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Sample records for improves ifosfamide-induced fanconi

  1. Ifosfamide-Induced Fanconi's Syndrome

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    Lin-Kun Lee

    2014-06-01

    Full Text Available Ifosfamide is an alkylating antineoplastic prodrug used to treat many solid tumors. The metabolism of ifosfamide is via CYP450 3A4 and 2B6 and produces active ifosfamide mustard, the toxic metabolite acrolein and chloroacetaldehyde (CAA. Additionally, CAA is believed to induce proximal tubular dysfunction which results in Fanconi's syndrome. It is a condition not commonly encountered in adults receiving ifosfamide but relatively common in children. Herein, we have reported a 25-year-old woman with a history of synovial sarcoma with multiple lung metastasis and repetitive locoregional recurrence. She received chemotherapy with high dose ifosfamide as her antineoplastic treatment. Before her 4th cycle of chemotherapy, the patient's pre-chemotherapy evaluation revealed proteinuria, glucosuria, phosphateuria, hypophosphatemia and non-anion gap metabolic acidosis. The above conditions were consistent with Fanconi's syndrome. We treated her with electrolyte supplement and close monitoring of the noted laboratory abnormalities. Fortunately, the laboratory abnormality gradually resolved. Our case highlights the rare potential complication of ifosfamide, especially in patients who had received a high cumulive dose. To avoid this rare but potentially debilitating condition, patients whose cumulative ifosfamide dose reaches threshold should be closely monitored.

  2. Carnitine Deficiency and Oxidative Stress Provoke Cardiotoxicity in an Ifosfamide-Induced Fanconi Syndrome Rat Model

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    Mohamed M. Sayed-Ahmed

    2010-01-01

    -depleted rats, IFO induced dramatic increase in serum creatinine, BUN, CK-MB, LDH, carnitine clearance and intramitochondrial acetyl-CoA/CoA-SH, as well as progressive reduction in total carnitine and ATP in cardiac tissues. Interestingly, PLC supplementation completely reversed the biochemical changes-induced by IFO to the control values. In conclusion, data from the present study suggest that: Carnitine deficiency and oxidative stress, secondary to Fanconi Syndrome, constitute risk factors and should be viewed as mechanisms during development of IFO-induced cardiotoxicity. Carnitine supplementation, using PLC, prevents the development of IFO-induced cardiotoxicity through antioxidant signalling and improving mitochondrial function.

  3. Downregulation of Oxidative and Nitrosative Apoptotic Signaling by L-Carnitine in Ifosfamide-Induced Fanconi Syndrome Rat Model

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    Mohamed M. Sayed-Ahmed

    2012-01-01

    Full Text Available It is well documented that ifosfamide (IFO therapy is associated with sever nephropathy in the form of Fanconi syndrome. Although oxidative stress has been reported as a major player in IFO-induced Fanconi syndrome, no mechanism for this effect has been ascertained. Therefore, this study has been initiated to investigate, on gene expression level, the mechanism of IFO-induce nephrotoxicity and those whereby carnitine supplementation attenuates this serious side effect of IFO. To achieve the ultimate goals of this study, adult male rats were assigned to one of four treatment groups, namely, control, L-carnitine, IFO, and IFO plus L-carnitine. Administration of IFO for 5 days significantly increased serum creatinine, blood urea nitrogen (BUN, and total nitrate/nitrite (NOx production in kidney tissues. In addition, IFO significantly increased mRNA expression of inducible nitric oxide synthase (iNOS, caspase-9, and caspase-3 and significantly decreased expression of glutathione peroxides (GPx, catalase (CAT, and Bcl2 in kidney tissues. Administration of L-carnitine to IFO-treated rats resulted in a complete reversal of the all biochemical and gene expression changes, induced by IFO, to the control values. Data from this study suggest that L-carnitine prevents the development of IFO-induced nephrotoxicity via downregulation of oxidative and nitrosative apoptotic signaling in kidney tissues.

  4. Antioxidant activity of simvastatin prevents ifosfamide-induced nephrotoxicity.

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    Mhaidat, Nizar Mahmoud; Ali, Reem Mustafa; Shotar, Ali Muhammad; Alkaraki, Almuthanna Khalaf

    2016-03-01

    Ifosfamide is an anticancer agent used largely in treatment of solid tumors. The mainstay dose-limiting toxicity of ifosfamide is nephrotoxicity. This is largely believde to be a result of ifosfamide-induced oxidative stress. In this study, we investigated the antioxidant activity of simvastatin and the possible protective role of simvastatin against ifosfamide induced nephrotoxicity. Thirty Sprague-Dawely rats were divided into five groups and given orally different drug combinations. Group I and II were regarded as control groups and received 0.1% DMSO and normal saline, respectively. Group III received ifosfamide at 50 mg/kg, group IV received simvastatin at 0.3 mg/kg and group V received both ifosfamide and simvastatin. All animals were decapitated 2 days after the last ifosfamide administration. Findings revealed that ifosfamide induced nephrotoxicity as indicated by a significant increase in plasma creatinine and lipid per oxidation. This increase was significantly inhibited in animals pretreated with simvastatin. Histopathological observations were in correlation with the biochemical parameters in that simvastatin minimized ifosfamide-induced renal tubular damage. The above results promote a future use of simvastatin in combination with ifosfamide in treatment of cancer patients to indicate that simvastatin protectics against ifosfamide-induced nephrotoxicity in terms of oxidative stress and might be given in combination.

  5. Living with Fanconi Anemia

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    ... from the NHLBI on Twitter. Living With Fanconi Anemia Improvements in blood and marrow stem cell transplants ... November 1, 2011 Twitter Facebook YouTube Google+ SITE INDEX ACCESSIBILITY PRIVACY STATEMENT FOIA NO FEAR ACT OIG ...

  6. Fanconi Anemia Research Fund

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    ... Support Publications Fundraising News What is the Fanconi Anemia Research Fund? Fanconi anemia is an inherited disease that can lead to ... population. Lynn and Dave Frohnmayer started the Fanconi Anemia Research Fund, in 1989 to find effective treatments ...

  7. The Sirt1 activator SRT3025 expands hematopoietic stem and progenitor cells and improves hematopoiesis in Fanconi anemia mice

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    Qing-Shuo Zhang

    2015-07-01

    Full Text Available Fanconi anemia is a genetic bone marrow failure syndrome. The current treatment options are suboptimal and do not prevent the eventual onset of aplastic anemia requiring bone marrow transplantation. We previously showed that resveratrol, an antioxidant and an activator of the protein deacetylase Sirt1, enhanced hematopoiesis in Fancd2 mutant mice and improved the impaired stem cell quiescence observed in this disease. Given that Sirt1 is important for the function of hematopoietic stem cells, we hypothesized that Sirt1 activation may improve hematopoiesis. Indeed, Fancd2−/− mice and wild-type mice treated with the selective Sirt1 activator SRT3025 had increased numbers of hematopoietic stem and progenitor cells, platelets and white blood cells. SRT3025 was also protective against acetaldehyde-induced hematopoietic damage. Unlike resveratrol, however, SRT3025 did not affect stem cell quiescence, suggesting distinct mechanisms of action. Conditional deletion of Sirt1 in hematopoietic cells did not abrogate the beneficial effects of SRT3025, indicating that the drug did not act by directly stimulating Sirt1 in stem cells, but must be acting indirectly via extra-hematopoietic effects. RNA-Seq transcriptome analysis revealed the down-regulation of Egr1–p21 expression, providing a potential mechanism for improved hematopoiesis. Overall, our data indicate that SRT3025 or related compounds may be beneficial in Fanconi anemia and other bone marrow failure syndromes.

  8. The Sirt1 activator SRT3025 expands hematopoietic stem and progenitor cells and improves hematopoiesis in Fanconi anemia mice.

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    Zhang, Qing-Shuo; Deater, Matthew; Schubert, Kathryn; Marquez-Loza, Laura; Pelz, Carl; Sinclair, David A; Grompe, Markus

    2015-07-01

    Fanconi anemia is a genetic bone marrow failure syndrome. The current treatment options are suboptimal and do not prevent the eventual onset of aplastic anemia requiring bone marrow transplantation. We previously showed that resveratrol, an antioxidant and an activator of the protein deacetylase Sirt1, enhanced hematopoiesis in Fancd2 mutant mice and improved the impaired stem cell quiescence observed in this disease. Given that Sirt1 is important for the function of hematopoietic stem cells, we hypothesized that Sirt1 activation may improve hematopoiesis. Indeed, Fancd2(-/-) mice and wild-type mice treated with the selective Sirt1 activator SRT3025 had increased numbers of hematopoietic stem and progenitor cells, platelets and white blood cells. SRT3025 was also protective against acetaldehyde-induced hematopoietic damage. Unlike resveratrol, however, SRT3025 did not affect stem cell quiescence, suggesting distinct mechanisms of action. Conditional deletion of Sirt1 in hematopoietic cells did not abrogate the beneficial effects of SRT3025, indicating that the drug did not act by directly stimulating Sirt1 in stem cells, but must be acting indirectly via extra-hematopoietic effects. RNA-Seq transcriptome analysis revealed the down-regulation of Egr1-p21 expression, providing a potential mechanism for improved hematopoiesis. Overall, our data indicate that SRT3025 or related compounds may be beneficial in Fanconi anemia and other bone marrow failure syndromes.

  9. Mouse models of Fanconi anemia

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    Parmar, Kalindi; D' Andrea, Alan [Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115 (United States); Niedernhofer, Laura J., E-mail: niedernhoferl@upmc.edu [Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine and Cancer Institute, 5117 Centre Avenue, Hillman Cancer Center, Research Pavilion 2.6, Pittsburgh, PA 15213-1863 (United States)

    2009-07-31

    Fanconi anemia is a rare inherited disease characterized by congenital anomalies, growth retardation, aplastic anemia and an increased risk of acute myeloid leukemia and squamous cell carcinomas. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia pathway, a response mechanism to replicative stress, including that caused by genotoxins that cause DNA interstrand crosslinks. Defects in the Fanconi anemia pathway lead to genomic instability and apoptosis of proliferating cells. To date, 13 complementation groups of Fanconi anemia were identified. Five of these genes have been deleted or mutated in the mouse, as well as a sixth key regulatory gene, to create mouse models of Fanconi anemia. This review summarizes the phenotype of each of the Fanconi anemia mouse models and highlights how genetic and interventional studies using the strains have yielded novel insight into therapeutic strategies for Fanconi anemia and into how the Fanconi anemia pathway protects against genomic instability.

  10. Mouse models of Fanconi anemia

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    Parmar, Kalindi; D'Andrea, Alan; Niedernhofer, Laura J.

    2009-01-01

    Fanconi anemia is a rare inherited disease characterized by congenital anomalies, growth retardation, aplastic anemia and an increased risk of acute myeloid leukemia and squamous cell carcinomas. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia pathway, a response mechanism to replicative stress, including that caused by genotoxins that cause DNA interstrand crosslinks. Defects in the Fanconi anemia pathway lead to genomic instability and apoptosis ...

  11. A simplified approach to improve the efficiency and safety of ex vivo hematopoietic gene therapy in fanconi anemia patients.

