prior to field planting, the intermediate hetero...

  15. When a Fly Has to Fly to Reproduce: Selection against Conditional Recessive Lethals in "Drosophila"

    Science.gov (United States)

    Plunkett, Andrea D.; Yampolsky, Lev Y.

    2010-01-01

    We propose an experimental model suitable for demonstrating allele frequency change in Drosophila melanogaster populations caused by selection against an easily scorable conditional lethal, namely recessive flightless alleles such as apterous and vestigial. Homozygotes for these alleles are excluded from reproduction because the food source used…

  16. Translational Research for Muscular Dystrophy

    Science.gov (United States)

    2012-05-01

    and interstitial fibrosis, as well as abnormal echocardiography results. By 15 weeks of age, the double homozygotes develop dilated cardiomyopathy . The...website also links to a An article in the JAX Search Magazine that features Dr. Greg Cox and his research on MD and Brian Denger’s two children

  17. Synthetic review on the different anthropological aspects of ...

    African Journals Online (AJOL)

    Hemoglobinopathies are a group of hereditary hemolytic anemia characterized by qualitative (sickle cell disease) or quantitative (thalassemia) defects in the alpha or beta-globin chain synthesis. Homozygotes or compound heterozygotes for the mutated alpha or beta-globin genes can cause severe anemia at an early age.

  18. Novel approaches in diabetic nephropathy

    NARCIS (Netherlands)

    Alkhalaf, Alaa

    2013-01-01

    Dit proefschrift laat zien dat het carnosinase-1 gen (CNDP1) voorspellend is voor het risico op eindstadium nierfalen bij patiënten met type 1 diabetes. In tegenstelling tot de bevindingen van cross-sectionele studies bij patiënten met type 2 diabetes, blijkt de homozygote variant voor het laagste

  19. Glucose-6-phosphate dehydrogenase status and risk of hemolysis in Plasmodium falciparum-infected African children receiving single-dose primaquine

    NARCIS (Netherlands)

    Eziefula, A.C.; Pett, H. van; Grignard, L.; Opus, S.; Kiggundu, M.; Kamya, M.R.; Yeung, S.; Staedke, S.G.; Bousema, T.; Drakeley, C.

    2014-01-01

    Glucose-6-phosphate dehydrogenase (G6PD) enzyme function and genotype were determined in Ugandan children with uncomplicated falciparum malaria enrolled in a primaquine trial after exclusion of severe G6PD deficiency by fluorescent spot test. G6PD A- heterozygotes and hemizygotes/homozygotes

  20. Discovery of a haplotype affecting fertility in Ayrshire dairy dattle and identification of a putative causal variant

    Science.gov (United States)

    Initial genomic test results for US Ayrshire dairy cattle became available in January of 2013. Several haplotypes that showed a deficiency of homozygotes were investigated to determine if they had an effect on fertility. A haplotype on chromosome 17 was determined to affect fertility, indicating tha...

  1. AJU 3076.indd

    African Journals Online (AJOL)

    mn

    Priapisme intermittent chronique chez l'enfant drépanocytaire homozygote au Togo]. Arch.Pediatr. 2007;14(7):861-3. McHardy P, McDonnell C, Lorenzo AJ, Salle JLP,. 28. Campbell FA. Management of priapism in a child with sickle cell anemia ...

  2. Influence of IL17A polymorphisms on the aberrant methylation of DAPK and CDH1 in non-cancerous gastric mucosa

    Directory of Open Access Journals (Sweden)

    Arisawa Tomiyasu

    2012-07-01

    Full Text Available Abstract Background CpG island aberrant methylation is shown to be an important mechanism in gene silencing. The important role of IL-17 in inflammatory response to H. pylori colonization has been indicated. We investigated the influence of IL17A polymorphisms, -197 G > A (rs2275913 and *1249 C > T (rs3748067, on the methylation of DAPK and CDH1. Methods Gastric mucosal samples were obtained from 401 subjects without malignancies. Methylation status of gene was determined by MSP. The genotyping of IL17A was performed by PCR-SSCP. Results Methylations of DAPK and CDH1 were seen in 196 and 149 of all 401 subjects, respectively. Overall, *1249 T carrier was associated with a decreased risk for DAPK methylation, whereas -197 G > A was not. In the subjects older than 60 years old, *1249 T carrier was more strongly associated with gene methylation and -197 A carrier tended to be associated with an increased risk for CDH1 methylation. When evaluating by inflammation promoting haplotype (-197 mutant carrier with *1249 homozygote, this haplotype had a more strongly increased risk for both DAPK and CDH1 methylations in comparatively older subjects. Both atrophy and metaplasia scores were significantly increased with age in -197 A carrier or *1249 CC homozygote, whereas were not in -197 GG homozygote or *1249 T carrier. PG I/II ratio was more significantly decreased in -197 A carrier than in GG homozygote under influence of H. pylori infection. Conclusions In -197 A allele carrier with *1249 CC homozygote, the methylations of both DAPK and CDH1 may be increased gradually, but more rapidly than the other genotypes, with age and altered gastric mucosal structure induced by H. pylori infection.

  3. Prevalence of CCR5-delta32 mutation in asthmatic and non-asthmatic subjects from department of medicine, JUCM, Cracow.

    Science.gov (United States)

    Gomulska, Martyna; Rusin, Gabriela; Gwiazdak, Piotr

    2014-01-01

    C-C chemokine receptor type 5 (CCR5) is chemokine receptor encoded by CCR5 gene located on the short arm of chromosome 3. Asthma is a chronic bronchial inflammatory disease of either allergic or idiopathic etiology. CCR5 Δ32 mutation is a common deletion of 32 nucleotides resulting in a frameshift and non-functional receptor. Its prevalence in European population ranges between 4 and 16% (frequency of homozygotes is 1%). The current study was aimed to assess frequency of this mutation in asthmatics and its possible impact on asthma. The study was conducted on 254 subjects (125 diagnosed with asthma and 129 in control group). Isolated DNA was analysed by PCR. Primers were designed to flank the deletion region, thus PCR products could be genotyped by mere agarose gel electrophoresis. The variant alleles were represented as bands of 270 and 238 pb lengths. The shorter amplification product was diagnostic for the presence of CCR5-delta32 deletion. Visualisation of agarose gel revealed non-mutated, mutated homozygotes as well as heterozygotes. In the control group there were 37 women and 92 men, whereas the study group comprised 87 women and 38 men. In the control group genotypes distribution was: 105 non-mutated homozygotes, 21 hetezygotes and 3 mutated homozygotes, whereas in the study group 103, 21 and 1 respectively. No statistically significant differences between these groups were detected. Prevalence of homozygotes was 1,6%. Current study revealed no association between CCR5 Δ32 mutation and incidence of asthma. It may be assumed that CCR5 Δ32 deletion is neutral as a risk factor of asthma.

  4. Genetic contribution of catechol-O-methyltransferase in hippocampal structural and functional changes of female migraine sufferers.

    Science.gov (United States)

    Liu, Jixin; Lan, Lei; Mu, Junya; Zhao, Ling; Yuan, Kai; Zhang, Yi; Huang, Liyu; Liang, Fanrong; Tian, Jie

    2015-05-01

    Physiological and emotional stressors are associated with or provoke each migraine attack and cause structural and functional changes in the central nervous system. The hippocampus, a limbic structure important in anxiety-related behavior, is vulnerable to long-term stress. Given that catechol-O-methyltransferase (COMT) is widely distributed in the hippocampus and its genetic variation is thought to contribute to the interindividual variability in pain perception and anxiety regulation, whether or not migraine and COMT val(158) met genotype have an interactive effect in the key brain area related to maladaptive stress, the hippocampus, is still poorly understood. Using T1-weighted and resting functional MRI, we evaluated the effect of COMT genetic variations on migraine and possible interactions between COMT and the disease in brain structure and function in 135 females with migraine without aura (MWoA) and 111 matched health controls (HC). Optimized voxel-based morphometry (VBM) and functional connectivity (FC) analyses were applied. From the whole brain VBM analysis, we found a significant disease × genotype interaction in the hippocampus, which overlapped with disease-related increase of gray matter (GM) in val homozygote migraineurs. In our results, increased GM in the hippocampus was only found in val homozygote MWoA compared to val homozygote HC. Moreover, FC between the hippocampus and the medial prefrontal cortex was significantly decreased in val homozygotes, and it was negatively correlated with self-rating anxiety scale values.Our results indicated that brain structure and function of the hippocampus are differentially affected by migraine in val homozygotes compared with met carriers. © 2015 Wiley Periodicals, Inc.

  5. Bovine NR1I3 gene polymorphisms and its association with feed efficiency traits in Nellore cattle.

    Science.gov (United States)

    Alexandre, Pâmela A; Gomes, Rodrigo C; Santana, Miguel H A; Silva, Saulo L; Leme, Paulo R; Mudadu, Maurício A; Regitano, Luciana C A; Meirelles, Flávio V; Ferraz, José B S; Fukumasu, Heidge

    2014-12-01

    The Nuclear receptor 1 family I member 3 (NR1I3), also known as the Constitutive Androstane Receptor (CAR), was initially characterized as a key regulator of xenobiotic metabolism. However, recent biochemical and structural data suggest that NR1I3 is activated in response to metabolic and nutritional stress in a ligand-independent manner. Thus, we prospected the Bovine NR1I3 gene for polymorphisms and studied their association with feed efficiency traits in Nellore cattle. First, 155 purebred Nellore bulls were individually measured for Residual Feed Intake (RFI) and the 25 best (High Feed Efficiency group, HFE) and the 25 worst animals (Low Feed Efficiency group, LFE) were selected for DNA extraction. The entire Bovine NR1I3 gene was amplified and polymorphisms were identified by sequencing. Then, one SNP different between HFE and LFE groups was genotyped in all the 155 animals and in another 288 animals totalizing 443 Nellore bulls genotyped for association of NR1I3 SNPs with feed efficiency traits. We found 24 SNPs in the NR1I3 gene and choose a statistically different SNP between HFE and LFE groups for further analysis. Genotyping of the 155 animals showed a significant association within SNP and RFI (p = 0.04), Residual Intake and BW Gain (p = 0.04) and Dry Matter Intake (p = 0.01). This SNP is located in the 5'flanking promoter region of NR1I3 gene and different alleles alter the binding site for predicted transcriptional factors as HNF4alpha, CREM and c-MYB, leading us to conclude that NR1I3 expression and regulation might be important to feed efficiency.