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    Jacome, A; Navarro, S; Casado, J A; Rio, P; Madero, L; Estella, J; Sevilla, J; Badell, I; Ortega, J J; Olivé, T; Hanenberg, H; Segovia, J C; Bueren, J A

    2006-02-01

    Fanconi anemia (FA) is an inherited DNA repair disorder characterized by genetic instability of cells lacking a functional FA/BRCA pathway. Previous studies have shown that in vitro stimulation of bone marrow cells (BMCs) from FA mice promotes apoptosis, reduces the reconstitution ability of the stem cells, and induces myelodysplasia and myeloid leukemia upon reinfusion of the cells. This suggests the convenience of adapting standard protocols of gene therapy to FA. Here we show that the reserve of BM progenitors in FA patients is generally below 20% of normal values. Because this reduced reserve could activate the cycling of BM progenitors, we developed a simplified protocol to transduce BMCs from FA patients with gammaretroviral vectors. We demonstrate that a short in vitro manipulation (12-24 hr) of fresh mononuclear BMCs is sufficient to transduce 42% of hematopoietic progenitors from FA-A patients, in the absence of in vitro prestimulation. When FANCA-expressing vectors were used, this simple procedure reversed the phenotype of the BM progenitors from these patients. We propose that our approach will be more efficient and safer compared with standard gene therapy protocols for FA.

  12. How Is Fanconi Anemia Diagnosed?

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    ... from the NHLBI on Twitter. How Is Fanconi Anemia Diagnosed? People who have Fanconi anemia (FA) are born with the disorder. They may ... questions about: Any personal or family history of anemia Any surgeries you’ve had related to the ...

  13. Fanconi anemia and radiation

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    Nakamura, Asako; Komatsu, Kenshi [Hiroshima Univ. (Japan). Research Inst. for Nuclear Medicine and Biology

    1999-09-01

    Aplastic Fanconi anemia (FA) accompanying malformation was firstly reported in 1927. This review concerns the recent findings on FA. FA belongs to the chromosomal instability syndrome and its detailed molecular mechanism is still unknown. The disease has been defined to be highly sensitive to radiation, however, which is quite an important problem since irradiation with a large dose of radiation is required before its radical treatment (bone marrow transplantation). FA cells are also mitomycin C-sensitive and FA patients are said to be the mosaic of the sensitive and normal cells. This enables to classify FA into 8 types of A-H groups, whose genotypes (FAA-FAH, FANCA-FANCH) are becoming clear. However, the intracellular function of the FANC-expressed protein, although known to form a big complex, is not elucidated yet. There is an abnormality in DNA processing such as re-linkage of the double strand-broken DNA in FA cells. FA causal gene FANCG is found identical to XRCC9 which is associated to high sensitivity to radiation. Analysis of FANC genes will provide useful findings on molecular mechanism of DNA-repair. (K.H.)

  14. Genetics Home Reference: Fanconi anemia

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    ... center of the brain (hydrocephalus) or an unusually small head size ( microcephaly ). Individuals with Fanconi anemia have an increased risk of developing a cancer of blood-forming cells in the bone marrow called acute myeloid leukemia (AML) or tumors of the head, neck, skin, ...

  15. Transient Fanconi syndrome in Quarter horses.

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    Ohmes, Cameon M; Davis, Elizabeth G; Beard, Laurie A; Vander Werf, Karie A; Bianco, Alex W; Giger, Urs

    2014-02-01

    Two Quarter horses with weight loss had glucosuria, euglycemia, and a mild metabolic acidosis suggesting a proximal renal tubular defect. Further testing revealed transient generalized aminoaciduria, lactic aciduria, and glucosuria, indicating Fanconi syndrome. Both horses recovered with supportive therapy. This is the first report of acquired Fanconi syndrome in horses.

  16. Fanconi anemia - learning from children

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    Johanna Svahn

    2011-06-01

    Full Text Available Fanconi Anemia (FA is a rare autosomic recessive and X-linked disease with chromosomal instability after exposure to crosslinking agents as the hallmark. Clinical features of FA are somatic malformations, progressive bone marrow failure and cancer proneness, however there is wide clinical heterogeneity. The symptom most frequently and early associated with morbidity and mortality is progressive pancytopenia in the first decade of life although acute myelogenous leukemia (AML or myelodysplastic syndrome (MDS can appear before aplastic anemia. Squamous cell carcinoma (SCC of the head-neck, intestinal or genital tract has a very high incidence in FA and can appear at young age. This paper will focus on treatment of bone marrow failure in FA.

  17. Anemia de Fanconi y embarazo: una combinación inusual Fanconi`s anemia and pregnancy: an unusual combination

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    Carlos Escalante-Gómez; Judith Jiménez-Torrealba

    2008-01-01

    La anemia de Fanconi es una falla clásica de la médula ósea, la cual tiene una incidencia de menos de 1 en 100,000 nacidos vivos. Hasta ahora, las pacientes femeninas normalmente no alcanzaban la edad reproductiva y mucho menos lograban el embarazo. Una revisión actual de la literatura identifica solamente 19 pacientes que han logrado el embarazo. Presentamos el caso de una paciente de 16 años portadora de anemia de Fanconi, la cual presenta un embarazo de 30 semanas complicado por un cuadro ...

  18. Recurrent aphthous ulcers in Fanconi's anaemia: a case report.

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    Otan, Feyza; Açikgöz, Gokhan; Sakallioglu, Umur; Ozkan, Burcu

    2004-05-01

    Fanconi's anaemia (FA) is an autosomal recessive disorder that is clinically characterized by aplastic anaemia, congenital malformations of the renal, cardiac, skeletal and skin structures, and an increased predisposition to malignancies. Patients with FA often present with bleeding and infection, which are symptoms related to thrombocytopenia and neutropenia. There are few reports of the oral manifestations of FA. We describe oral aphthous ulcerations in two siblings with FA. There was a rapid improvement and healing of ulcers after blood transfusions and increased haemoglobin levels. This may support the role of severe anaemia in oral ulcerations.

  19. Fanconi anemia: in all its glory

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    Rajesh Rai

    2015-04-01

    Full Text Available Fanconi Anemia (FA is a rare autosomal recessive disorder affecting multiple body systems. The diagnosis is based on morphological abnormalities, hematological abnormalities (pancytopenia, macrocytic anemia and progressive bone marrow failure and genetic testing. However, genetic testing is complicated for FA because there are often many genes that are associated with its development, and large duplications, deletions or sequence variations are frequently observed in some of these genes. We report a patient with cytogenetically confirmed Fanconi anemia. Although morphological abnormalities were present from birth, diagnosis was suspected and made at 8 years of age when he presented to us. We report this case to create awareness among clinicians to use modern modalities of diagnosis for such cases in addition to the clinical assessment. This would further help these children reach their adulthood with good quality of life. [Int J Res Med Sci 2015; 3(4.000: 998-1001

  20. The Fanconi anaemia pathway: new players and new functions.

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    Ceccaldi, Raphael; Sarangi, Prabha; D'Andrea, Alan D

    2016-06-01

    The Fanconi anaemia pathway repairs DNA interstrand crosslinks (ICLs) in the genome. Our understanding of this complex pathway is still evolving, as new components continue to be identified and new biochemical systems are used to elucidate the molecular steps of repair. The Fanconi anaemia pathway uses components of other known DNA repair processes to achieve proper repair of ICLs. Moreover, Fanconi anaemia proteins have functions in genome maintenance beyond their canonical roles of repairing ICLs. Such functions include the stabilization of replication forks and the regulation of cytokinesis. Thus, Fanconi anaemia proteins are emerging as master regulators of genomic integrity that coordinate several repair processes. Here, we summarize our current understanding of the functions of the Fanconi anaemia pathway in ICL repair, together with an overview of its connections with other repair pathways and its emerging roles in genome maintenance.

  1. What Are the Signs and Symptoms of Fanconi Anemia?

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    ... What Are the Signs and Symptoms of Fanconi Anemia? Major Signs and Symptoms Your doctor may suspect ... sisters also should be tested for the disorder. Anemia The most common symptom of all types of ...

  2. Anemia de Fanconi y embarazo: una combinación inusual Fanconi`s anemia and pregnancy: an unusual combination

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    Carlos Escalante-Gómez

    2008-06-01

    Full Text Available La anemia de Fanconi es una falla clásica de la médula ósea, la cual tiene una incidencia de menos de 1 en 100,000 nacidos vivos. Hasta ahora, las pacientes femeninas normalmente no alcanzaban la edad reproductiva y mucho menos lograban el embarazo. Una revisión actual de la literatura identifica solamente 19 pacientes que han logrado el embarazo. Presentamos el caso de una paciente de 16 años portadora de anemia de Fanconi, la cual presenta un embarazo de 30 semanas complicado por un cuadro de preeclampsia severa asociada a trombocitopenia severa, hemorragia intraparenquimatosa, convulsiones y neumonía. El manejo obstétrico de estas pacientes es muy complejo. El tratamiento debe ser individualizado a las necesidades de cada paciente hasta que la literatura agrupe más casos y se ofrezcan normas de manejo.Fanconi’s anemia is a classic marrow-failure disorder with an incidence of less than 1 case per 100,000 live births. Until now, female patients do not usually reach childbearing age and even less achieved pregnancy. A review of the literature identifies only 19 patients who have become pregnant. We present a case of 16 year old patient with a 30 week pregnancy complicated by a rapid onset severe preeclampsia associated with extreme thrombocytopenia, intraparenquimal hemorrhage seizures and pneumonia. Obstetric management of these patients is complicated; treatment should be tailored to the patients’ needs until more cases are reported and guidelines recommended.

  3. A comprehensive strategy for the subtyping of patients with Fanconi anaemia: conclusions from the Spanish Fanconi Anemia Research Network

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    Casado, José Antonio; Callén, Elsa; Jacome, Ariana; Río, Paula; Castella, Maria; Lobitz, Stephan; Ferro, Teresa; Muñoz, Arturo; Sevilla, Julián; Cantalejo, Ángeles; Cela, Elena; Cervera, José; Sánchez‐Calero, Jesús; Badell, Isabel; Estella, Jesús; Dasí, Ángeles; Olivé, Teresa; Ortega, Juan José; Rodriguez‐Villa, Antonia; Tapia, María; Molinés, Antonio; Madero, Luis; Segovia, José C; Neveling, Kornelia; Kalb, Reinhard; Schindler, Detlev; Hanenberg, Helmut; Surrallés, Jordi; Bueren, Juan A

    2007-01-01

    Background Fanconi anaemia is a heterogeneous genetic disease, where 12 complementation groups have been already described. Identifying the complementation group in patients with Fanconi anaemia constitutes a direct procedure to confirm the diagnosis of the disease and is required for the recruitment of these patients in gene therapy trials. Objective To determine the subtype of Fanconi anaemia patients in Spain, a Mediterranean country with a relatively high population (23%) of Fanconi anaemia patients belonging to the gypsy race. Methods Most patients could be subtyped by retroviral complementation approaches in peripheral blood T cells, although some mosaic patients were subtyped in cultured skin fibroblasts. Other approaches, mainly based on western blot analysis and generation of nuclear RAD51 and FANCJ foci, were required for the subtyping of a minor number of patients. Results and conclusions From a total of 125 patients included in the Registry of Fanconi Anaemia, samples from 102 patients were available for subtyping analyses. In 89 cases the subtype could be determined and in 8 cases exclusions of common complementation groups were made. Compared with other international studies, a skewed distribution of complementation groups was observed in Spain, where 80% of the families belonged to the Fanconi anaemia group A (FA‐A) complementation group. The high proportion of gypsy patients, all of them FA‐A, and the absence of patients with FA‐C account for this characteristic distribution of complementation groups. PMID:17105750

  4. Fanconi DNA repair pathway is required for survival and long-term maintenance of neural progenitors

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    Sii-Felice, Karine; Etienne, Olivier; Hoffschir, Francoise; Mathieu, Celine; Riou, Lydia; Barroca, Vilma; Haton, Celine; Arwert, Fre; Fouchet, Pierre; Boussin, Francois D.; Mouthon, Marc-Andre

    2008-01-01

    Although brain development abnormalities and brain cancer predisposition have been reported in some Fanconi patients, the possible role of Fanconi DNA repair pathway during neurogenesis is unclear. We thus addressed the role of fanca and fancg, which are involved in the activation of Fanconi pathway

  5. GAUCHER´S DISEASE: A RARE CAUSE OF FANCONI SYNDROME?

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    Musso CG

    2007-01-01

    Full Text Available Gaucher´s disease consists of a genetic autosomic recesive alteration that leads to a reduction in the acid glucosil-ceramide beta-glucosidase enzyme. This enzyme brakes the glucosilceramide, a substance from which many esphingo and glucolipids are synthesized. Even though the renal compromise is not frequent in Gaucher disease, proteinuria (in nephrotic range or not and glomerulonephritis have been described in this illness.Fanconi syndrome is charaterized by a dysfunction in the proximal tubular reabsorption. Among the etiologies of Fanconi syndrome there are many metabolic diseases, but no association has been described yet in the literature between Fanconi syndrome and Gaucher disease. We present the following case report where this association was observed.

  6. Cytokine overproduction and crosslinker hypersensitivity are unlinked in Fanconi anemia macrophages.

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    Garbati, Michael R; Hays, Laura E; Rathbun, R Keaney; Jillette, Nathaniel; Chin, Kathy; Al-Dhalimy, Muhsen; Agarwal, Anupriya; Newell, Amy E Hanlon; Olson, Susan B; Bagby, Grover C

    2016-03-01

    The Fanconi anemia proteins participate in a canonical pathway that repairs cross-linking agent-induced DNA damage. Cells with inactivated Fanconi anemia genes are universally hypersensitive to such agents. Fanconi anemia-deficient hematopoietic stem cells are also hypersensitive to inflammatory cytokines, and, as importantly, Fanconi anemia macrophages overproduce such cytokines in response to TLR4 and TLR7/8 agonists. We questioned whether TLR-induced DNA damage is the primary cause of aberrantly regulated cytokine production in Fanconi anemia macrophages by quantifying TLR agonist-induced TNF-α production, DNA strand breaks, crosslinker-induced chromosomal breakage, and Fanconi anemia core complex function in Fanconi anemia complementation group C-deficient human and murine macrophages. Although both M1 and M2 polarized Fanconi anemia cells were predictably hypersensitive to mitomycin C, only M1 macrophages overproduced TNF-α in response to TLR-activating signals. DNA damaging agents alone did not induce TNF-α production in the absence of TLR agonists in wild-type or Fanconi anemia macrophages, and mitomycin C did not enhance TLR responses in either normal or Fanconi anemia cells. TLR4 and TLR7/8 activation induced cytokine overproduction in Fanconi anemia macrophages. Also, although TLR4 activation was associated with induced double strand breaks, TLR7/8 activation was not. That DNA strand breaks and chromosome breaks are neither necessary nor sufficient to account for the overproduction of inflammatory cytokines by Fanconi anemia cells suggests that noncanonical anti-inflammatory functions of Fanconi anemia complementation group C contribute to the aberrant macrophage phenotype and suggests that suppression of macrophage/TLR hyperreactivity might prevent cytokine-induced stem cell attrition in Fanconi anemia.

  7. Fanconi anemia proteins and endogenous stresses

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    Pang Qishen [Division of Experimental Hematology and Cancer Biology, Cincinnati Children' s Research Foundation, Cincinnati, OH (United States); Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH (United States); Andreassen, Paul R., E-mail: Paul.Andreassen@cchmc.org [Division of Experimental Hematology and Cancer Biology, Cincinnati Children' s Research Foundation, Cincinnati, OH (United States); Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH (United States)

    2009-07-31

    Each of the thirteen identified Fanconi anemia (FA) genes is required for resistance to DNA interstrand crosslinking agents, such as mitomycin C, cisplatin, and melphalan. While these agents are excellent tools for understanding the function of FA proteins in DNA repair, it is uncertain whether a defect in the removal of DNA interstrand crosslinks (ICLs) is the basis for the pathophysiology of FA. For example, DNA interstrand crosslinking agents induce other types of DNA damage, in addition to ICLs. Further, other DNA-damaging agents, such as ionizing or ultraviolet radiation, activate the FA pathway, leading to monoubiquitination of FANCD2 and FANCI. Also, FA patients display congenital abnormalities, hematologic deficiencies, and a predisposition to cancer in the absence of an environmental source of ICLs that is external to cells. Here we consider potential sources of endogenous DNA damage, or endogenous stresses, to which FA proteins may respond. These include ICLs formed by products of lipid peroxidation, and other forms of oxidative DNA damage. FA proteins may also potentially respond to telomere shortening or replication stress. Defining these endogenous sources of DNA damage or stresses is critical for understanding the pathogenesis of deficiencies for FA proteins. We propose that FA proteins are centrally involved in the response to replication stress, including replication stress arising from oxidative DNA damage.

  8. Fanconi Anemia: A Rarely Considered Cause of Macrocytosis During Childhood.

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    Aslan, Deniz

    2017-10-01

    We describe a Turkish boy newly diagnosed with Fanconi anemia with mutation in the FANCA gene. The patient, with normal clinical phenotype and negative chromosomal breakage test result, presented with macrocytosis. No clinical or laboratory changes were observed in a follow-up period of 4 years. The diagnosis was confirmed molecularly after a prolonged and exhaustive investigation. He was found to be a compound heterozygote for 2 mutations in the FANCA gene (1 of which is novel, c.4261-2A>C). We present this experience to alert physicians that Fanconi anemia should be considered in the differential diagnosis of otherwise unexplained macrocytosis during childhood.

  9. An atypical case of Fanconi anemia in elderly sibs

    NARCIS (Netherlands)

    Kwee, ML; vanderKleij, JM; vanEssen, AJ; Begeer, JH; Joenje, H; Arwert, F; tenKate, LP

    1997-01-01

    We describe a 56-year-old woman suspected of Fanconi anemia on the basis of the following clinical findings: microcephaly, short stature, congenital deafness, and the clinical findings in her deceased brother. Hematologic or other signs of malignancy were absent. The diagnosis was confirmed by

  10. An atypical case of Fanconi anemia in elderly sibs

    NARCIS (Netherlands)

    Kwee, ML; vanderKleij, JM; vanEssen, AJ; Begeer, JH; Joenje, H; Arwert, F; tenKate, LP

    1997-01-01

    We describe a 56-year-old woman suspected of Fanconi anemia on the basis of the following clinical findings: microcephaly, short stature, congenital deafness, and the clinical findings in her deceased brother. Hematologic or other signs of malignancy were absent. The diagnosis was confirmed by demon

  11. p53 downregulates the Fanconi anaemia DNA repair pathway.

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    Jaber, Sara; Toufektchan, Eléonore; Lejour, Vincent; Bardot, Boris; Toledo, Franck

    2016-04-01

    Germline mutations affecting telomere maintenance or DNA repair may, respectively, cause dyskeratosis congenita or Fanconi anaemia, two clinically related bone marrow failure syndromes. Mice expressing p53(Δ31), a mutant p53 lacking the C terminus, model dyskeratosis congenita. Accordingly, the increased p53 activity in p53(Δ31/Δ31) fibroblasts correlated with a decreased expression of 4 genes implicated in telomere syndromes. Here we show that these cells exhibit decreased mRNA levels for additional genes contributing to telomere metabolism, but also, surprisingly, for 12 genes mutated in Fanconi anaemia. Furthermore, p53(Δ31/Δ31) fibroblasts exhibit a reduced capacity to repair DNA interstrand crosslinks, a typical feature of Fanconi anaemia cells. Importantly, the p53-dependent downregulation of Fanc genes is largely conserved in human cells. Defective DNA repair is known to activate p53, but our results indicate that, conversely, an increased p53 activity may attenuate the Fanconi anaemia DNA repair pathway, defining a positive regulatory feedback loop.

  12. Anesthesia for a patient with Fanconi anemia for developmental dislocation of the hip: a case report

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    Zafer Dogan

    2014-06-01

    Full Text Available Fanconi anemia is a rare autosomal recessive inherited bone marrow failure syndrome with congenital and hematological abnormalities. Literature regarding the anesthetic management in these patients is limited. A management of a developmental dislocation of the hip was described in a patient with fanconi anemia. Because of the heterogeneous nature, a patient with fanconi anemia should be established thorough preoperative evaluation in order to diagnose on clinical features. In conclusion, we preferred caudal anesthesia in this patient with fanconi anemia without thrombocytopenia, because of avoiding from N2O, reducing amount of anesthetic, existing microcephaly, hypothyroidism and elevated liver enzymes, providing postoperative analgesia, and reducing amount of analgesic used postoperatively.

  13. Fanconi anemia associated with moyamoya disease in Saudi Arabia

    OpenAIRE

    Al-Hawsawi, Zakaria M.; Al-Zaid, Mohamed A.; Barnawi, Ashwaq I.; Yassine, Saadeddine M.

    2015-01-01

    We report a 10-year-old Saudi girl who has Fanconi anemia (FA) and was admitted due to acute hemiplegia, of the right side. She had a previous attack of left side hemiplegia that resolved spontaneously. The brain magnetic resonance angiography showed a cerebrovascular pattern of moyamoya disease. She underwent partially matched related donor stem cell transplantation (SCT), but unfortunately died 3 months later with post SCT complications. The association of moyamoya disease with FA is uncomm...

  14. Fanconi Anemia — Case Report of Rare Aplastic Anemia at Child

    Directory of Open Access Journals (Sweden)

    Deaconu Alina

    2014-06-01

    Full Text Available Introduction: Fanconi anemia is an autosomal recessive disease characterized by congenital abnormalities, defective haematopoiesis, and a high risk of developing acute myeloid leukaemia, myelodysplastic syndrome and cancers. FA was first described in 1927 by the Swiss pediatrician Guido Fanconi. The diagnosis is based on morphological abnormalities, hematologic abnormalities (pancytopenia, macrocytic anemia and progressive bone marrow failure and genetic tests (cariograma.

  15. Pregnancy after allogeneic hematopoietic stem cell transplantation in a Fanconi anemia patient

    Science.gov (United States)

    Atashkhoei, Simin; Fakhari, Solmaz; Bilehjani, Eissa; Farzin, Haleh

    2017-01-01

    Pregnancy in patients with Fanconi anemia (FA) is rare. However, there are reports of successful pregnancy in Fanconi patients after bone marrow transplantation (BMT, hematopoietic stem cell transplantation). We describe the case of a term pregnant woman with FA who was treated with BMT 2 years earlier. She underwent successful delivery with cesarean section using spinal anesthesia without any complications.

  16. Bilineal Acute Leukemia Associated With Fanconi Syndrome: The First Case Report

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    Ghasem Miri-Aliabad

    2016-05-01

    Full Text Available Fanconi syndrome is a metabolic disorder involving dysfunction of the renal proximal tubules, resulting in excessive urinary excretion of several metabolites. Various factors may lead to Fanconi syndrome, as it may be a genetic disease with primary or secondary etiologies, or may be acquired. In this study, we report a unique case of Fanconi syndrome with development of a relatively rare acute leukemia, a condition that has not been reported before. The case was an 8-year-old boy with familial occurrence of Fanconi syndrome, presenting with pallor, asthenia, recurrent infections, growth failure, and a variety of biochemical and hematological abnormalities. After physical examination, radiographic studies, and comprehensive laboratory analyses, Fanconi syndrome associated with bilineal acute leukemia, of myeloid and T-lymphoid lineages, was diagnosed.