  6. APPLICATION OF EYE TRACKING FOR MEASUREMENT AND EVALUATION IN HUMAN FACTORS STUDIES IN CONTROL ROOM MODERNIZATION

    Energy Technology Data Exchange (ETDEWEB)

    Kovesdi, C.; Spielman, Z.; LeBlanc, K.; Rice, B.

    2017-05-01

    An important element of human factors engineering (HFE) pertains to measurement and evaluation (M&E). The role of HFE-M&E should be integrated throughout the entire control room modernization (CRM) process and be used for human-system performance evaluation and diagnostic purposes with resolving potential human engineering deficiencies (HEDs) and other human machine interface (HMI) design issues. NUREG-0711 describes how HFE in CRM should employ a hierarchical set of measures, particularly during integrated system validation (ISV), including plant performance, personnel task performance, situation awareness, cognitive workload, and anthropometric/ physiological factors. Historically, subjective measures have been primarily used since they are easier to collect and do not require specialized equipment. However, there are pitfalls with relying solely on subjective measures in M&E such that negatively impact reliability, sensitivity, and objectivity. As part of comprehensively capturing a diverse set of measures that strengthen findings and inferences made of the benefits from emerging technologies like advanced displays, this paper discusses the value of using eye tracking as an objective method that can be used in M&E. A brief description of eye tracking technology and relevant eye tracking measures is provided. Additionally, technical considerations and the unique challenges with using eye tracking in full-scaled simulations are addressed. Finally, this paper shares preliminary findings regarding the use of a wearable eye tracking system in a full-scale simulator study. These findings should help guide future full-scale simulator studies using eye tracking as a methodology to evaluate human-system performance.

  7. Human Factors Considerations in New Nuclear Power Plants: Detailed Analysis.

    Energy Technology Data Exchange (ETDEWEB)

    OHara,J.; Higgins, J.; Brown, W.; Fink, R.

    2008-02-14

    This Nuclear Regulatory Commission (NRC) sponsored study has identified human-performance issues in new and advanced nuclear power plants. To identify the issues, current industry developments and trends were evaluated in the areas of reactor technology, instrumentation and control technology, human-system integration technology, and human factors engineering (HFE) methods and tools. The issues were organized into seven high-level HFE topic areas: Role of Personnel and Automation, Staffing and Training, Normal Operations Management, Disturbance and Emergency Management, Maintenance and Change Management, Plant Design and Construction, and HFE Methods and Tools. The issues where then prioritized into four categories using a 'Phenomena Identification and Ranking Table' methodology based on evaluations provided by 14 independent subject matter experts. The subject matter experts were knowledgeable in a variety of disciplines. Vendors, utilities, research organizations and regulators all participated. Twenty issues were categorized into the top priority category. This Brookhaven National Laboratory (BNL) technical report provides the detailed methodology, issue analysis, and results. A summary of the results of this study can be found in NUREG/CR-6947. The research performed for this project has identified a large number of human-performance issues for new control stations and new nuclear power plant designs. The information gathered in this project can serve as input to the development of a long-term strategy and plan for addressing human performance in these areas through regulatory research. Addressing human-performance issues will provide the technical basis from which regulatory review guidance can be developed to meet these challenges. The availability of this review guidance will help set clear expectations for how the NRC staff will evaluate new designs, reduce regulatory uncertainty, and provide a well-defined path to new nuclear power plant

  8. With eloquence and humanity? Human factors/ergonomics in sustainable human development.

    Science.gov (United States)

    Moore, Dave; Barnard, Tim

    2012-12-01

    This article is based on a keynote presentation given at the 18th Congress of the International Ergonomics Association in Recife, Brazil, February 2012. It considers new, and not so new, approaches and practical roles for the emerging field of human factors/ergonomics (HFE) in sustainable development (SD).The material for this article was largely drawn from the literature in the fields of human development, sustainability, climate change mitigation and adaptation, and social/environmental impact assessment. Identifying the role of HFE in SD is not a simple one and from the outset is complicated by the widely differing ideas in the sustainability literature about what exactly it is we are hoping to sustain. Is it individual companies, business models, cultures, or the carrying capacity of our planet? Or combinations of these? For the purposes of this article, certain assumptions are made, and various emerging opportunities and responsibilities associated with our changing world of work are introduced. First, there are new versions of traditional tasks for us, such as working with the people and companies in the renewable energy sectors. Beyond this, however, it is suggested that there are emerging roles for HFE professionals in transdisciplinary work where we might play our part, for example, in tackling the twinned issues of climate change and human development in areas of significant poverty. In particular we have the tools and capabilities to help define and measure what groups have reason to value, and wish to sustain. It is suggested, that to do this effectively, however, will require a philosophical shift, or perhaps just a philosophical restatement at a collective level, regarding who and what we ultimately serve.

  9. The A736V TMPRSS6 polymorphism influences hepatic iron overload in nonalcoholic fatty liver disease.

    Directory of Open Access Journals (Sweden)

    Luca Valenti

    Full Text Available Hepatic iron accumulation due to altered trafficking is frequent in patients with nonalcoholic fatty liver disease (NAFLD, and is associated with more severe liver damage and hepatocellular carcinoma. The p.Ala736Val TMPRSS6 variant influences iron metabolism regulating the transcription of the hepatic hormone hepcidin, but its role in the pathogenesis of iron overload disorders is controversial. Aim of this study was to evaluate the whether the TMPRSS6 p.Ala736Val variant influences hepatic iron accumulation in a well-characterized series of Italian patients with histological NAFLD.216 patients with histological NAFLD. TMPRSS6 and HFE variants were assessed by allele specific PCR, liver histology by the NAFLD activity score and Perls' staining for iron.Homozygosity for the p.736Val allele previously linked to higher hepcidin did not influence transferrin saturation (TS, but was associated with lower hepatic iron stores (p = 0.01, and ferritin levels (median 223 IQR 102-449 vs. 308 IQR 141-618 ng/ml; p = 0.01. Homozygosity for TMPRSS6 p.736Val was nearly associated with lower ballooning (p = 0.05, reflecting hepatocellular damage related to oxidative stress. The influence of TMPRSS6 on hepatic iron accumulation was more marked in patients negative for HFE genotypes predisposing to iron overload (p.Cys282Tyr + and p.His63Asp +/+; p = 0.01, and the p.736Val variant was negatively associated with hepatic iron accumulation independently of age, gender, HFE genotype, and beta-thalassemia trait (OR 0.59, 0.39-0.88.The p.Ala736Val TMPRSS6 variant influences secondary hepatic iron accumulation in patients with NAFLD.

  10. Applying Human Factors during the SIS Life Cycle

    Energy Technology Data Exchange (ETDEWEB)

    Avery, K.

    2010-05-05

    Safety Instrumented Systems (SIS) are widely used in U.S. Department of Energy's (DOE) nonreactor nuclear facilities for safety-critical applications. Although use of the SIS technology and computer-based digital controls, can improve performance and safety, it potentially introduces additional complexities, such as failure modes that are not readily detectable. Either automated actions or manual (operator) actions may be required to complete the safety instrumented function to place the process in a safe state or mitigate a hazard in response to an alarm or indication. DOE will issue a new standard, Application of Safety Instrumented Systems Used at DOE Nonreactor Nuclear Facilities, to provide guidance for the design, procurement, installation, testing, maintenance, operation, and quality assurance of SIS used in safety significant functions at DOE nonreactor nuclear facilities. The DOE standard focuses on utilizing the process industry consensus standard, American National Standards Institute/ International Society of Automation (ANSI/ISA) 84.00.01, Functional Safety: Safety Instrumented Systems for the Process Industry Sector, to support reliable SIS design throughout the DOE complex. SIS design must take into account human-machine interfaces and their limitations and follow good human factors engineering (HFE) practices. HFE encompasses many diverse areas (e.g., information display, user-system interaction, alarm management, operator response, control room design, and system maintainability), which affect all aspects of system development and modification. This paper presents how the HFE processes and principles apply throughout the SIS life cycle to support the design and use of SIS at DOE nonreactor nuclear facilities.

  11. Bovine NR1I3 gene polymorphisms and its association with feed efficiency traits in Nellore cattle

    Science.gov (United States)

    Alexandre, Pâmela A.; Gomes, Rodrigo C.; Santana, Miguel H.A.; Silva, Saulo L.; Leme, Paulo R.; Mudadu, Maurício A.; Regitano, Luciana C.A.; Meirelles, Flávio V.; Ferraz, José B.S.; Fukumasu, Heidge

    2014-01-01

    Abstract The Nuclear receptor 1 family I member 3 (NR1I3), also known as the Constitutive Androstane Receptor (CAR), was initially characterized as a key regulator of xenobiotic metabolism. However, recent biochemical and structural data suggest that NR1I3 is activated in response to metabolic and nutritional stress in a ligand-independent manner. Thus, we prospected the Bovine NR1I3 gene for polymorphisms and studied their association with feed efficiency traits in Nellore cattle. First, 155 purebred Nellore bulls were individually measured for Residual Feed Intake (RFI) and the 25 best (High Feed Efficiency group, HFE) and the 25 worst animals (Low Feed Efficiency group, LFE) were selected for DNA extraction. The entire Bovine NR1I3 gene was amplified and polymorphisms were identified by sequencing. Then, one SNP different between HFE and LFE groups was genotyped in all the 155 animals and in another 288 animals totalizing 443 Nellore bulls genotyped for association of NR1I3 SNPs with feed efficiency traits. We found 24 SNPs in the NR1I3 gene and choose a statistically different SNP between HFE and LFE groups for further analysis. Genotyping of the 155 animals showed a significant association within SNP and RFI (p = 0.04), Residual Intake and BW Gain (p = 0.04) and Dry Matter Intake (p = 0.01). This SNP is located in the 5′flanking promoter region of NR1I3 gene and different alleles alter the binding site for predicted transcriptional factors as HNF4alpha, CREM and c-MYB, leading us to conclude that NR1I3 expression and regulation might be important to feed efficiency. PMID:25606404

  12. Use of Composite Fingerprinting Technique to Determine Contribution of Paria River Sediments to Dam-Release Flood Deposits in Marble Canyon, Grand Canyon, Az

    Science.gov (United States)

    Chapman, K.; Parnell, R. A.; Smith, M. E.; Grams, P. E.; Mueller, E. R.