  17. Oxymetholone Therapy of Fanconi Anemia Suppresses Osteopontin Transcription and Induces Hematopoietic Stem Cell Cycling

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    Qing-Shuo Zhang

    2015-01-01

    Full Text Available Androgens are widely used for treating Fanconi anemia (FA and other human bone marrow failure syndromes, but their mode of action remains incompletely understood. Aged Fancd2−/− mice were used to assess the therapeutic efficacy of oxymetholone (OXM and its mechanism of action. Eighteen-month-old Fancd2−/− mice recapitulated key human FA phenotypes, including reduced bone marrow cellularity, red cell macrocytosis, and peripheral pancytopenia. As in humans, chronic OXM treatment significantly improved these hematological parameters and stimulated the proliferation of hematopoietic stem and progenitor cells. RNA-Seq analysis implicated downregulation of osteopontin as an important potential mechanism for the drug’s action. Consistent with the increased stem cell proliferation, competitive repopulation assays demonstrated that chronic OXM therapy eventually resulted in stem cell exhaustion. These results expand our knowledge of the regulation of hematopoietic stem cell proliferation and have direct clinical implications for the treatment of bone marrow failure.

  18. Oral carnitine therapy in children with cystinosis and renal Fanconi syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Gahl, W.A.; Bernardini, I.; Dalakas, M.; Rizzo, W.B.; Harper, G.S.; Hoeg, J.M.; Hurko, O.; Bernar, J.

    1988-02-01

    11 children with either cystinosis or Lowe's syndrome had a reduced content of plasma and muscle carnitine due to renal Fanconi syndrome. After treatment with oral L-carnitine, 100 mg/kg per d divided every 6 h, plasma carnitine concentrations became normal in all subjects within 2 d. Initial plasma free fatty acid concentrations, inversely related to free carnitine concentrations, were reduced after 7-20 mo of carnitine therapy. Muscle lipid accumulation, which varied directly with duration of carnitine deficiency (r = 0.73), improved significantly in three of seven rebiopsied patients after carnitine therapy. One Lowe's syndrome patient achieved a normal muscle carnitine level after therapy. Muscle carnitine levels remained low in all cystinosis patients, even though cystinotic muscle cells in culture took up L-(/sup 3/H)carnitine normally. The half-life of plasma carnitine for cystinotic children given a single oral dose approximated 6.3 h; 14% of ingested L-carnitine was excreted within 24 h. Studies in a uremic patient with cystinosis showed that her plasma carnitine was in equilibrium with some larger compartment and may have been maintained by release of carnitine from the muscle during dialysis. Because oral L-carnitine corrects plasma carnitine deficiency, lowers plasma free fatty acid concentrations, and reverses muscle lipid accumulation in some patients, its use as therapy in renal Fanconi syndrome should be considered. However, its efficacy in restoring muscle carnitine to normal, and the optimal dosage regimen, have yet to be determined.

  19. Anemia de Fanconi: Consideraciones actuales Updating Fanconi’s anaemia

    OpenAIRE

    M. Sagaseta de Ilurdoz; J. Molina; I. Lezáun; Valiente, A; G Durán

    2003-01-01

    La anemia de Fanconi (AF) es un síndrome de inestabilidad cromosómica, autosómico recesivo, caracterizado por una hipersensibilidad del DNA a agentes clastogénicos. Clínicamente presenta una insuficiencia medular progresiva, diversas anomalías congénitas e incremento en la predisposición a padecer enfermedades malignas. Se han definido ocho grupos de complementación y se han clonado los genes correspondientes a seis de ellos. Recientes avances en biología molecular han permitido investigar la...

  20. Development of acute leukemia in a known case of fanconi anaemia ( aplastic anaemai

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    Preeti Jhaveri

    2013-01-01

    Full Text Available Fanconi anemia is an autosomal recessive disease associated with an abnormal DNA damage. Although Fanconi anemia is well known for its association of Aplastic anemia and characteristic birth defects, leukemia and solid tumors also occur at a high rate in this group of patients. A patient male / 20yrs, known case of Fanconi anemia presented with ulcer over left lower limb. On further evaluation, the patient was found to have pancytopenia and his peripheral smear revealed many atypical blast like cells. So bone marrow study was done which revealed it to be Acute leukemia probably Acute Myeloid leukemia.

  1. Pregnancy after allogeneic hematopoietic stem cell transplantation in a Fanconi anemia patient

    Directory of Open Access Journals (Sweden)

    Atashkhoei S

    2017-01-01

    Full Text Available Simin Atashkhoei, Solmaz Fakhari, Eissa Bilehjani, Haleh Farzin Department of Anesthesiology, Al-Zahra Hospital, Tabriz University of Medical Sciences, Tabriz, Iran Abstract: Pregnancy in patients with Fanconi anemia (FA is rare. However, there are reports of successful pregnancy in Fanconi patients after bone marrow transplantation (BMT, hematopoietic stem cell transplantation. We describe the case of a term pregnant woman with FA who was treated with BMT 2 years earlier. She underwent successful delivery with cesarean section using spinal anesthesia without any complications. Keywords: Fanconi anemia, bone marrow transplantation, pregnancy, cesarean section, spinal anesthesia

  2. Transient renal Fanconi syndrome in a Chihuahua exposed to Chinese chicken jerky treats.

    Science.gov (United States)

    Hooijberg, E H; Furman, E; Leidinger, J; Brandstetter, D; Hochleithner, C; Sewell, A C; Leidinger, E; Giger, U

    2015-01-01

    Transient Fanconi syndrome without azotemia was diagnosed in a dog and was associated with ingestion of Chinese chicken jerky treats. Fanconi syndrome is a proximal renal tubular defect and a diagnosis was made based upon severe glucosuria with normoglycemia, and severe generalized aminoaciduria. The clinical signs of polyuria and polydipsia as well as the massive urinary metabolic abnormalities resolved after jerky treat withdrawal. While frequently seen in North America and Australia, this is the first report of jerky treat induced Fanconi syndrome in continental Europe. Clinicians should be aware of this potential intoxication and be vigilant for a history of jerky treat consumption in a dog with glucosuria.

  3. Endocrine disorders in Fanconi anemia: recommendations for screening and treatment.

    Science.gov (United States)

    Petryk, Anna; Kanakatti Shankar, Roopa; Giri, Neelam; Hollenberg, Anthony N; Rutter, Meilan M; Nathan, Brandon; Lodish, Maya; Alter, Blanche P; Stratakis, Constantine A; Rose, Susan R

    2015-03-01

    Endocrine problems are common in patients with Fanconi anemia (FA). About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility. The goal of this report is to provide an overview of endocrine abnormalities and guidelines for routine screening and treatment to allow early diagnosis and timely intervention. This work is based on a comprehensive literature review, including relevant articles published between 1971 and 2014, and proceedings of a Consensus Conference held by the Fanconi Anemia Research Fund in 2013. The panel of experts collected published evidence and discussed its relevance to reflect current information about the endocrine care of children and adults with FA before the Consensus Conference and through subsequent deliberations that led to the consensus. Individuals with FA should be routinely screened for endocrine abnormalities, including evaluation of growth; glucose, insulin, and lipid metabolism; thyroid function; puberty; gonadal function; and bone mineral metabolism. Inclusion of an endocrinologist as part of the multidisciplinary patient care team is key to providing comprehensive care for patients with FA.

  4. Endocrine Disorders in Fanconi Anemia: Recommendations for Screening and Treatment

    Science.gov (United States)

    Kanakatti Shankar, Roopa; Giri, Neelam; Hollenberg, Anthony N.; Rutter, Meilan M.; Nathan, Brandon; Lodish, Maya; Alter, Blanche P.; Stratakis, Constantine A.

    2015-01-01

    Context: Endocrine problems are common in patients with Fanconi anemia (FA). About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility. The goal of this report is to provide an overview of endocrine abnormalities and guidelines for routine screening and treatment to allow early diagnosis and timely intervention. Evidence Acquisition: This work is based on a comprehensive literature review, including relevant articles published between 1971 and 2014, and proceedings of a Consensus Conference held by the Fanconi Anemia Research Fund in 2013. Evidence Synthesis: The panel of experts collected published evidence and discussed its relevance to reflect current information about the endocrine care of children and adults with FA before the Consensus Conference and through subsequent deliberations that led to the consensus. Conclusions: Individuals with FA should be routinely screened for endocrine abnormalities, including evaluation of growth; glucose, insulin, and lipid metabolism; thyroid function; puberty; gonadal function; and bone mineral metabolism. Inclusion of an endocrinologist as part of the multidisciplinary patient care team is key to providing comprehensive care for patients with FA. PMID:25575015

  5. FANCM: A Landing Pad for the Fanconi Anemia and Bloom's Syndrome Complexes

    OpenAIRE

    Vinciguerra, Patrizia; D'Andrea, Alan D.

    2009-01-01

    Here, Deans and West (2009) reveal the molecular basis of the phenotypic similarities between Fanconi Anemia (FA) and Bloom's Syndrome, identifying FANCM as the anchor for both FA and Bloom's complexes at the site of the DNA interstrand crosslink.

  6. Pregnancy in fanconi anaemia with bone marrow failure: a case report and review of the literature.

    Science.gov (United States)

    Sorbi, Flavia; Mecacci, Federico; Di Filippo, Alessandro; Fambrini, Massimiliano

    2017-02-03

    Fanconi anaemia is a rare inherited disease characterized by congenital abnormalities, progressive bone marrow failure and predisposition to malignancy. Successful pregnancies in transplanted patients have been reported. In this paper we will describe the pregnancy of a patient with Fanconi anaemia without transplantation. A 34-year-old nulliparous woman with Fanconi anaemia was referred to our institution. Pregnancy was complicated by progressive pancytopenia and two severe infections. C-section was performed at 36 weeks. Both infant and mother are well. Successful pregnancy in a Fanconi anaemia patient with bone marrow failure is possible. The mode of delivery in patients with bone marrow failure should be determined by obstetric indications. The case highlights the safe outcome of the pregnancy with strict clinical and laboratory control by a multidisciplinary team.

  7. The clinical and radiological features of Fanconi's anaemia pictorial review

    Energy Technology Data Exchange (ETDEWEB)

    De Kerviler, E.; Guermazi, A.; Zagdanski, A.-M.; Gluckman, E.; Frija, J

    2000-05-01

    Fanconi's anaemia is a severe refractory anaemia, associated with congenital malformations in approximately two-thirds of cases. Although these malformations may involve every organ system, suggestive dysmorphic features include growth retardation, radial ray deformities and urinary malformations. These malformations are not specific for Fanconi's anaemia, but should be recognized during pregnancy, or later in childhood, and suggest the possibility of inherited haematopoiesis disorders. De Kerviler, E. (2000)

  8. Pregnancy after allogeneic hematopoietic stem cell transplantation in a Fanconi anemia patient

    OpenAIRE

    Atashkhoei S; Fakhari S; Bilehjani E; Farzin H

    2017-01-01

    Simin Atashkhoei, Solmaz Fakhari, Eissa Bilehjani, Haleh Farzin Department of Anesthesiology, Al-Zahra Hospital, Tabriz University of Medical Sciences, Tabriz, Iran Abstract: Pregnancy in patients with Fanconi anemia (FA) is rare. However, there are reports of successful pregnancy in Fanconi patients after bone marrow transplantation (BMT, hematopoietic stem cell transplantation). We describe the case of a term pregnant woman with FA who was treated with BMT 2 years earlie...

  9. Pregnancy after allogeneic hematopoietic stem cell transplantation in a Fanconi anemia patient

    OpenAIRE

    Atashkhoei,Simin; Fakhari,Solmaz; Bilehjani,Eissa; Farzin,Haleh

    2017-01-01

    Simin Atashkhoei, Solmaz Fakhari, Eissa Bilehjani, Haleh Farzin Department of Anesthesiology, Al-Zahra Hospital, Tabriz University of Medical Sciences, Tabriz, Iran Abstract: Pregnancy in patients with Fanconi anemia (FA) is rare. However, there are reports of successful pregnancy in Fanconi patients after bone marrow transplantation (BMT, hematopoietic stem cell transplantation). We describe the case of a term pregnant woman with FA who was treated with BMT 2&n...

  10. Fever of unknown origin as the initial manifestation of valproate-induced Fanconi syndrome.

    Science.gov (United States)

    Nozaki, Fumihito; Kumada, Tomohiro; Kusunoki, Takashi; Fujii, Tatsuya; Murayama, Kei; Ohtake, Akira

    2014-12-01

    Valproate-induced Fanconi syndrome is a rare adverse effect of valproate. Severely disabled patients who require tube feeding are reported to be susceptible to valproate-induced Fanconi syndrome. Although most patients with valproate-induced Fanconi syndrome are asymptomatic and detected incidentally with findings such as hypophosphatemia, hypouricemia, increased urinary β2-microglobulin, and generalized hyperaminoaciduria, clinical symptoms such as bone fracture, fever, tachypnea, and edema have been reported. This 15-year-old, severely disabled, tube-fed, male patient with cytochrome oxidase deficiency had taken valproate for 3 years when he developed fever for 3 weeks. Hypophosphatemia, hypouricemia, hypokalemia, increased urinary β2-microglobulin, and generalized hyperaminoaciduria, as well as hypocarnitinemia, were found, indicating that he had Fanconi syndrome. Valproate was the most likely cause of Fanconi syndrome in this patient. After discontinuation of valproate, the fever resolved immediately, and the laboratory findings normalized. Valproate-induced Fanconi syndrome should be considered when individuals taking valproate develop fever of unknown origin. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Use Massive Parallel Sequencing and Exome Capture Technology to Sequence the Exome of Fanconi Anemia Children and Their Patents

    Science.gov (United States)

    2013-11-21

    Fanconi Anemia; Autosomal or Sex Linked Recessive Genetic Disease; Bone Marrow Hematopoiesis Failure, Multiple Congenital Abnormalities, and Susceptibility to Neoplastic Diseases.; Hematopoiesis Maintainance.

  12. Towards a Molecular Understanding of the Fanconi Anemia Core Complex

    Directory of Open Access Journals (Sweden)

    Charlotte Hodson

    2012-01-01

    Full Text Available Fanconi Anemia (FA is a genetic disorder characterized by the inability of patient cells to repair DNA damage caused by interstrand crosslinking agents. There are currently 14 verified FA genes, where mutation of any single gene prevents repair of DNA interstrand crosslinks (ICLs. The accumulation of ICL damage results in genome instability and patients having a high predisposition to cancers. The key event of the FA pathway is dependent on an eight-protein core complex (CC, required for the monoubiquitination of each member of the FANCD2-FANCI complex. Interestingly, the majority of patient mutations reside in the CC. The molecular mechanisms underlying the requirement for such a large complex to carry out a monoubiquitination event remain a mystery. This paper documents the extensive efforts of researchers so far to understand the molecular roles of the CC proteins with regard to its main function in the FA pathway, the monoubiquitination of FANCD2 and FANCI.

  13. Tenofovir induced Fanconi syndrome: A possible pharmacokinetic interaction

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    Jigar Kapadia

    2013-01-01

    Full Text Available Tenofovir was introduced as a second line drug for the treatment of human immunodeficiency virus (HIV infection in India in December 2009. Although rare, renal toxicity is a recognized adverse drug reaction (ADR of this drug, especially when administered with boosted lopinavir-ritonavir. In this case, an HIV positive patient receiving tenofovir based antiretroviral therapy (ART for last 1 year developed albuminuria, glycosuria and hypophosphatemia. Renal function tests and random blood sugar were within normal limits. He was diagnosed as a case of tenofovir induced Fanconi syndrome. Tenofovir was discontinued and patient was prescribed an alternate regimen. Five months later clinical symptoms and renal functions returned to normal. A pharmacokinetic interaction between tenofovir and ritonavir may have resulted in the toxicity. A periodic monitoring of renal functions is desirable in patients on tenofovir based ART.

  14. Targeting the Fanconi Anemia Pathway to Identify Tailored Anticancer Therapeutics

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    Chelsea Jenkins

    2012-01-01

    Full Text Available The Fanconi Anemia (FA pathway consists of proteins involved in repairing DNA damage, including interstrand cross-links (ICLs. The pathway contains an upstream multiprotein core complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and a downstream pathway that converges with a larger network of proteins with roles in homologous recombination and other DNA repair pathways. Selective killing of cancer cells with an intact FA pathway but deficient in certain other DNA repair pathways is an emerging approach to tailored cancer therapy. Inhibiting the FA pathway becomes selectively lethal when certain repair genes are defective, such as the checkpoint kinase ATM. Inhibiting the FA pathway in ATM deficient cells can be achieved with small molecule inhibitors, suggesting that new cancer therapeutics could be developed by identifying FA pathway inhibitors to treat cancers that contain defects that are synthetic lethal with FA.

  15. Cancer incidence in relatives of British Fanconi Anaemia patients

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    Hodgson Shirley V

    2008-09-01

    Full Text Available Abstract Background Fanconi anemia (FA is an autosomal recessive DNA repair disorder with affected individuals having a high risk of developing acute myeloid leukaemia and certain solid tumours. Thirteen complementation groups have been identified and the genes for all of these are known (FANCA, B, C, D1/BRCA2, D2, E, F, G, I, J/BRIP1, L, M and N/PALB2. Previous studies of cancer incidence in relatives of Fanconi anemia cases have produced conflicting results. A study of British FA families was therefore carried out to investigate this question, since increases in cancer risk in FA heterozygotes would have implications for counselling FA family members, and possibly also for the implementation of preventative screening measures in FA heterozygotes. Methods Thirty-six families took part and data was collected on 575 individuals (276 males, 299 females, representing 18,136 person years. In this cohort, 25 males and 30 females were reported with cancer under the age of 85 years, and 36 cancers (65% could be confirmed from death certificates, cancer registries or clinical records. Results A total of 55 cancers were reported in the FA families compared to an estimated incidence of 56.95 in a comparable general population cohort, and the relative risk of cancer was 0.97 (95% C.I. = 0.71–1.23, p = 0.62 for FA family members. Analysis of relative risk for individual cancer types in each carrier probability group did not reveal any significant differences with the possible exception of prostate cancer (RR = 3.089 (95% C.I. = 1.09 – 8.78; Χ2 = 4.767, p = 0.029. Conclusion This study has not shown a significant difference in overall cancer risk in FA families.

  16. TGF-β Inhibition Rescues Hematopoietic Stem Cell Defects and Bone Marrow Failure in Fanconi Anemia.

    Science.gov (United States)

    Zhang, Haojian; Kozono, David E; O'Connor, Kevin W; Vidal-Cardenas, Sofia; Rousseau, Alix; Hamilton, Abigail; Moreau, Lisa; Gaudiano, Emily F; Greenberger, Joel; Bagby, Grover; Soulier, Jean; Grompe, Markus; Parmar, Kalindi; D'Andrea, Alan D

    2016-05-05

    Fanconi anemia (FA) is an inherited DNA repair disorder characterized by progressive bone marrow failure (BMF) from hematopoietic stem and progenitor cell (HSPC) attrition. A greater understanding of the pathogenesis of BMF could improve the therapeutic options for FA patients. Using a genome-wide shRNA screen in human FA fibroblasts, we identify transforming growth factor-β (TGF-β) pathway-mediated growth suppression as a cause of BMF in FA. Blocking the TGF-β pathway improves the survival of FA cells and rescues the proliferative and functional defects of HSPCs derived from FA mice and FA patients. Inhibition of TGF-β signaling in FA HSPCs results in elevated homologous recombination (HR) repair with a concomitant decrease in non-homologous end-joining (NHEJ), accounting for the improvement in cellular growth. Together, our results suggest that elevated TGF-β signaling contributes to BMF in FA by impairing HSPC function and may be a potential therapeutic target for the treatment of FA.

  17. Interleukin-11 attenuates ifosfamide-induced hemorrhagic cystitis

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    Jose M. Mota

    2007-10-01

    Full Text Available OBJECTIVE: To investigate the possible protective effect of recombinant human interleukin-11 (rhIL-11 against ifosfamide (IFS-induced hemorrhagic cystitis (HC MATERIALS AND METHODS: Male Swiss mice (20-30g were pretreated with rhIL-11 (25-625 mg, subcutaneously. 30 min before intraperitoneal injection of IFS (400 mg/kg or with saline (control group. Twelve hours later, HC was evaluated by bladder wet weight (BWW to quantify edema, Evans blue extravasation (EBE to measure vascular permeability, and macroscopic and microscopic analysis. All bladders were assessed by histopathological analysis RESULTS: rhIL-11 (at 125 and 625 mg attenuated the IFS- induced increase of BWW (37.48% and 45.44%, respectively, p < 0.05 and EBE (62.35% and 56.47%, respectively, p < 0.05. IFS- induced macroscopic edema and hemorrhage and microscopic alterations, were also prevented by rhIL-11 at 625 mg. (p < 0.05 CONCLUSION: Our results demonstrate a protective effect of rhIL-11 on experimental IFS- induced HC, not previously reported.

  18. Oxidative Stress -a Phenotypic Hallmark of Fanconi Anemia and Down Syndrome: The Effect of Antioxidants

    Science.gov (United States)

    El-Bassyouni, HT; Afifi, HH; Eid, MM; Kamal, RM; El-Gebali, HH; El-Saeed, GSM; Thomas, MM; Abdel-Maksoud, SA

    2015-01-01

    Background: Oxidative stress plays a major role in the pathogenesis of leukemia-prone diseases such as Fanconi anemia (FA) and Down syndrome (DS) Aim: To explore the oxidative stress state in children with DS and FA by estimating the levels of antioxidants (e.g., malondialdehyde [MDA], total antioxidant capacity, and superoxide dismutase [SOD] activity) and DNA damage, and to evaluate of the effect of antioxidant treatment on these patients. Subjects and methods The study included 32 children clinically diagnosed with (15 patients) and FA (17 patients) in addition to 17 controls matched for age and sex. MDA, total antioxidant capacity, SOD activity, and DNA damage were measured. Antioxidants including Vitamin A, E, and C were given to the patients according to the recommended daily allowance for 6 months. Clinical follow-up and re-evaluation were conducted for all patients. Laboratory tests including complete blood count, karyotyping, DNA damage, and oxidative stress were re-evaluated. Statistical analysis was performed using statistical computer program Statistical Package for the Social Sciences version 14.0. Results: Children with FA and DS had elevated levels of oxidative stress and more DNA damage than controls. Oxidative stress parameters and DNA damage improved in FA and DS patients after antioxidant administration. Conclusion: Early administration of antioxidants to FA and DS patients is recommended for slowing of the disease course with symptoms amelioration and improvement of general health. PMID:26097763

  19. Diagnosis of Fanconi anemia in children with atypical clinical features: a primary study

    Institute of Scientific and Technical Information of China (English)

    LIU Rong; HU Tao; LI Jun-hui; LIANG Chao; GU Wei-yue; SHI Xiao-dong; WANG Hong-xing

    2013-01-01

    Background Fanconi anemia is a severe congenital disorder associated with mutations in a cluster of genes responsible for DNA repair.Arriving at an accurate and timely diagnosis can be difficult in cases of Fanconi anemia with atypical clinical features.It is very important to increase the rate of accurate diagnosis for such cases in a clinical setting.The purpose of this study is to explore the clinical diagnosis of Fanconi anemia in children with atypical clinical features.Methods Six cases of Fanconi anemia with atypical clinical features were enrolled in the study,and their clinical features were recorded,their FANCA gene transcription was assessed by RT-PCR,and FANCA mutations and the ubiquitination of FANCD2 protein were analyzed using DNA sequencing and western blotting respectively.Results All six cases showed atypical clinical features including no apparent deformities,lack of response to immune therapy,and progressively increasing bone marrow failure.They also have significantly increased fetal hemoglobin,negative mitomycin-induced fracture test results,and carry a FANCA gene missense mutation.Single protein ubiquitination of FANCD2 was not observed in those patients.Conclusion The combination of clinical features,FANCA pathogenic gene mutation genotype and the absence of FANCD2 protein ubiquitination are helpful in the accurate and timely diagnosis of Fanconi anemia in children.