    2015-12-01

    The 1963 closure of Glen Canyon Dam drastically reduced the downstream sediment supply and altered daily flow regimes of the Colorado River through Grand Canyon, resulting in significant sandbar erosion downstream of the dam. Dam-release floods, known as High Flow Experiments (HFEs), have occurred six times since 1996 and are intended to rebuild Grand Canyon sandbars using tributary-supplied sediment. In Marble Canyon (first 100 km of Grand Canyon) the targeted tributary is the Paria River which supplies approximately 90% of the annual suspended sediment flux through Marble Canyon; the same input contributed less than 6% prior to the dam. Annual topographic surveys have established that HFEs are effective at rebuilding sandbars. However, the long-term viability of using HFEs for sandbar maintenance is dependent on a sustainable source of sediments comprising HFE deposits. Significant use of non-tributary, main-stem sediments (i.e. pre-dam sand stored in eddies or the channel bed) in HFE deposits would indicate reliance on a limited resource, and diminishing returns in the ability of HFEs to rebuild sandbars. In this study, we sampled vertically throughout 12 bars in Marble Canyon to document temporal and downstream changes in the proportion of sediment sourced from the Paria River during the 2013 and 2014 HFEs. Preliminary data suggest that heavy mineral compositions and concentrations of Ti, S, Cr and Rb, all of which are influenced by grainsize, could be sufficiently capable of differentiating Paria-derived and main-stem sediments when combined into a composite fingerprint (CF). A multivariate mixing model using these CFs quantitatively determines the contribution of Paria-derived sediment in each HFE deposit sample. Mixing model endmembers for non-Paria sand include pre-dam flood deposits in Glen and Marble Canyons, and Marble Canyon dredge samples. These results elucidate the role of contemporary versus legacy sediment in long-term sandbar maintenance.

  13. Development of fingermarks on Latex gloves: The solution to a challenging surface.

    Science.gov (United States)

    Arbeli, Tomer; Liptz, Yakir; Bengiat, Ravell; Levin-Elad, Michal

    2017-11-01

    Used Latex gloves found at crime scenes can provide strong evidence against a suspect as they almost certainly contain both the fingermarks and DNA of the perpetrator who had worn them. However, over the years, Latex gloves have proved to be a rather difficult substrate for fingermarks development, with most of the standard techniques producing poor results. In this study, the two main protocols for development on either porous or non-porous surfaces: Ninhydrin-HFE and superglue fuming followed by crystal violet (CV) dyeing, respectively, had been examined on 100 disposable Latex gloves from twenty five donors. The results distinctly showed a high superiority of Ninhydrin-HFE over the superglue fuming indicating the porous rather than the non-porous properties of the interior of the gloves. Yet, not all the usual ninhydrin development formulations yielded the desirable results, leading to the conclusion that the success of development rests on the solvent-sensitive structure of the gloves. As natural latex contains contaminant proteins, that were found to cause allergic reactions in different people, the manufacturing of disposable gloves had been altered over the years to prevent contact with these proteins by adding an intrinsic polymer-coating. Thus, it was essential to use an inert solvent system that should keep the interior polymer-coating intact, allowing a reaction only with the amino acids on the surface rather than the latex proteins in the glove. The SEM analyses showed that HFE-7100 as opposed to petroleum ether, does not harm the inner coating, hence, providing the ideal solution to this challenging surface. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Fatty acid desaturase (FADS gene polymorphisms and insulin resistance in association with serum phospholipid polyunsaturated fatty acid composition in healthy Korean men: cross-sectional study

    Directory of Open Access Journals (Sweden)

    Yang Long In

    2011-04-01

    Full Text Available Abstract Background We investigated the relationship between fatty acid desaturase (FADS gene polymorphisms and insulin resistance (IR in association with serum phospholipid polyunsaturated fatty acid (FA composition in healthy Korean men. Methods Healthy men (n = 576, 30 ~ 79 years old were genotyped for rs174537 near FADS1 (FEN1-10154G>T, FADS2 (rs174575C>G, rs2727270C>T, and FADS3 (rs1000778C>T SNPs. Dietary intake, serum phospholipid FA composition and HOMA-IR were measured. Results Fasting insulin and HOMA-IR were significantly higher in the rs174575G allele carriers than the CC homozygotes, but lower in the rs2727270T allele carriers than the CC homozygotes. The proportion of linoleic acid (18:2ω-6, LA was higher in the minor allele carriers of FEN1-10154G>T, rs174575C>G and rs2727270C>T than the major homozygotes, respectively. On the other hand, the proportions of dihomo-γ-linolenic acid (20:3ω-6, DGLA and arachidonic acid (20:4ω-6, AA in serum phospholipids were significantly lower in the minor allele carriers of FEN1-10154 G>T carriers and rs2727270C>T than the major homozygotes respectively. AA was also significantly lower in the rs1000778T allele carriers than the CC homozygotes. HOMA-IR positively correlated with LA and DGLA and negatively with AA/DGLA in total subjects. Interestingly, rs174575G allele carriers showed remarkably higher HOMA-IR than the CC homozygotes when subjects had higher proportions of DLGA (≥1.412% in total serum phospholipid FA composition (P for interaction = 0.009 or of AA (≥4.573% (P for interaction = 0.047. Conclusion HOMA-IR is associated with FADS gene cluster as well as with FA composition in serum phospholipids. Additionally, HOMA-IR may be modulated by the interaction between rs174575C>G and the proportion of DGLA or AA in serum phospholipids.

  15. Fatty acid desaturase (FADS) gene polymorphisms and insulin resistance in association with serum phospholipid polyunsaturated fatty acid composition in healthy Korean men: cross-sectional study.

    Science.gov (United States)

    Kim, Oh Yoen; Lim, Hyo Hee; Yang, Long In; Chae, Jey Sook; Lee, Jong Ho

    2011-04-23

    We investigated the relationship between fatty acid desaturase (FADS) gene polymorphisms and insulin resistance (IR) in association with serum phospholipid polyunsaturated fatty acid (FA) composition in healthy Korean men. Healthy men (n = 576, 30 ~ 79 years old) were genotyped for rs174537 near FADS1 (FEN1-10154G>T), FADS2 (rs174575C>G, rs2727270C>T), and FADS3 (rs1000778C>T) SNPs. Dietary intake, serum phospholipid FA composition and HOMA-IR were measured. Fasting insulin and HOMA-IR were significantly higher in the rs174575G allele carriers than the CC homozygotes, but lower in the rs2727270T allele carriers than the CC homozygotes. The proportion of linoleic acid (18:2ω-6, LA) was higher in the minor allele carriers of FEN1-10154G>T, rs174575C>G and rs2727270C>T than the major homozygotes, respectively. On the other hand, the proportions of dihomo-γ-linolenic acid (20:3ω-6, DGLA) and arachidonic acid (20:4ω-6, AA) in serum phospholipids were significantly lower in the minor allele carriers of FEN1-10154 G>T carriers and rs2727270C>T than the major homozygotes respectively. AA was also significantly lower in the rs1000778T allele carriers than the CC homozygotes. HOMA-IR positively correlated with LA and DGLA and negatively with AA/DGLA in total subjects. Interestingly, rs174575G allele carriers showed remarkably higher HOMA-IR than the CC homozygotes when subjects had higher proportions of DLGA (≥1.412% in total serum phospholipid FA composition) (P for interaction = 0.009) or of AA (≥4.573%) (P for interaction = 0.047). HOMA-IR is associated with FADS gene cluster as well as with FA composition in serum phospholipids. Additionally, HOMA-IR may be modulated by the interaction between rs174575C>G and the proportion of DGLA or AA in serum phospholipids.

  16. ACTN3 genotype influences exercise-induced muscle damage during a marathon competition.

    Science.gov (United States)

    Del Coso, Juan; Valero, Marjorie; Salinero, Juan José; Lara, Beatriz; Díaz, Germán; Gallo-Salazar, César; Ruiz-Vicente, Diana; Areces, Francisco; Puente, Carlos; Carril, Juan Carlos; Cacabelos, Ramón

    2017-03-01

    Exercise-induced muscle damage has been identified as one of the main causes of the progressive decrease in running and muscular performance in marathoners. The aim of this investigation was to determine the influence of the ACTN3 genotype on exercise-induced muscle damage produced during a marathon. Seventy-one experienced runners competed in a marathon race. Before and after the race, a sample of venous blood was obtained and maximal voluntary leg muscle power was measured during a countermovement jump. In the blood samples, the ACTN3 genotype (R577X) and the changes in serum creatine kinase and myoglobin concentrations were measured. Data from RX heterozygotes and XX mutant homozygotes were grouped as X allele carriers and compared to RR homozygotes. At the end of the race, X allele carriers presented higher serum myoglobin (774 ± 852 vs 487 ± 367 U L -1 ; P = 0.02) and creatine kinase concentrations (508 ± 346 vs 359 ± 170 ng mL -1 ; P = 0.04) than RR homozygotes. Pre-to-post-race maximal voluntary leg muscle power reduction was more pronounced in X allele carriers than RR homozygotes (-34.4 ± 16.1 vs -27.3 ± 15.4%; P = 0.05). X allele carriers self-reported higher levels of lower limb muscle pain (7 ± 2 vs 6 ± 2 cm; P = 0.02) than RR homozygotes at the end of the race. In comparison to RR homozygotes, X allele carriers for the R577X polymorphism of the ACTN3 gene presented higher values for typical markers of exercise-induced muscle damage during a competitive marathon. Thus, the absence of a functional α-actinin-3 produced by the X allele might induce higher levels of muscle breakdown during prolonged running events.