  20. Ectopic germinal center and megalin defect in primary Sjogren syndrome with renal Fanconi syndrome.

    Science.gov (United States)

    Wang, Jing; Wen, Yubing; Zhou, Mengyu; Shi, Xiaoxiao; Jiang, Lanping; Li, Mingxi; Yu, Yang; Li, Xuemei; Li, Xuewang; Zhang, Wen; Lundquist, Andrew L; Chen, Limeng

    2017-06-02

    This study reports the clinical and pathological features of 12 cases of primary Sjogren syndrome (pSS) with renal involvement presenting with proximal tubular dysfunction in a single center, and investigates the possible correlation of ectopic germinal center formation and megalin/cubilin down-expression. Clinical and pathological records were reviewed. Immunohistochemistry was carried out to detect megalin, cubilin, CD21 and IL-17 expression. Patients presented with different degrees of proximal renal tubule lesion and decreased estimated glomerular filtration rate (eGFR). Renal biopsy revealed tubulointerstitial nephritis, with tubular epithelial cell degeneration, tubular atrophy, interstitial inflammation and focal fibrosis. Immunohistochemistry revealed decreased expression of megalin and cubilin, two important multiligand protein receptors on the brush border of proximal tubular epithelial cells. IL-17 secreted by Th17 subtype effector T cells was diffusely detected in the renal proximal tubule, with a negative correlation of IL-17 and megalin expression. In addition, ectopic germinal centers characterized by CD21(+) follicular dendritic cells were present in the renal interstitium. In patients with a decreased eGFR, treatment with 4 weeks of glucocorticoid therapy resulted in an improved eGFR in 75% of patients. We report 12 cases of pSS characterized by Fanconi syndrome. The decreased megalin and cubilin expression may contribute to the proximal tubular reabsorption defect, possibly secondary to Th17 infiltration and formation of ectopic germinal centers.

  1. [Tenofovir-associated Fanconi's syndrome and rickets in a HIV infected girl].

    Science.gov (United States)

    Zúñiga, Marcela; Galindo, Armando; Galaz, María Isabel; Vivanco, Maritza; Romero, Patricio; Balboa, Paulina; Torrejón, Claudia

    2016-09-09

    Tenofovir (TDF) is an inhibitor of reverse transcriptase nucleotide analogue, although it has good tolerability and high anti-retroviral activity, its effect on the kidney has been a concern. To describe a girl infected with HIV who presented Fanconi syndrome during antiretroviral therapy with TDF. We describe a HIV-1-infected girl, who after 18 months treatment with TDF presented loss of strength and pain of the lower extremities with functional impairment. Laboratory findings were consistent with Fanconi syndrome. Radiographs showed bilateral hip fracture and wrists. Full recovery of Fanconi syndrome was achieved four months after changing antiretroviral therapy. TDF-prescribing physicians must be prepared to detect signs and symptoms of renal dysfunction and immediately consider switching to another antiviral drug. Copyright © 2016 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  2. Structure of the FANCI-FANCD2 Complex: Insights into the Fanconi Anemia DNA Repair Pathway

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    Joo, Woo; Xu, Guozhou; Persky, Nicole S.; Smogorzewska, Agata; Rudge, Derek G.; Buzovetsky, Olga; Elledge, Stephen J.; Pavletich, Nikola P. (Harvard-Med); (Cornell); (MSKCC)

    2011-08-29

    Fanconi anemia is a cancer predisposition syndrome caused by defects in the repair of DNA interstrand cross-links (ICLs). Central to this pathway is the Fanconi anemia I-Fanconi anemia D2 (FANCI-FANCD2) (ID) complex, which is activated by DNA damage-induced phosphorylation and monoubiquitination. The 3.4 angstrom crystal structure of the {approx}300 kilodalton ID complex reveals that monoubiquitination and regulatory phosphorylation sites map to the I-D interface, suggesting that they occur on monomeric proteins or an opened-up complex and that they may serve to stabilize I-D heterodimerization. The 7.8 angstrom electron-density map of FANCI-DNA crystals and in vitro data show that each protein has binding sites for both single- and double-stranded DNA, suggesting that the ID complex recognizes DNA structures that result from the encounter of replication forks with an ICL.

  3. Structure of the FANCI-FANCD2 Complex: Insights into the Fanconi Anemia DNA Repair Pathway

    Energy Technology Data Exchange (ETDEWEB)

    W Joo; G Xu; n Persky; A Smogorzewska; D Rudge; O Buzovetsky; S Elledge; N Pavletich

    2011-12-31

    Fanconi anemia is a cancer predisposition syndrome caused by defects in the repair of DNA interstrand cross-links (ICLs). Central to this pathway is the Fanconi anemia I-Fanconi anemia D2 (FANCI-FANCD2) (ID) complex, which is activated by DNA damage-induced phosphorylation and monoubiquitination. The 3.4 angstrom crystal structure of the {approx}300 kilodalton ID complex reveals that monoubiquitination and regulatory phosphorylation sites map to the I-D interface, suggesting that they occur on monomeric proteins or an opened-up complex and that they may serve to stabilize I-D heterodimerization. The 7.8 angstrom electron-density map of FANCI-DNA crystals and in vitro data show that each protein has binding sites for both single- and double-stranded DNA, suggesting that the ID complex recognizes DNA structures that result from the encounter of replication forks with an ICL.

  4. Deferasirox therapy in children with Fanconi aplastic anemia.

    Science.gov (United States)

    Tunç, Bahattin; Tavil, Betul; Karakurt, Neslihan; Yarali, Nese; Azik, Fatih Mehmet; Kara, Abdurrahman; Culha, Vildan; Ozkasap, Serdar

    2012-05-01

    Thirty-nine children with Fanconi aplastic anemia (FAA) have been followed up in our center between January 2008 and November 2010. Eight of these children (20%) with a transfusional iron overload had been undergoing deferasirox treatment during the study period. In the English literature, transfusional iron overload and the use of an iron chelator in children with FAA has not yet been evaluated. Here, we have presented the effectivity and tolerability of deferasirox in children with FAA and a transfusional iron overload. Before the deferasirox treatment, the mean serum ferritin level was 3377 ± 2200 ng/mL. After a mean 13.6-month treatment duration, the mean ferritin level decreased to 2274 ± 1300 ng/mL (Pdeferasirox treatment in patients with FAA. In our series, despite the low number of cases, nephrotoxicity and hepatotoxicity were common side effects instead of gastrointestinal disturbances reported in other studies. Deferasirox is an oral, easily applicable, and effective iron chelator; baseline hepatotoxicity and nephrotoxicity may increase the development of toxic side effects in children with FAA. Patients with FAA receiving deferasirox treatment should be followed up closely for these side effects.

  5. Saethre-Chotzen syndrome presenting with incomplete renal Fanconi syndrome.

    Science.gov (United States)

    Oktenli, Cagatay; Saglam, Mutlu; Zafer, Emre; Gül, Davut

    2002-10-01

    Here we report on a patient with findings of acrocephaly, craniosynostosis, low frontal hairline, ptosis of eyelids, deviated nasal septum, broad great toes, moderate hallux valgus, bilateral symmetrical complete soft tissue syndactyly of toes 2 and 3, and partial soft tissue syndactyly of toes 4 and 5 consistent with the diagnosis of Saethre-Chotzen syndrome. Additionally, the patient had some unusual findings as part of generalized dysfunction of the renal tubules including hypophosphatemia with renal phosphate wasting, normocalcemic hypercalciuria, hypomagnesemia with renal magnesium wasting, low-molecular-weight proteinuria, decreased serum PTH levels, osteopenia, and nephrolithiasis. In the light of these findings, the diagnosis of incomplete renal Fanconi syndrome was made. In conclusion, on the basis of the present findings, it is difficult to say whether renal tubular dysfunction are somehow connected to the Saethre-Chotzen syndrome or not. Therefore, we consider that this is probably just a coincident. However, further studies may show the connection between renal tubular dysfunction and Saethre-Chotzen syndrome.

  6. Acquired Fanconi syndrome in four cats treated with chlorambucil.

    Science.gov (United States)

    Reinert, Natalie C; Feldman, David G

    2016-12-01

    Fanconi syndrome (FS) is well described in humans and dogs, but has not been reported in cats. This case series describes four cats with acquired FS. On the basis of clinical signs and intestinal biopsies, all cats were initially diagnosed with alimentary lymphoma or inflammatory bowel disease. Treatment with chlorambucil and corticosteroids was started at standard doses, based on published protocols. Within 2-26 months of the start of treatment, glucosuria, despite normoglycemia, was identified incidentally on routine biochemical screening; FS was diagnosed with urine metabolic assays, confirming aminoaciduria and glucosuria in all four cases. Neither polyuria nor polydipsia were noted in any case, and only 1/4 cats had any clinical signs at the time of diagnosis. Partial or complete resolution of FS was seen in 3/4 cases within 3 months of discontinuing chlorambucil therapy. This is the first case series to document acquired FS in the cat, and the first to suggest a possible association between chlorambucil and acquired FS. Cats treated with chlorambucil should be monitored for the development of glucosuria, and discontinuation of chlorambucil should be considered if FS is identified. Further study into the association between chlorambucil and acquired FS in cats is warranted. © The Author(s) 2015.

  7. Identification of the Fanconi Anemia Complementation Group I Gene, FANCI

    Directory of Open Access Journals (Sweden)

    Josephine C. Dorsman

    2007-01-01

    Full Text Available To identify the gene underlying Fanconi anemia (FA complementation group I we studied informative FA-I families by a genome-wide linkage analysis, which resulted in 4 candidate regions together encompassing 351 genes. Candidates were selected via bioinformatics and data mining on the basis of their resemblance to other FA genes/proteins acting in the FA pathway, such as: degree of evolutionary conservation, presence of nuclear localization signals and pattern of tissue-dependent expression. We found a candidate, KIAA1794 on chromosome 15q25-26, to be mutated in 8 affected individuals previously assigned to complementation group I. Western blots of endogenous FANCI indicated that functionally active KIAA1794 protein is lacking in FA-I individuals. Knock-down of KIAA1794 expression by siRNA in HeLa cells caused excessive chromosomal breakage induced by mitomycin C, a hallmark of FA cells. Furthermore, phenotypic reversion of a patient-derived cell line was associated with a secondary genetic alteration at the KIAA1794 locus. These data add up to two conclusions. First, KIAA1794 is a FA gene. Second, this gene is identical to FANCI, since the patient cell lines found mutated in this study included the reference cell line for group I, EUFA592.