  17. Genome-Wide Association Scan Shows Genetic Variants in the FTO Gene Are Associated with Obesity-Related Traits

    Science.gov (United States)

    Chen, Wei-Min; Uda, Manuela; Albai, Giuseppe; Strait, James; Najjar, Samer; Nagaraja, Ramaiah; Orrú, Marco; Usala, Gianluca; Dei, Mariano; Lai, Sandra; Maschio, Andrea; Busonero, Fabio; Mulas, Antonella; Ehret, Georg B; Fink, Ashley A; Weder, Alan B; Cooper, Richard S; Galan, Pilar; Chakravarti, Aravinda; Schlessinger, David; Cao, Antonio; Lakatta, Edward; Abecasis, Gonçalo R

    2007-01-01

    The obesity epidemic is responsible for a substantial economic burden in developed countries and is a major risk factor for type 2 diabetes and cardiovascular disease. The disease is the result not only of several environmental risk factors, but also of genetic predisposition. To take advantage of recent advances in gene-mapping technology, we executed a genome-wide association scan to identify genetic variants associated with obesity-related quantitative traits in the genetically isolated population of Sardinia. Initial analysis suggested that several SNPs in the FTO and PFKP genes were associated with increased BMI, hip circumference, and weight. Within the FTO gene, rs9930506 showed the strongest association with BMI (p = 8.6 ×10− 7), hip circumference (p = 3.4 × 10− 8), and weight (p = 9.1 × 10− 7). In Sardinia, homozygotes for the rare “G” allele of this SNP (minor allele frequency = 0.46) were 1.3 BMI units heavier than homozygotes for the common “A” allele. Within the PFKP gene, rs6602024 showed very strong association with BMI (p = 4.9 × 10− 6). Homozygotes for the rare “A” allele of this SNP (minor allele frequency = 0.12) were 1.8 BMI units heavier than homozygotes for the common “G” allele. To replicate our findings, we genotyped these two SNPs in the GenNet study. In European Americans (N = 1,496) and in Hispanic Americans (N = 839), we replicated significant association between rs9930506 in the FTO gene and BMI (p-value for meta-analysis of European American and Hispanic American follow-up samples, p = 0.001), weight (p = 0.001), and hip circumference (p = 0.0005). We did not replicate association between rs6602024 and obesity-related traits in the GenNet sample, although we found that in European Americans, Hispanic Americans, and African Americans, homozygotes for the rare “A” allele were, on average, 1.0–3.0 BMI units heavier than homozygotes for the more common “G” allele. In summary, we have completed a whole

  18. Forces of Tool-Tissue Interaction to Assess Surgical Skill Level.

    Science.gov (United States)

    Sugiyama, Taku; Lama, Sanju; Gan, Liu Shi; Maddahi, Yaser; Zareinia, Kourosh; Sutherland, Garnette R

    2017-11-15

    The application of optimal forces between surgical instruments and tissue is fundamental to surgical performance and learning. To date, this force has not been measured clinically during the performance of microsurgery. To establish a normative catalog of force profiles during the performance of surgery, to compare force variables among surgeons with different skill levels, and to evaluate whether such a force-based metric determines or differentiates skill level. Through installation of strain gauge sensors, a force-sensing bipolar forceps was developed, and force data were obtained from predetermined surgical tasks at the Foothills Medical Centre, University of Calgary, a tertiary care center that serves Southern Alberta, Canada. Sixteen neurosurgeons (3 groups: novice, intermediate, and experienced) performed surgery on 26 neurosurgical patients with various conditions. Normative baseline force ranges were obtained using the force profiles (mean and maximum forces and force variability) from the experienced surgeons. Standardized force profiles and force errors (high force error [HFE], low force error [LFE], and force variability error [FVE]) were analyzed and compared among surgeons with different skill levels. Each trial of the forceps use was termed successful or unsuccessful. The force profiles and force errors were analyzed and compared. This study included 26 patients (10 [38%] male and 16 [62%] female; mean [SD] age, 43 [15] years) undergoing neurosurgery by 16 surgeons (6 in the novice group, 5 in the intermediate group, and 5 in the experienced group). Unsuccessful trial-incomplete significantly correlated with LFE and FVE, and unsuccessful trial-bleeding correlated with HFE and FVE. The force strengths exerted by novice surgeons were significantly higher than those of experienced surgeons (mean force, 0.74N vs 0.00N; P intermediate (mean force, 0.28N) to experienced (mean force, 0.00N) surgeons; however, these differences varied among surgical tasks

  19. An Investigation for Arranging the Video Display Unit Information in a Main Control Room of Advanced Nuclear Power Plants

    Energy Technology Data Exchange (ETDEWEB)

    Hsu, Chong Cheng; Yang, Chih Wei [Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan (China)

    2014-08-15

    Current digital instrumentation and control and main control room (MCR) technology has extended the capability of integrating information from numerous plant systems and transmitting needed information to operations personnel in a timely manner that could not be envisioned when previous generation plants were designed and built. A MCR operator can complete all necessary operating actions on the video display unit (VDU). It is extremely flexible and convenient for operators to select and to control the system display on the screen. However, a high degree of digitalization has some risks. For example, in nuclear power plants, failures in the instrumentation and control devices could stop the operation of the plant. Human factors engineering (HFE) approaches would be a manner to solve this problem. Under HFE considerations, there exists 'population stereotype' for operation. That is, the operator is used to operating a specific display on the specific VDU for operation. Under emergency conditions, there is possibility that the operator will response with this habit population stereotype, and not be aware that the current situation has already changed. Accordingly, the advanced nuclear power plant should establish the MCR VDU configuration plan to meet the consistent teamwork goal under normal operation, transient and accident conditions. On the other hand, the advanced nuclear power plant should establish the human factors verification and validation plan of the MCR VDU configuration to verify and validate the configuration of the MCR VDUs, and to ensure that the MCR VDU configuration allows the operator shift to meet the HFE consideration and the consistent teamwork goal under normal operation, transient and accident conditions. This paper is one of the HF V V plans of the MCR VDU configuration of the advanced nuclear power plant. The purpose of this study is to confirm whether the VDU configuration meets the human factors principles and the consistent

  20. A Modification on the Hesitant Fuzzy Set Lexicographical Ranking Method

    Directory of Open Access Journals (Sweden)

    Xiaodi Liu

    2016-12-01

    Full Text Available Recently, a novel hesitant fuzzy set (HFS ranking technique based on the idea of lexicographical ordering is proposed and an example is presented to demonstrate that the proposed ranking method is invariant with multiple occurrences of any element of a hesitant fuzzy element (HFE. In this paper, we show by examples that the HFS lexicographical ordering method is sometimes invalid, and a modified ranking method is presented. In comparison with the HFS lexicographical ordering method, the modified ranking method is more reasonable in more general cases.

  1. Heterotypic interactions between transferrin receptor and transferrin receptor 2

    OpenAIRE

    Vogt, TM; Blackwell, AD; Giannetti, AM; Bjorkman, PJ; Enns, CA

    2003-01-01

    Cellular iron uptake in most tissues occurs via endocytosis of diferric transferrin (Tf) bound to the transferrin receptor (TfR). Recently, a second transferrin receptor, transferrin receptor 2 (TfR2), has been identified and shown to play a critical role in iron metabolism. TfR2 is capable of Tf-mediated iron uptake and mutations in this gene result in a rare form of hereditary hemochromatosis unrelated to the hereditary hemochromatosis protein, HFE. Unlike TfR, TfR2 expression is not contro...

  2. Hemochromatosis and severe iron overload associated with compound heterozygosity for TFR2 R455Q and two novel mutations TFR2 R396X and G792R.

    Science.gov (United States)

    Lee, Pauline L; Barton, James C

    2006-01-01

    We report three mutations of transferrin receptor 2 (TFR2)--R396X (exon 9; nt 1186C-->T), R455Q (exon 10; nt 1364G-->A) and G792R (exon 18; nt 2374G-->A)--in a man of Scottish descent with hemochromatosis and severe iron overload. He was also heterozygous for the common HFE H63D polymorphism. The patient did not have coding region mutations in HAMP, FPN1, HJV or ALAS2. We conclude that this patient represents another example of hemochromatosis due to mutations of the gene encoding transferrin receptor 2. Copyright 2006 S. Karger AG, Basel.

  3. Homozygous p.M172K mutation of the TFR2 gene in an Italian family with type 3 hereditary hemochromatosis and early onset iron overload.

    Science.gov (United States)

    Majore, S; Milano, F; Binni, F; Stuppia, L; Cerrone, A; Tafuri, A; De Bernardo, C; Palka, G; Grammatico, P

    2006-08-01

    The p.M172K TFR2 mutation was identified in two Italian siblings aged 32 and 40 years old with primary iron overload. The two patients showed a severe increase in serum iron indices. From the age of 25, the male sib also revealed abnormal levels of hepatic enzymes, presumably in relation to iron induced liver damage. Clinical findings seem to evidence that type 3 hemochromatosis can be more serious than classic hemochromatosis. This report adds two more type 3 hereditary hemochromatosis cases which suggest that TFR2 mutations could be more frequently involved in non-HFE hemochromatosis than has been actually thought.

  4. A Prototyping Environment for Research on Human-Machine Interfaces in Process Control: Use of Microsoft WPF for Microworld and Distributed Control System Development

    Energy Technology Data Exchange (ETDEWEB)

    Roger Lew; Ronald L. Boring; Thomas A. Ulrich

    2014-08-01

    Operators of critical processes, such as nuclear power production, must contend with highly complex systems, procedures, and regulations. Developing human-machine interfaces (HMIs) that better support operators is a high priority for ensuring the safe and reliable operation of critical processes. Human factors engineering (HFE) provides a rich and mature set of tools for evaluating the performance of HMIs, but the set of tools for developing and designing HMIs is still in its infancy. Here we propose that Microsoft Windows Presentation Foundation (WPF) is well suited for many roles in the research and development of HMIs for process control.

  5. The effect of exercise frequency on neuropathic pain and pain-related cellular reactions in the spinal cord and midbrain in a rat sciatic nerve injury model

    Directory of Open Access Journals (Sweden)

    Sumizono M

    2018-02-01

    Full Text Available Megumi Sumizono,1,2 Harutoshi Sakakima,1 Shotaro Otsuka,1 Takuto Terashi,1 Kazuki Nakanishi,1,2 Koki Ueda,1,2 Seiya Takada,1,2 Kiyoshi Kikuchi3 1Course of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, Kagoshima, Japan; 2Kirishima Orthopedics, Kirishima, Japan; 3Division of Brain Science, Department of Physiology, Kurume University School of Medicine, Kurume, Japan Background: Exercise regimens are established methods that can relieve neuropathic pain. However, the relationship between frequency and intensity of exercise and multiple cellular responses of exercise-induced alleviation of neuropathic pain is still unclear. We examined the influence of exercise frequency on neuropathic pain and the intracellular responses in a sciatic nerve chronic constriction injury (CCI model. Materials and methods: Rats were assigned to four groups as follows: CCI and high-frequency exercise (HFE group, CCI and low-frequency exercise (LFE group, CCI and no exercise (No-Ex group, and naive animals (control group. Rats ran on a treadmill, at a speed of 20 m/min, for 30 min, for 5 (HFE or 3 (LFE days a week, for a total of 5 weeks. The 50% withdrawal threshold was evaluated for mechanical sensitivity. The activation of glial cells (microglia and astrocytes, expression of brain-derived neurotrophic factor (BDNF and μ-opioid receptor in the spinal dorsal horn and endogenous opioid in the midbrain were examined using immunohistochemistry. Opioid receptor antagonists (naloxone were administered using intraperitoneal injection. Results: The development of neuropathic pain was related to the activation of glial cells, increased BDNF expression, and downregulation of the μ-opioid receptor in the ipsilateral spinal dorsal horn. In the No-Ex group, neuropathic pain showed the highest level of mechanical hypersensitivity at 2 weeks, which improved slightly until 5 weeks after CCI. In both exercise groups, the alleviation of

  6. NOD2/CARD15 genotype and common gastrointestinal diseases in 43 600 individuals

    DEFF Research Database (Denmark)

    Yazdanyar, S.; Nordestgaard, B.G.

    2010-01-01

    heterozygotes. Cumulative incidences differed by genotype for appendicitis (log-rank P = 0.02), anal fissure, fistula and abscess (P = 0.003) and gastrointestinal cancer (P = 0.004), but not for any of the other endpoints. Compared with non-carriers, age and sex adjusted hazard ratios were 2.7 (95% CI 1...... appendicitis, 646 irritable bowel syndrome, 1301 infectious diseases of the gastrointestinal tract, 681 anal fissure, fistula and abscess, 826 gastrointestinal cancer and 161 developed cancer in liver and pancreas. Results. Some 89% were non-carriers, 11% heterozygotes, 0.15% homozygotes and 0.23% compound.......4-5.5) for appendicitis amongst compound heterozygotes, 3.2 (1.3-7.8) for anal fissure, fistula and abscess amongst compound heterozygotes, and 3.8 (1.6-9.2) for gastrointestinal cancer amongst homozygotes, whilst other genotypes did not have increased risk. The increased risk of gastrointestinal cancer amongst...

  7. Historical analysis of Newfoundland dog fur colour genetics

    Directory of Open Access Journals (Sweden)

    J. Bondeson

    2015-06-01

    Full Text Available This article makes use of digitized historic newspapers to analyze Newfoundland dog fur colour genetics, and fur colour variations over time. The results indicate that contrary to the accepted view, the ‘Solid’ gene was introduced into the British population of Newfoundland dogs in the 1840s. Prior to that time, the dogs were white and black (Landseer or white and brown, and thus spotted/spotted homozygotes. Due to ‘Solid’ being dominant over ‘spotted’, and selective breeding, today the majority of Newfoundland dogs are solid black. Whereas small white marks on the chest and/or paw appears to be a random event, the historical data supports the existence of an ‘Irish spotted’ fur colour pattern, with white head blaze, breast, paws and tail tip, in spotted/spotted homozygotes.

  8. NOD2/CARD15 genotype and common gastrointestinal diseases in 43 600 individuals

    DEFF Research Database (Denmark)

    Yazdanyar, S.; Nordestgaard, B.G.

    2010-01-01

    appendicitis, 646 irritable bowel syndrome, 1301 infectious diseases of the gastrointestinal tract, 681 anal fissure, fistula and abscess, 826 gastrointestinal cancer and 161 developed cancer in liver and pancreas. Results. Some 89% were non-carriers, 11% heterozygotes, 0.15% homozygotes and 0.23% compound...... heterozygotes. Cumulative incidences differed by genotype for appendicitis (log-rank P = 0.02), anal fissure, fistula and abscess (P = 0.003) and gastrointestinal cancer (P = 0.004), but not for any of the other endpoints. Compared with non-carriers, age and sex adjusted hazard ratios were 2.7 (95% CI 1.......4-5.5) for appendicitis amongst compound heterozygotes, 3.2 (1.3-7.8) for anal fissure, fistula and abscess amongst compound heterozygotes, and 3.8 (1.6-9.2) for gastrointestinal cancer amongst homozygotes, whilst other genotypes did not have increased risk. The increased risk of gastrointestinal cancer amongst...

  9. Combinations of genetic variants associated with bipolar disorder

    DEFF Research Database (Denmark)

    Mellerup, Erling; Andreassen, Ole A.; Bennike, Bente

    2017-01-01

    The main objective of the study was to find genetic variants that in combination are significantly associated with bipolar disorder. In previous studies of bipolar disorder, combinations of three and four single nucleotide polymorphisms (SNP) genotypes taken from 803 SNPs were analyzed, and five...... clusters of combinations were found to be significantly associated with bipolar disorder. In the present study, combinations of ten SNP genotypes taken from the same 803 SNPs were analyzed, and one cluster of combinations was found to be significantly associated with bipolar disorder. Combinations from......, heterozygote or variant homozygote. In the combinations containing 10 SNP genotypes almost all the genotypes were the normal homozygote. Such a finding may indicate that accumulation in the genome of combinations containing few SNP genotypes may be a risk factor for bipolar disorder when those combinations...

  10. NOD2/CARD15 genotype, cardiovascular disease and cancer in 43 600 individuals from the general population

    DEFF Research Database (Denmark)

    Yazdanyar, S.; Nordestgaard, B.G.

    2010-01-01

    from two large Danish general population cohorts followed for 31 years: the Copenhagen City Heart Study (n = 10 597) and the Copenhagen General Population Study (n = 32 999). We examined the risk of cardiovascular disease (2743 and 3890, respectively, in the two studies) and cancer (2144 and 3241......, respectively) by NOD2/CARD15 genotype using Cox and logistic regressions in both studies. To maximize statistical power, the three NOD2/CARD15 genetic variants were analysed together as follows: noncarriers for all three variants, heterozygotes for one of the three variants and homozygotes for one of the three...... variants pooled with compound heterozygotes for two variants. Results. Multifactorially adjusted hazard ratios for cardiovascular disease and cancer in NOD2/CARD15 heterozygotes or homozygotes/compound heterozygotes versus noncarries did not differ from 1.0 in the Copenhagen City Heart Study...

  11. [Polymorphism of dental formula and segregation of its variants in a pedigree of kerry blue terrier dogs].

    Science.gov (United States)

    Aksenovich, T I; Kulikova, A V; Kniazev, S P; Zorkal'tseva, I V; Borodin, P M

    2006-03-01

    Polymorphism of the dental formula was analyzed in a sophisticated pedigree of Kerry Blue Terrier. A lack of one or more lower premolars was observed in some dogs. Two different patterns of missing teeth were identified. One pattern consisted in agenesis of a second premolar, often in combination with agenesis of neighbor teeth, including the fourth premolar. In the second pattern, agenesis of a fourth premolar was expressed as an isolated abnormality. It was shown previously that the first pattern is inherited as a recessive trait with near complete penetrance. In this work, the control of a major-gene was demonstrated for the second pattern. This abnormality develops in 70-80% of mutant homozygotes and in no more than 20% of heterozygotes and wild-type homozygotes. It was shown that the two dentition abnormalities are controlled by different genes, which were designated LPA2 and LPA4 (Lower Premolar Agenesis).

  12. The effects of a single nucleotide polymorphism in SLCO1B1 on the pharmacodynamics of pravastatin.

    Science.gov (United States)

    Martin, Nicholas G; Li, Ka Wah; Murray, Heather; Putt, Wendy; Packard, Chris J; Humphries, Steve E

    2012-02-01

    To determine whether the SNP rs4149056 in SLCO1B1 alters the pharmacodynamics of pravastatin. rs4149056 was genotyped in 626 pravastatin-treated participants in the WOSCOPS trial and the response after 1 year of treatment was compared between the different genotypes. Pravastatin reduced serum LDL cholesterol by 22.2% in TT homozygotes, by 22.2% in TC heterozygotes and by 17.7% in CC homozygotes (TT + TC vs. CC P value 0.33). There were no significant differences in the response of total cholesterol, LDL, HDL, triglycerides or CRP to pravastatin between the genotypes. The rs4149056 SNP did not significantly affect the pharmacodynamics of pravastatin. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

  13. The catechol-O-methyltransferase (COMT) Val158Met genotype modulates working memory-related dorsolateral prefrontal response and performance in bipolar disorder

    DEFF Research Database (Denmark)

    Miskowiak, K. W.; Kjærstad, H. L.; Støttrup, M. M.

    2017-01-01

    -O-methyltransferase (COMT) gene is associated with reduced prefrontal cortex dopamine and exaggerated working memory-related prefrontal activity. This functional magnetic resonance imaging (fMRI) study investigated for the first time whether the COMT Val158Met genotype modulates prefrontal activity during spatial working...... memory in BD. METHODS: Sixty-four outpatients with BD in full or partial remission were stratified according to COMT Val158Met genotype (ValVal [n=13], ValMet [n=34], and MetMet [n=17]). The patients completed a spatial n-back working memory task during fMRI and the Cambridge Neuropsychological Test...... Automated Battery (CANTAB) Spatial Working Memory test outside the scanner. RESULTS: During high working memory load (2-back vs 1-back), Val homozygotes displayed decreased activity relative to ValMet individuals, with Met homozygotes displaying intermediate levels of activity in the right dorsolateral...

  14. Phenotypic and pathologic evaluation of the myd mouse. A candidate model for facioscapulohumeral dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Mathews, K.D.; Rapisarda, D.; Bailey, H.L. [Univ. of Iowa College of Medicine, Iowa City, IA (United States)] [and others

    1995-07-01

    Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant disease of unknown pathogenesis which is characterized by weakness of the face and shoulder girdle. It is associated with a sensorineural hearing loss which may be subclinical. FSHD has been mapped to the distalmost portion of 4q35, although the gene has not yet been identified. Distal 4q has homology with a region of mouse chromosome 8 to which a mouse mutant, myodystrophy (myd), has been mapped. Muscle from homozygotes for the myd mutation appears dystrophic, showing degenerating and regenerating fibers, inflammatory infiltrates, central nuclei, and variation in fiber size. Brainstem auditory evoked potentials reveal a sensorineural hearing loss in myd homozygotes. Based on the homologous genetic map locations, and the phenotypic syndrome of dystrophic muscle with sensorineural hearing loss, we suggest that myd represents an animal model for the human disease FSHD. 28 refs., 4 figs.