  8. Successful Treatment of Fanconi Anemia and T-Cell Acute Lymphoblastic Leukemia

    Directory of Open Access Journals (Sweden)

    Terrie Flatt

    2012-01-01

    Full Text Available Fanconi anemia is associated with an increased risk of malignancy. Patients are sensitive to the toxic effects of chemotherapy. We report the case of a patient with Fanconi anemia who developed T-cell acute lymphoblastic leukemia. He experienced chemotherapy-related complications including prolonged neutropenia, grade IV vincristine neuropathy, and disseminated aspergillosis. He was successfully treated with modified dosing of cytarabine and intrathecal methotrexate followed by allogeneic bone marrow transplant. The aspergillosis was treated with systemic antifungal treatment and surgical resection. Now 30 months after bone marrow transplant the patient is without evidence of aspergillosis or leukemia.

  9. Unraveling the Fanconi anaemia-DNA repair connection through DNA helicase and translocase activities

    Energy Technology Data Exchange (ETDEWEB)

    Thompson, L H

    2005-08-16

    How the Fanconi anaemia (FA) chromosome stability pathway functions to cope with interstrand crosslinks and other DNA lesions has been elusive, even after FANCD1 proved to be BRCA2, a partner of Rad51 in homologous recombination. The identification and characterization of two new Fanconi proteins having helicase motifs, FANCM and FANCJ/BRIP1/BACH1, implicates the FANC nuclear core complex as a participant in recognizing or processing damaged DNA, and the BRIP1 helicase as acting independently of this complex.

  10. Fanconi syndrome due to prolonged use of low-dose adefovir

    Directory of Open Access Journals (Sweden)

    Xiao-Bing Wang

    2015-01-01

    Full Text Available Fanconi syndrome results from a generalized abnormality of the proximal tubules of the kidney and owing to phosphate depletion can cause hypophosphatemic osteomalacia. Adefovir dipivoxyl (ADV effectively suppresses hepatitis B virus replication but exhibits nephrotoxicity when administered at a low dosage. We report two cases of Fanconi syndrome induced by ADV at 10 mg/day to call for regular screening for evidence of proximal tubular dysfunction and detailed bone metabolic investigations for prompt detection of ADV nephrotoxicity is critically important to ensure timely drug withdrawal before the development of irreversible tubulointerstitial injury.

  11. Anemia de Fanconi y embarazo: una combinación inusual

    OpenAIRE

    Carlos Escalante-Gómez; Judith Jiménez-Torrealba

    2008-01-01

    La anemia de Fanconi es una falla clásica de la médula ósea, la cual tiene una incidencia de menos de 1 en 100,000 nacidos vivos. Hasta ahora, las pacientes femeninas normalmente no alcanzaban la edad reproductiva y mucho menos lograban el embarazo. Una revisión actual de la literatura identifica solamente 19 pacientes que han logrado el embarazo. Presentamos el caso de una paciente de 16 años portadora de anemia de Fanconi, la cual presenta un embarazo de 30 semanas complicado por un cuadro ...

  12. Anemia de Fanconi: Consideraciones actuales Updating Fanconi’s anaemia

    Directory of Open Access Journals (Sweden)

    M. Sagaseta de Ilurdoz

    2003-04-01

    Full Text Available La anemia de Fanconi (AF es un síndrome de inestabilidad cromosómica, autosómico recesivo, caracterizado por una hipersensibilidad del DNA a agentes clastogénicos. Clínicamente presenta una insuficiencia medular progresiva, diversas anomalías congénitas e incremento en la predisposición a padecer enfermedades malignas. Se han definido ocho grupos de complementación y se han clonado los genes correspondientes a seis de ellos. Recientes avances en biología molecular han permitido investigar la relación entre el genotipo de AF y la naturaleza y severidad del fenotipo clínico. El tratamiento de la AF es también objeto de una intensa investigación que actualmente se centra en el trasplante de progenitores hematopoyéticos, con éxito especialmente en caso de donante hermano HLA-idéntico, y en la terapia génica todavía en fase de investigación clínica.Fanconi’s anaemia (FA is an autosomal recessive syndrome associated with chromosomal instability, and hypersensitivity of the DNA to claustrogenic agents. Clinically it presents a progressive marrow insufficiency, different congenital anomalies and an predisposition to malignancy. Eight complementation groups have been defined and the genes corresponding to six of them have been cloned. Recent advances in molecular biology have made it possible to investigate the relationship between the FA genotype and the nature and severity of the clinical phenotype. The treatment of FA is also the object of intense research that is currently centred on the transplant of hematopoyetic progenitors, especially successful in cases of an HLA-identical brother or sister donor, and in gene therapy, which is still in the phase of clinical research.

  13. Fanconi Syndrome and Antiretrovirals: It Is Never Too Late.

    Science.gov (United States)

    Luni, Faraz Khan; Khan, Abdur Rahman; Prashar, Rohini; Vetteth, Sandeep; Duggan, Joan M

    2016-01-01

    Antiretroviral medications such as tenofovir have been associated with Fanconi syndrome (FS) usually identified within the first 1-29 months after exposure to the medication. We present a case of life-threatening FS which developed in a 37-year-old woman with HIV after 8 years of asymptomatic tenofovir use. The patient was diagnosed with HIV in 1996 at 20 years of age, hepatitis C 10 years later, and Staphylococcus aureus sepsis with secondary osteomyelitis of the spine 3 years before admission for FS. She developed nausea, vomiting, diarrhea, and generalized weakness over a 2-week time period and presented to the hospital. In the emergency department, her serum potassium was 1.5 mEq/L, bicarbonate was 12 mEq/L, chloride was 111 mEq/L, phosphorus was 1.8 mg/dL, and creatinine was 1.95 mg/dL (baseline, 1.4). Arterial blood gas revealed a non-anion gap (hyperchloremic) metabolic acidosis. Type 2 renal tubular acidosis induced by antiretroviral therapy (ART) was suspected and the ART was discontinued with resolution of the renal abnormalities within 7 days. A non-tenofovir-containing ART regimen consisting of lamivudine/abacavir and efavirenz was begun, and over the next 8 months, the patient was without recurrence of the FS. This case report demonstrates the acute development of FS after prolonged exposure to tenofovir without exposure to additional nephrotoxins such as nonsteroidal medications or aminoglycosides. Tenofovir can cause FS at any time and should be considered in any patient presenting with renal tubular acidosis type 2 while on tenofovir regardless of the duration of drug exposure.

  14. Ubiquitin-like protein UBL5 promotes the functional integrity of the Fanconi anemia pathway

    DEFF Research Database (Denmark)

    Oka, Yasuyoshi; Bekker-Jensen, Simon; Mailand, Niels

    2015-01-01

    in promoting the function of the Fanconi anemia (FA) pathway for repair of DNA interstrand crosslinks (ICLs), mediated by a specific interaction with the central FA pathway component FANCI. UBL5-deficient cells display spliceosome-independent reduction of FANCI protein stability, defective FANCI function...

  15. Ubiquitin-SUMO Circuitry Controls Activated Fanconi Anemia ID Complex Dosage in Response to DNA Damage

    DEFF Research Database (Denmark)

    Gibbs-Seymour, Ian; Oka, Yasuyoshi; Rajendra, Eeson

    2015-01-01

    We show that central components of the Fanconi anemia (FA) DNA repair pathway, the tumor suppressor proteins FANCI and FANCD2 (the ID complex), are SUMOylated in response to replication fork stalling. The ID complex is SUMOylated in a manner that depends on the ATR kinase, the FA ubiquitin ligase...

  16. Interaction between the helicases genetically linked to Fanconi anemia group J and Bloom's syndrome

    DEFF Research Database (Denmark)

    Suhasini, Avvaru N; Rawtani, Nina A; Wu, Yuliang

    2011-01-01

    Bloom's syndrome (BS) and Fanconi anemia (FA) are autosomal recessive disorders characterized by cancer and chromosomal instability. BS and FA group J arise from mutations in the BLM and FANCJ genes, respectively, which encode DNA helicases. In this work, FANCJ and BLM were found to interact...

  17. Structural Chromosomal Alterations Induced by Dietary Bioflavonoids in Fanconi Anemia Lymphocytes

    Directory of Open Access Journals (Sweden)

    Gonzalo Guevara

    2007-06-01

    Full Text Available IntroductionFanconi anemia is an autosomal recessive diseasecharacterized by a variety of congenital abnormalities,progressive bone marrow failure,increased chromosomal instability and higherrisk to acute myeloid leukemia, solid tumors. Thisentity can be considered an appropriate biologicalmodel to analyze natural substances with possiblegenotoxic effect. The aims of this study wereto describe and quantify structural chromosomalaberrations induced by 5 flavones, 2 isoflavonesand a topoisomerase II chemotherapeutic inhibitorin Fanconi anemia lymphocytes in order todetermine chromosomal numbers changes and/or type of chromosomal damage.Materials and methodsChromosomes stimulated by phytohaemagglutininM, from Fanconi anemia lymphocytes,were analysed by conventional cytogenetic culture.For each chemical substance and controls,one hundred metaphases were evaluated. Chromosomalalterations were documented by photographyand imaging analyzer. To statisticalanalysis was used chi square test to identify significantdifferences between frequencies of chromosomaldamage of basal and exposed cellcultured a P value less than 0.05.ResultsThere were 431 chromosomal alterations in1000 metaphases analysed; genistein was themore genotoxic bioflavonoid, followed in descendentorder by genistin, fisetin, kaempferol,quercetin, baicalein and miricetin. Chromosomalaberrations observed were: chromatidbreaks, chromosomal breaks, cromatid andchromosomal gaps, quadriratials exchanges,dicentrics chromosome and complex rearrangements.ConclusionBioflavonoids as genistein, genistin and fisetin,which are commonly present in the human diet,showed statistical significance in the number ofchromosomal aberrations in Fanconi anemialymphocytes, regarding the basal damage.

  18. Drug-induced Fanconi syndrome associated with fumaric acid esters treatment for psoriasis: A case series

    NARCIS (Netherlands)

    D.M.W. Balak (Deepak); J.N.B. Bavinck (Jan Nico Bouwes); De Vries, A.P.J. (Aiko P. J.); Hartman, J. (Jenny); Martino Neumann, H.A. (Hendrik A.); R. Zietse (Bob); H.B. Thio (Bing)

    2016-01-01

    textabstractBackground: Fumaric acid esters (FAEs), an oral immunomodulating treatment for psoriasis and multiple sclerosis, have been anecdotally associated with proximal renal tubular dysfunction due to a drug-induced Fanconi syndrome. Few data are available on clinical outcomes of FAE-induced Fan

  19. Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors.

    NARCIS (Netherlands)

    Taniguchi, T; Tischkowitz, M; Ameziane, N.; Hodgson, SV; Mathew, C.G.; Joenje, H.; Mok, SC; Andrea, d' AD

    2003-01-01

    Ovarian tumor cells are often genomically unstable and hypersensitive to cisplatin. To understand the molecular basis for this phenotype, we examined the integrity of the Fanconi anemia-BRCA (FANC-BRCA) pathway in those cells. This pathway regulates cisplatin sensitivity and is governed by the coord

  20. De Novo Chromosome Copy Number Variation in Fanconi Anemia-Associated Hematopoietic Defects

    Science.gov (United States)

    2014-08-01

    Laboratory used two cell types for these experimental approaches: 090 hTERT and HCT116. 090 hTERT are a normal hTERT-immortalized skin fibroblast...Adam, Z., Rani, R., Zhang, X. and Pang, Q. (2008) Oxidative stress in Fanconi anemia hematopoiesis and disease progression. Antioxid Redox Signal, 10

  1. Gene editing in hematopoietic stem cells: a potential therapeutic approach for Fanconi anemia

    Energy Technology Data Exchange (ETDEWEB)

    Diez Cabezas, B.