  15. Exploratory aspirin resistance trial in healthy Japanese volunteers (J-ART) using platelet aggregation as a measure of thrombogenicity.

    Science.gov (United States)

    Fujiwara, T; Ikeda, M; Esumi, K; Fujita, T D; Kono, M; Tokushige, H; Hatoyama, T; Maeda, T; Asai, T; Ogawa, T; Katsumata, T; Sasaki, S; Suzuki, E; Suzuki, M; Hino, F; Fujita, T K; Zaima, H; Shimada, M; Sugawara, T; Tsuzuki, Y; Hashimoto, Y; Hishigaki, H; Horimoto, S; Miyajima, N; Yamamoto, T; Imagawa, K; Sesoko, S; Fujisawa, Y

    2007-12-01

    Aspirin prevents the production of thromboxane A2 (TXA2) by irreversibly inhibiting platelet cyclooxygenase, exhibiting antiplatelet actions. This agent has been reported to prevent relapse in patients with ischemic heart disease or cerebral infarction via this action mechanism. However, there are individual differences in this action, and aspirin is not effective in some patients, which is referred to as 'aspirin resistance'. In this study, we analyzed laboratory aspirin resistance by platelet aggregation in 110 healthy adult Japanese males using 24 single-nucleotide polymorphisms (SNPs) of nine genes involved in platelet aggregation/hemorrhage. Among SNPs involved in platelet aggregation, aspirin was less effective for 924T homozygote of a TXA2 receptor, 924T>C, and 1018C homozygote of a platelet membrane glycoprotein GPIbalpha, 1018C>T, suggesting that 924T and 1018C alleles are involved in aspirin resistance.

  16. Novel harmful recessive haplotypes identified for fertility traits in Nordic Holstein cattle

    DEFF Research Database (Denmark)

    Sahana, Goutam; Nielsen, Ulrik Sander; Aamand, Gert Pedersen

    2013-01-01

    . A total of 7,937 Nordic Holstein animals were genotyped with BovineSNP50 BeadChip and haplotypes including 25 consecutive markers were constructed and tested for absence of homozygotes states. We have identified 17 homozygote deficient haplotypes which could be loosely clustered into eight genomic regions...... harboring possible recessive lethal alleles. Effects of the identified haplotypes were estimated on two fertility traits: non-return rates and calving interval. Out of the eight identified genomic regions, six regions were confirmed as having an effect on fertility. The information can be used to avoid...... carrier-by-carrier mattings in practical animal breeding. Further, identification of causative genes/polymorphisms responsible for lethal effects will lead to accurate testing of the individuals carrying a lethal allele...

  17. Case series

    African Journals Online (AJOL)

    abp

    4 févr. 2015 ... La prévalence de l'infection par le virus C est de 7% chez les patients homozygotes SS faisant des crises vaso occlusive. Cette série confirme que la ... Tenon, un traitement par Interféron Pégylé et Ribavirine avait été effectué chez 6 .... virus infection with peginterferon alpha-2a and ribavirin in patients with ...

  18. Gene homozygosis and mitotic recombination induced by camptothecin and irinotecan in Aspergillus nidulans diploid cells

    OpenAIRE

    GIOVANA N.M. ESQUISSATO; SANT'ANNA,JULIANE R. DE; CLAUDINÉIA C.S. FRANCO; ROSADA, LÚCIA J.; PAULA A.S.R. DOS SANTOS; Marialba A. A. Castro-Prado

    2014-01-01

    Mitotic recombination is a process involved in carcinogenesis which can lead to genetic loss through the loss of heterozygosity. The recombinogenic potentials of two anticancer drugs topoisomerase I inhibitors, camptothecin (CPT) and irinotecan (CPT-11), were evaluated in the present study. The homozygotization assay, which assess the induction of mitotic recombination and gene homozygosis, as well as the heterozygous A757//UT448 diploid strain of Aspergillus nidulans were employed. The three...

  19. Haemoglobin genotype in a sub-urban commercial community in ...

    African Journals Online (AJOL)

    The hemoglobin electrophoretic pattern showed a distribution of 80, 4% Hb.AA; 19.2% Hb.AS; 0.4% Hb.AC; Hb.SS and Hb.SC 0%. This finding will serve as a guide in genetic counseling of would be couples in marriage. It will also help to eradicate the incidence of Hb.SS homozygotes with all its attendant social problem, ...

  20. Therapeutic Effect of and Evaluation Method for LDL Apheresis in Familial Hypercholesterolemia

    OpenAIRE

    槇野, 久士; 斯波, 真理子; Hisashi, Makino; Mariko, Harada-Shiba; 国立循環器病研究センター糖尿病代謝内科; 国立循環器病研究センター研究所病態代謝部; Division of Endocrinology and Metabolism, National Cerebral and Cardiovasular Center; National Cerebral and Cardiovasular Center Research Institute

    2014-01-01

    Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutation in the gene encoding low-density lipoprotein (LDL) receptor. Since atherosclerotic disease in homozygotes is often severe, prognosis of these patients is poor. They are resistant to drug therapy and LDL apheresis is the only practical treatment. On the other hand, heterozygotes with only serious cardiovascular disease or resistance to statin should be treated with LDL apheresis. LDL apheresis is expected t...

  1. A revisit to the natural history of homocystinuria due to cystathionine beta-synthase deficiency

    DEFF Research Database (Denmark)

    Skovby, Flemming; Gaustadnes, Mette; Mudd, S Harvey

    2010-01-01

    of such individuals expected on the basis of the heterozygote frequency for this mutation found by molecular screening. We conclude that the predominant portion of such homozygotes may be clinically unaffected, or may be ascertained for thromboembolic events occurring no sooner than the third decade of life. If so......, there was significant ascertainment bias in the time-to-event curves previously published describing the natural history of untreated CBS deficiency Mudd et al. and these curves should be used with care....

  2. The Shapes of Z-α1-Antitrypsin Polymers in Solution Support the C-Terminal Domain-Swap Mechanism of Polymerization

    DEFF Research Database (Denmark)

    Behrens, Manja Annette; Sendall, Timothy J.; Pedersen, Jan Skov

    2014-01-01

    Emphysema and liver cirrhosis can be caused by the Z mutation (Glu342Lys) in the serine protease inhibitor α1-antitrypsin (α1AT), which is found in more than 4% of the Northern European population. Homozygotes experience deficiency in the lung concomitantly with a massive accumulation of polymers......-like structures in strong support of a common domain-swap polymerization mechanism that can lead to self-terminating polymers...

  3. Effect of α(+)-thalassaemia on episodes of fever due to malaria and other causes: a community-based cohort study in Tanzania.

    Science.gov (United States)

    Veenemans, Jacobien; Jansen, Esther J S; Baidjoe, Amrish Y; Mbugi, Erasto V; Demir, Ayşe Y; Kraaijenhagen, Rob J; Savelkoul, Huub F J; Verhoef, Hans

    2011-09-22

    It is controversial to what degree α(+)-thalassaemia protects against episodes of uncomplicated malaria and febrile disease due to infections other than Plasmodium. In Tanzania, in children aged 6-60 months and height-for-age z-score malaria and other causes were compared between those with heterozygous or homozygotes α(+)-thalassaemia and those with a normal genotype, using Cox regression models that accounted for multiple events per child. The overall incidence of malaria was 3.0/child-year (1, 572/526 child-years); no differences were found in malaria rates between genotypes (hazard ratios, 95% CI: 0.93, 0.82-1.06 and 0.91, 0.73-1.14 for heterozygotes and homozygotes respectively, adjusted for baseline factors that were predictive for outcome). However, this association strongly depended on age: among children aged 6-17 months, those with α(+)-thalassaemia experienced episodes more frequently than those with a normal genotype (1.30, 1.02-1.65 and 1.15, 0.80-1.65 for heterozygotes and homozygotes respectively), whereas among their peers aged 18-60 months, α(+)-thalassaemia protected against malaria (0.80, 0.68-0.95 and 0.78, 0.60-1.03; p-value for interaction 0.001 and 0.10 for hetero- and homozygotes respectively). No effect was observed on non-malarial febrile episodes. In this population, the association between α(+)-thalassaemia and malaria depends on age. Our data suggest that protection by α(+)-thalassaemia is conferred by more efficient acquisition of malaria-specific immunity.

  4. In-vivo effects of Glu298Asp endothelial nitric oxide synthase polymorphism.

    Science.gov (United States)

    Sofowora, G; Dishy, V; Xie, H G; Imamura, H; Nishimi, Y; Morales, C R; Morrow, J D; Kim, R B; Stein, C M; Wood, A J

    2001-12-01

    Endothelial nitric oxide synthase catalyses the formation of the vasodilator nitric oxide, a major regulator of vascular tone. The Asp298 polymorphism of the nitric oxide synthase gene is associated with altered function and expression of the enzyme in vitro and myocardial infarction and coronary artery spasm in vivo. We examined the effect of the Glu298Asp polymorphism on: (1) local vascular responses to phenylephrine, acetylcholine, glyceryl trinitrate and prostaglandin E1 in the dorsal hand vein; (2) changes in forearm blood flow during mental stress, a measure of nitric oxide-mediated effect on resistance vessels; (3) excretion of urinary nitrite/nitrate as a measure of total body nitric oxide production; and (4) F2-isoprostane metabolite, a measure of oxidative stress, in healthy Glu298 (n = 12) and Asp298 (n = 13) homozygotes. There were no significant differences in acetylcholine dose responses (P = 0.29) in Glu298 and Asp298 homozygotes. Responses to glyceryl trinitrate, prostaglandin E1 and the alpha-adrenergic agonist phenylephrine did not differ by genotype. Forearm blood flow was similar at rest and increased significantly (from 7.5 ml/min/100 ml to 12.2 ml/min/100 ml; P = 0.003), but similarly (P = 0.2), during mental stress in both genotypes. Asp298 homozygotes excreted significantly less nitrate/nitrite than Glu298 homozygotes (nitrate + nitrite/creatinine ratio 0.05 +/- 0.01 vs. 0.09 +/- 0.01, respectively; P < 0.005). Urinary F2-isoprostane metabolite excretion did not differ (Glu298, 2.04 +/- 0.25 ng/mg creatinine; Asp298, 1.85 +/- 0.37 ng/mg creatinine; P = 0.7). We conclude that in healthy volunteers the Glu298Asp polymorphism affects endogenous nitric oxide production without affecting nitric oxide-mediated vascular responses. This polymorphism may only have clinical significance in the presence of endothelial dysfunction.

  5. Intrinsic factors that can affect sensitivity to chromosome-aberration induction

    Energy Technology Data Exchange (ETDEWEB)

    Preston, R.J.

    1982-01-01

    The paper addresses the question, are there individuals who are hypersensitive, or are more likely to be hypersensitive, to the induction of chromosome aberrations by radiation and chemicals. Lymphocytes of persons heterozygous for xeroderma pigmentosum, ataxia telangiectasia, and Fauconi's anemia were subjected to chemical and/or ionizing radiations to determine their sensitivity to chromosome aberration induction. In the majority of cases the sensitivity was intermediate between that of normal individuals and homozygotes for these genes. (ACR)

  6. Collagen type 1 (COL1A1) Sp1 binding site polymorphism is associated with osteoporotic fractures but not with bone density in post-menopausal women from the Canary Islands: a preliminary study.

    Science.gov (United States)

    Navarro, Mary C; Sosa, Manuel; del Pino-Montes, Javier; Torres, Armando; Salido, Eduardo; Saavedra, Pedro; Corral-Gudino, Luis; Montilla, Carlos A

    2007-02-01

    An association between the polymorphism for transcription factor Sp1 in the gene COL1A1 and low bone density (BMD) and osteoporotic fractures has been described but not confirmed for all races and ages. The aim of this preliminary work was to ascertain whether this association is present in women from the Canary Islands. Polymerase chain reaction RFLP was used to determine COL1A1 polymorphism Sp1 in 199 consecutive outpatient post-menopausal Caucasian women from the Canary Islands, aged 50-70 years. BMD was measured at lumbar spine and hip by DXA and at third lumbar vertebrae by QCT. Prevalent vertebral fractures were recorded on standard lateral X-ray film. Non-vertebral osteoporotic fractures were registered by medical record and self-reported history. Biochemical markers (serum osteocalcin, tartrate-resistant acid phosphatase), blood calcium and phosphate were also assessed. Distribution genotypes were 113 (50.8%) GG homozygotes, 73 (36.7%) Ss heterozygotes and 7 (3.5%) TT homozygotes. All patients with osteoporotic fractures carried the GG allele more frequently than TT homozygotic women. The odds ratio was 3.01 (95% CI 1.6-5.7) for prevalent vertebral fractures (n=62) and 2.33 (95% CI 1.2-4.4) for all osteoporotic fractures (n=65) for the T-carrying allele vs TT homozygotic women. There was no difference in BMD measured by DXA or QCT, nor in bone markers, blood calcium or phosphate. This preliminary study confirmed that the presence of at least one copy of the T allele is associated with osteoporotic fractures, but not with low BMD, in women from the Canary Islands.

  7. Visual evoked potentials in Negro carriers of the gene for tyrosinase positive oculocutaneous albinism.

    Science.gov (United States)

    Castle, D; Kromberg, J; Kowalsky, R; Moosa, R; Gillman, N; Zwane, E; Fritz, V

    1988-01-01

    Visual evoked potential testing was performed on 15 Negro carriers of the gene for tyrosinase positive oculocutaneous albinism in order to detect whether they have the same visual pathway decussation anomalies as do homozygotes. No subject showed 01-02 asymmetry on monocular testing, indicating that decussation follows the normal pattern. It is concluded that visual evoked potential testing is probably not useful in the detection of Negroes heterozygous for the gene for tyrosinase positive oculocutaneous albinism. PMID:3148727

  8. [Hermaphroditos in Greek mythology--DSD in moderne medicine].

    Science.gov (United States)

    Oestmann, A; Mullis, P E; Stanga, Z

    2009-01-07

    We report a case of 34 year old woman how has been hospitalized at the age of 6 month with persistent vomitus. The vomitus was found to be caused by adrenal insufficiency with lack of all hormones of steroidobiosynthesis. The phenotypical femal child was diagnosed to have congenital lipoid adrenal hyperplasia with 46,XY DSD. 24 years later a homozygote mutation in the StAR-gene (L260P), which was first described in Switzerland, has been identified.

  9. Interethnic diversity of the CD209 (rs4804803 gene promoter polymorphism in African but not American sickle cell disease

    Directory of Open Access Journals (Sweden)

    Jenelle A. Noble

    2015-02-01

    Full Text Available Elucidating the genomic diversity of CD209 gene promoter polymorphism could assist in clarifying disease pathophysiology as well as contribution to co-morbidities. CD209 gene promoter polymorphism has been shown to be associated with susceptibility to infection. We hypothesize that CD209 mutant variants occur at a higher frequency among Africans and in sickle cell disease. We analyzed the frequency of the CD209 gene (rs4804803 in healthy control and sickle cell disease (SCD populations and determined association with disease. Genomic DNA was extracted from blood samples collected from 145 SCD and 231 control Africans (from Mali, 331 SCD and 379 control African Americans and 159 Caucasians. Comparative analysis among and between groups was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP. Per ethnic diversification, we found significant disparity in genotypic (23.4% versus 16.9% versus 3.2% and allelic frequencies (48.7% versus 42.1% versus 19.8% of the homozygote mutant variant of the CD209 (snp 309A/G gene promoter between Africans, African Americans and Caucasians respectively. Comparative evaluation between disease and control groups reveal a significant difference in genotypic (10.4% versus 23.4%; p = 0.002 and allelic frequencies (39.7% versus 48.7%; p = 0.02 of the homozygote mutant variant in African SCD and healthy controls respectively, an observation that is completely absent among Americans. Comparing disease groups, we found no difference in the genotypic (p = 0.19 or allelic (p = 0.72 frequencies of CD209 homozygote mutant variant between Africans and Americans with sickle cell disease. The higher frequency of CD209 homozygote mutant variants in the African control group reveals a potential impairment of the capacity to mount an immune response to infectious diseases, and possibly delineate susceptibility to or severity of infectious co-morbidities within and between groups.

  10. A dopamine D2 receptor gene polymorphism and physical activity in two family studies.

    Science.gov (United States)

    Simonen, Riitta L; Rankinen, Tuomo; Pérusse, Louis; Leon, Arthur S; Skinner, James S; Wilmore, Jack H; Rao, D C; Bouchard, Claude

    2003-04-01

    A role for dopamine neurotransmission in the regulation of motor activity and reinforcement of behavior is supported by considerable evidence. We studied the association between a marker in the dopamine D2 receptor gene (DRD2) and physical activity level in two cohorts. A first cohort consisted of 721 participants from 161 families of the Quebec Family Study (QFS). Physical activity phenotypes were obtained from a three-day diary and a questionnaire probing physical activity during the past year. The second cohort was the HERITAGE Family Study (HERITAGE), which included 275 Black and 497 White participants from 228 families, among whom past year leisure time and occupational physical activity were probed. A fragment length polymorphism in exon 6 of the DRD2 gene was detected by the polymerase chain reaction (PCR) and NcoI digestion. Frequencies for the T and C alleles were 28% and 72% in the QFS. In the QFS, TT homozygote women had 25% and 34% lower age and BMI-adjusted physical activity level during the past year, compared to CC homozygotes and CT heterozygotes (F=4.42, P=.016). The DRD2 genotype was not associated with the QFS phenotypes obtained from the three-day diary. In the HERITAGE, the frequency of the T allele was 30% among Whites and 63% among Blacks. Similarly, the TT homozygote White women had 29-38% lower sports index (F=4.09, P=.023) and 27-33% lower work index (F=6.23, P=.004) than the CC homozygotes and CT heterozygotes. The results suggest that DNA sequence variation in the DRD2 gene is associated with physical activity levels among White women.

  11. Associations of Cigarette Smoking and Polymorphisms in Brain-Derived Neurotrophic Factor and Catechol-O-Methyltransferase with Neurocognition in Alcohol Dependent Individuals during Early Abstinence

    Directory of Open Access Journals (Sweden)

    Timothy eDurazzo

    2012-10-01

    Full Text Available Chronic cigarette smoking and polymorphisms in brain-derived neurotrophic factor (BDNF and catechol-o-methyltransferase (COMT are associated with neurocognition in normal controls and those with various neuropsychiatric conditions. The influence of these polymorphisms on neurocognition in alcohol dependence is unclear. The goal of this report was to investigate the associations of single nucleotide polymorphisms (SNP in BDNF Val66Met and COMT Val158Met with neurocognition in a treatment-seeking alcohol dependent cohort and determine if neurocognitive differences between non-smokers and smokers previously observed in this cohort persist when controlled for these functional SNPs. Genotyping was conducted on 70 primarily male treatment-seeking alcohol dependent participants (ALC who completed a comprehensive neuropsychological battery after 33 ± 9 days of monitored abstinence. Smoking ALC performed significantly worse than non-smoking ALC on the domains of auditory-verbal and visuospatial learning and memory, cognitive efficiency, general intelligence, processing speed and global neurocognition. In smoking ALC, greater number of years of smoking over lifetime was related to poorer performance on multiple domains. COMT Met homozygotes were superior to Val homozygotes on measures of executive skills and showed trends for higher general intelligence and visuospatial skills, while COMT Val/Met heterozygotes showed significantly better general intelligence than Val homozygotes. COMT Val homozygotes performed better than heterozygotes on auditory-verbal memory. BDNF genotype was not related to any neurocognitive domain. The findings are consistent with studies in normal controls and neuropsychiatric cohorts that observed COMT Met carriers showed better performance on measures of executive skills and general intelligence. Overall, the findings support to the expanding clinical movement to make smoking cessation programs available at the inception of

  12. Genotyping of mannose-binding lectin (MBL2 codon 54 and promoter alleles in Egyptian infants with acute respiratory tract infections

    Directory of Open Access Journals (Sweden)

    Rabah M. Shawky

    2014-01-01

    Conclusion: Although there is a significantly increased incidence of LX promoter coding for low serum MBL concentrations among the ARTI patients; the YA/XA heterozygote promoter genotype was more prevalent over the homozygote mutant genotype. Also, the heterozygote codon 54 A/B genotype was more prevalent in the group of patients compared to the control. This may be an example of heterosis (heterozygote advantage which may support the concept of balanced polymorphism.

  13. CYP1A2 Genotype Variations Do Not Modify the Benefits and Drawbacks of Caffeine during Exercise: A Pilot Study

    Directory of Open Access Journals (Sweden)

    Juan J. Salinero

    2017-03-01

    Full Text Available Previous investigations have determined that some individuals have minimal or even ergolytic performance effects after caffeine ingestion. The aim of this study was to analyze the influence of the genetic variations of the CYP1A2 gene on the performance enhancement effects of ingesting a moderate dose of caffeine. In a double-blind randomized experimental design, 21 healthy active participants (29.3 ± 7.7 years ingested 3 mg of caffeine per kg of body mass or a placebo in testing sessions separated by one week. Performance in the 30 s Wingate test, visual attention, and side effects were evaluated. DNA was obtained from whole blood samples and the CYP1A2 polymorphism was analyzed (rs762551. We obtained two groups: AA homozygotes (n = 5 and C-allele carriers (n = 16. Caffeine ingestion increased peak power (682 ± 140 vs. 667 ± 137 W; p = 0.008 and mean power during the Wingate test (527 ± 111 vs. 518 ± 111 W; p < 0.001 with no differences between AA homozygotes and C-allele carriers (p > 0.05. Reaction times were similar between caffeine and placebo conditions (276 ± 31 vs. 269 ± 71 milliseconds; p = 0.681 with no differences between AA homozygotes and C-allele carriers. However, 31.3% of the C-allele carriers reported increased nervousness after caffeine ingestion, while none of the AA homozygotes perceived this side effect. Genetic variations of the CYP1A2 polymorphism did not affect the ergogenic effects and drawbacks derived from the ingestion of a moderate dose of caffeine.

  14. COMT Val158Met genotype selectively alters prefrontal [18F]fallypride displacement and subjective feelings of stress in response to a psychosocial stress challenge.

    Directory of Open Access Journals (Sweden)

    Dennis Hernaus

    Full Text Available Catechol-O-methyltransferase (COMT plays an essential role in degradation of extracellular dopamine in prefrontal regions of the brain. Although a polymorphism in this gene, COMT Val(158Met, affects human behavior in response to stress little is known about its effect on dopaminergic activity associated with the human stress response, which may be of interest for stress-related psychiatric disorders such as psychosis. We aimed to investigate the effect of variations in COMT genotype on in vivo measures of stress-induced prefrontal cortex (PFC dopaminergic processing and subjective stress responses. A combined sample of healthy controls and healthy first-degree relatives of psychosis patients (n = 26 were subjected to an [(18F]fallypride Positron Emission Tomography scan. Psychosocial stress during the scan was induced using the Montreal Imaging Stress Task and subjective stress was assessed every 12 minutes. Parametric t-maps, generated using the linear extension of the simplified reference region model, revealed an effect of COMT genotype on the spatial extent of [(18F]fallypride displacement. Detected effects of exposure to psychosocial stress were unilateral and remained restricted to the left superior and right inferior frontal gyrus, with Met-hetero- and homozygotes showing less [(18F]fallypride displacement than Val-homozygotes. Additionally, Met-hetero- and homozygotes experienced larger subjective stress responses than Val-homozygotes. The direction of the effects remained the same when the data was analyzed separately for controls and first-degree relatives. The human stress response may be mediated in part by COMT-dependent dopaminergic PFC activity, providing speculation for the neurobiology underlying COMT-dependent differences in human behaviour following stress. Implications of these results for stress-related psychopathology and models of dopaminergic functioning are discussed.

  15. The -675 4G/5G polymorphism at the Plasminogen Activator Inhibitor 1 (PAI-1) gene modulates plasma Plasminogen Activator Inhibitor 1 concentrations in response to dietary fat consumption.

    Science.gov (United States)

    Pérez-Martínez, P; Adarraga-Cansino, M D; Fernández de la Puebla, R A; Blanco-Molina, A; Delgado-Lista, J; Marín, C; Ordovás, J M; López-Miranda, J; Pérez-Jiménez, F

    2008-04-01

    The objective of the study was to determine whether Plasminogen Activator Inhibitor Type 1 (PAI-1) -675 4G/5G polymorphism is associated with the response of functional plasma PAI-1 concentrations to changes in the amount and quality of dietary fat in healthy subjects. PAI-1 is the major inhibitor of fibrinolysis, and a lower level of fibrinolytic activity could be implicated in an increased risk of IHD. Fifty-nine healthy Spanish volunteers (ten 4G/4G homozygotes, twenty-eight heterozygotes 4G/5G and twenty-one 5G/5G homozygotes) consumed three diets for periods of 4 weeks each: a SFA-rich diet (38 % fat, 20 % SFA), followed by a carbohydrate-rich diet (30 % fat, 55 % carbohydrate) and a MUFA-rich diet (38 % fat, 22 % MUFA) according to a randomized crossover design. At the end of each dietary period plasma lipid and functional plasma PAI-1 concentrations were determined. Subjects carrying the 4G allele (4G/4G and 4G/5G) showed a significant decrease in PAI-1 concentrations after the MUFA diet, compared with the SFA-rich and carbohydrate-rich diets (genotype x diet interaction: P = 0.028). 5G/5G homozygotes had the lowest plasma PAI-1 concentrations compared with 4G/4G and 4G/5G subjects (genotype: P = 0.002), without any changes as a result of the amount and the quality of the dietary fat. In summary, no differences in plasma PAI-1 concentration response were found after changes in dietary fat intake in 5G/5G homozygotes, although these subjects displayed the lowest concentrations of PAI-1. On the other hand, carriers of the 4G allele are more likely to hyper-respond to the presence of MUFA in the diet because of a greater decrease in PAI-1 concentrations.

  16. Роль поліморфізму гену матриксної металопротеїнази-1 (1607insG) в формуванні бронхолегеневої дисплазії у новонароджених

    OpenAIRE

    G.S. Senatorova; Logvinova, A. L.; Omelchenko, A. V.; Onikiyenko, A. L.

    2016-01-01

    The environmental (0.54) and hereditary (0.46) factors contribute equally to development of BPD, which requires studying of the polymorphism of genes and their regulatory functions for the prediction of chronic disease during pregnancy and in newborns. MMP-1 gene (1607insG) polymorphism affects on the individual tending to bronchopulmonary dysplasia (KW = H (n = 58) = 18.85, p = 0.0001). The prevalence of dominant homozygotes (AA) and heterozygotes (Aa) by insertion of guanine at position 160...

  17. numb one

    African Journals Online (AJOL)

    PROPRIETAIRE

    individus homozygotes mais exige une haute compétence en techniques obstétricales et en biologie molécu- laire. La maladie drépanocytaire entraîne des anomalies biologiques d'une grande hétérogénéité, caractéris- tique de cette affection héréditaire. MOTS CLEFS : Drépanocytose –Diagnostic-Anomalies biologiques.

  18. The BDNFval66metpolymorphism and individual differences in temperament in 4-month-old infants: A pilot study.

    Science.gov (United States)

    Giusti, Lorenzo; Provenzi, Livio; Tavian, Daniela; Missaglia, Sara; Butti, Niccolò; Montirosso, Rosario

    2017-05-01

    Individual differences in infants' temperament are under genetic control. We investigated the association between brain-derived-neurotrophic-factor (BDNF val66met ) polymorphism and temperament in 63 full-term infants. Met-carriers (N=25) had lower Regulatory capacities compared to val-homozygotes (N=38). These findings suggest that the BDNF polymorphism affects early temperament individual differences. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Generaliserede kramper som debutsymptom ved Gitelmans syndrom

    DEFF Research Database (Denmark)

    Hvelplund, Carolina; Jeppesen, Eva Mosfeldt; Mortensen, Henrik B

    2009-01-01

    Gitelman's syndrome is a rare autosomal recessive syndrome presenting with hypocalciuria, hypomagnesiemia and hypokalemic metabolic alkalosis. This case reports a patient admitted with generalized seizures with the above-mentioned biochemical abnormalities, thus representing a rare onset...... of Gitelman's syndrome which - to our knowledge - has not been described previously. The patient had a homozygote deletion of the CLC-KB gene, CLCNKB. The case was successfully treated by correcting hypokalemia and hypomagnesiemia with supplemental potassium and magnesium. Udgivelsesdato: 2009-Mar-2...

  20. Fluconazole induces rapid high-frequency MTL homozygosis with microbiological polymorphism in Candida albicans

    Directory of Open Access Journals (Sweden)

    Tsong-Yih Ou

    2017-12-01

    Full Text Available Background: Candida albicans, a common fungal pathogen that can cause opportunistic infections, is regarded as an apparently asexual, diploid fungus. A parasexual cycle was previously found between homozygotes with opposite mating type-like loci (MTLa/α. Fluconazole-resistant strains had a higher proportion of MTL homozygotes, whereas MTL homozygous C. albicans was found in only about 3.2% of clinical strains. MTL heterozygotes had a low frequency (1.4 × 10−4 of white–opaque switching to MTL homozygotes in nature. Methods: Here, a reference C. albicans strain (SC5314 was used in a fluconazole-induced assay to obtain standard opaque MTL homozygous strains and first-generation daughter strains from the fluconazole inhibition zone. Further separation methods were employed to produce second- and third-generation daughter strains. Polymerase chain reaction analysis based on MTL genes was used to define MTL genotypes, and microscopic observations, a flow-cytometric assay, and an antifungal E-test were used to compare microbiological characteristics. Results: MTL homozygotes were found at a high frequency (17 of 35; 48.6% in fluconazole-induced first-generation daughter strains, as were morphological polymorphisms, decreased DNA content, and modified antifungal drug susceptibility. High-frequency MTL homozygosity was identified inside the fluconazole inhibition zone within 24 hours. The DNA content of fluconazole-induced daughter strains was reduced compared with their progenitor SC5314 and standard MTL homozygous strains. Conclusion: Treatment with fluconazole, commonly used to treat invasive candidiasis, inhibited the growth of C. albicans and altered its microbiological characteristics. Our results suggest that fluconazole treatment induces the high frequency of loss of heterozygosity and microbiological polymorphism in C. albicans. Keywords: Candida albicans, fluconazole, loss of heterozygosity, mating type-like gene