    2015-07-01

    Gene therapy nowadays constitutes a safe and efficient treatment for a number of monogenic diseases affecting the hematopoietic system. Risks of insertional mutagenesis derived from the use of integrative vectors cannot, however, be completely excluded. Therefore, gene targeting has been proposed as a safer alternative, since the insertion of the herapeutic gene is driven to a specific locus in the genome. Gene targeting approaches are based on the use of specific nucleases which generate double strand breaks (DSBs) in a specific site of the genome,markedly enhancing the efficacy of homologous recombination (HR) with donor constructs harboring the gene of interest flanked by the corresponding homology arms. In this study we have optimized the conditions to target human lymphoblastic cell lines (LCLs) and also hematopoietic stem cells (HSCs) from healthy donors, with the final aim of correcting by gene editing the hematopoietic progenitor cells from Fanconi anemia subtype A (FA-A) patients. In particular, we have established a robust method to target both LCLs and HSCs in a safe harbor site in the genome, the AAVS1 locus. Our approach is based on the transduction of these cells with integrase-defective lentiviral vectors carrying a donor with the gene of interest, followed by the nucleofection of these cells with zinc finger nucleases used as mRNA. Using a control donor vector carrying the GFP reporter gene we have obtained, on average, 9.43% gene targeting efficiency in cord blood CD34+ cells from healthy donors. Moreover, we confirmed that gene targeting was also efficient in HSCs with long term and multipotent repopulation capacity, as demonstrated by transplants into immunodeficient mice. To improve the gene targeting efficiency, we investigated the feasibility of using gold nanoparticles, which were shown to improve the transduction efficiency of integrase-defective and competent lentiviral vectors in HSCs. This increment, however, did not lead to a higher gene

  2. Association of aplastic anaemia and Fanconi's disease with HLA-DRB1 alleles.

    Science.gov (United States)

    Yari, F; Sobhani, M; Vaziri, M Z; Bagheri, N; Sabaghi, F; Talebian, A

    2008-12-01

    One of the most fascinating areas of research within the field of histocompatibility at present time concerns an observation that a major human histocompatibility system, human leucocyte antigen (HLA), is deeply involved in the development of a great number of diseases. Major histocompatibility complex is the most polymorphic system in the genome of different species. Recognition of HLA alleles could be useful in transplantation and disease studies. Genetic construct of HLA DRB1 was studied in Iranian normal populations and patients with aplastic anaemia and Fanconi's disease. DNA was extracted from the whole blood of 466 normal, 35 aplastic anaemia and 10 Fanconi's individuals. Then DRB1 gene polymorphism was studied by polymerase chain reaction-sequence-specific primer method. The HLA DRB1 gene analysis showed increase of DRB1*07 in aplastic anaemia patients compared to normal population (P = 0.02). According to this study, the frequency of DRB1*07 in normal individuals was 8.3, and in aplastic anaemia patients, 15.7%. Additionally, the frequency of DRB1*04 in normal, aplastic anaemia and Fanconi's individuals was 10, 5.7 and 20%, respectively. Our results of investigation showed correlation between some HLA alleles with the studied diseases. We reported the frequency of various DR types in aplastic and Fanconi's patients. This study could imply the possible role of HLA-DRB1*07 in the incidence of aplastic anaemia. Moreover, the frequency of DRB1*04, DRB1*03 and DRB1*15 alleles showed intermediate correlation with Fanconi's anaemia.

  3. Sjögren's syndrome complicated with Fanconi syndrome and Hashimoto's thyroiditis: Case report and literature review.

    Science.gov (United States)

    Shi, Mingmin; Chen, Lei

    2016-06-01

    We report a unique case of Sjögren's syndrome complicated with Fanconi syndrome and Hashimoto's thyroiditis in a 53-year-old Chinese woman, initially found to have proteinuria, fatigue and multiple old costal fractures. Distal tubular dysfunction is the most common renal damage in Sjögren's syndrome, while Fanconi syndrome (which is caused by proximal tubular dysfunction) and Hypothyroidism are rare complications of Sjögren's syndrome.

  4. Fulminant limb and retroperitoneal necrotizing fasciitis in a 15-year-old girl with Fanconi anaemia

    Energy Technology Data Exchange (ETDEWEB)

    O' Regan, Kevin; Maher, Michael M. [Mercy University Hospital, Department of Radiology, Cork (Ireland); Cork University Hospital, Department of Radiology, Cork (Ireland); O' Mahony, Edward; MacEneaney, Peter; Fitzgerald, Edward [Mercy University Hospital, Department of Radiology, Cork (Ireland)

    2009-10-15

    Necrotizing fasciitis (NF) is an uncommon soft-tissue infection in children that carries a high mortality rate. We present a 15-year-old girl with chronic pancytopenia secondary to Fanconi anaemia who developed extensive NF of the lower limb, which unfortunately resulted in a fatal outcome. Immunodeficiency is a known risk factor for the development of this condition. The findings in this case demonstrate that patients with Fanconi anaemia may be susceptible to NF and that the clinical course may be more aggressive due to underlying immunosuppression. Prompt diagnosis of NF is vital in order to initiate appropriate treatment and to optimize patient outcome. Radiological investigation demonstrated extensive soft-tissue gas and destruction affecting the entire lower limb, abdominal wall and retroperitoneum, which led to timely definitive diagnosis and management. (orig.)

  5. Fulminant limb and retroperitoneal necrotizing fasciitis in a 15-year-old girl with Fanconi anaemia.

    LENUS (Irish Health Repository)

    O'Regan, Kevin

    2012-01-31

    Necrotizing fasciitis (NF) is an uncommon soft-tissue infection in children that carries a high mortality rate. We present a 15-year-old girl with chronic pancytopenia secondary to Fanconi anaemia who developed extensive NF of the lower limb, which unfortunately resulted in a fatal outcome. Immunodeficiency is a known risk factor for the development of this condition. The findings in this case demonstrate that patients with Fanconi anaemia may be susceptible to NF and that the clinical course may be more aggressive due to underlying immunosuppression. Prompt diagnosis of NF is vital in order to initiate appropriate treatment and to optimize patient outcome. Radiological investigation demonstrated extensive soft-tissue gas and destruction affecting the entire lower limb, abdominal wall and retroperitoneum, which led to timely definitive diagnosis and management.

  6. Fulminant limb and retroperitoneal necrotizing fasciitis in a 15-year-old girl with Fanconi anaemia.

    LENUS (Irish Health Repository)

    O'Regan, Kevin

    2009-10-01

    Necrotizing fasciitis (NF) is an uncommon soft-tissue infection in children that carries a high mortality rate. We present a 15-year-old girl with chronic pancytopenia secondary to Fanconi anaemia who developed extensive NF of the lower limb, which unfortunately resulted in a fatal outcome. Immunodeficiency is a known risk factor for the development of this condition. The findings in this case demonstrate that patients with Fanconi anaemia may be susceptible to NF and that the clinical course may be more aggressive due to underlying immunosuppression. Prompt diagnosis of NF is vital in order to initiate appropriate treatment and to optimize patient outcome. Radiological investigation demonstrated extensive soft-tissue gas and destruction affecting the entire lower limb, abdominal wall and retroperitoneum, which led to timely definitive diagnosis and management.

  7. Anemia de Fanconi y embarazo: una combinación inusual

    Directory of Open Access Journals (Sweden)

    Carlos Escalante-Gómez

    2008-06-01

    Full Text Available La anemia de Fanconi es una falla clásica de la médula ósea, la cual tiene una incidencia de menos de 1 en 100,000 nacidos vivos. Hasta ahora, las pacientes femeninas normalmente no alcanzaban la edad reproductiva y mucho menos lograban el embarazo. Una revisión actual de la literatura identifica solamente 19 pacientes que han logrado el embarazo. Presentamos el caso de una paciente de 16 años portadora de anemia de Fanconi, la cual presenta un embarazo de 30 semanas complicado por un cuadro de preeclampsia severa asociada a trombocitopenia severa, hemorragia intraparenquimatosa, convulsiones y neumonía. El manejo obstétrico de estas pacientes es muy complejo. El tratamiento debe ser individualizado a las necesidades de cada paciente hasta que la literatura agrupe más casos y se ofrezcan normas de manejo.

  8. Renal artery stenosis: An unusual etiology of hypertensive encephalopathy in a child with fanconi anemia

    Directory of Open Access Journals (Sweden)

    Radheshyam Purkait

    2015-01-01

    Full Text Available A 9-year-old girl, diagnosed case of Fanconi anemia, presented with generalized convulsion with altered sensorium. She had fever, severe pallor, sinus tachycardia, blood pressure of 180/120 mmHg in both upper and lower limb, pan-systolic murmur of grade 2/6, abdominal bruit and bilateral papilledema. A provisional diagnosis of hypertensive encephalopathy was made and managed with continuous labetalol infusion. Detailed evaluation including magnetic resonance angiography of renal artery detected underlying atrophic and non-functioning right kidney secondary to severe renal artery stenosis on the same side. She was started with multiple antihypertensives, but her blood pressure was maintained poorly. Later on, she underwent rightsided nephrectomy. Following surgery, she was doing well and maintaining normal blood pressure without any antihypertensives. Our child is the second reported case of Fanconi anemia associated with renal artery stenosis presenting with hypertensive encephalopathy.

  9. Tubulointerstitial Nephritis Complicated by Fanconi Syndrome and Renal Tubular Acidosis Associated with three autoimmune diseases

    OpenAIRE

    Io, Kumiko; Obata, Yoko; Nishino, Tomoya; Hirose, Misaki; Yamashita, Hiroshi; Uramatsu, Tadashi; Ichikawa, Tatsuki; Hayashi, Tomayoshi; Kawakami, Atsushi; Taguchi, Takashi; Kohno, Shigeru

    2013-01-01

    A 45-year-old woman experiencing back pain showed signs of metabolic acidosis and electrolyte imbalances. The results of blood and urine tests indicated Fanconi syndrome and renal tubular acidosis. An x-ray showed vertebral fractures, which were thought to responsible for the back pain. In addition, the patient had proteinuria and renal dysfunction; therefore, renal biopsy was performed, and tubulointerstitial nephritis (TIN) was diagnosed. While investigating TIN, primary biliary cirrhosis a...

  10. Formaldehyde catabolism is essential in cells deficient for the Fanconi anemia DNA-repair pathway.

    Science.gov (United States)

    Rosado, Ivan V; Langevin, Frédéric; Crossan, Gerry P; Takata, Minoru; Patel, Ketan J

    2011-11-13

    Metabolism is predicted to generate formaldehyde, a toxic, simple, reactive aldehyde that can damage DNA. Here we report a synthetic lethal interaction in avian cells between ADH5, encoding the main formaldehyde-detoxifying enzyme, and the Fanconi anemia (FA) DNA-repair pathway. These results define a fundamental role for the combined action of formaldehyde catabolism and DNA cross-link repair in vertebrate cell survival.

  11. Anemia de Fanconi: relato de dois casos na mesma família

    Directory of Open Access Journals (Sweden)

    Patricia J. Campos Olazábal

    1983-09-01

    Full Text Available São registrados dois casos, ocorridos na mesma família, de anemia hipoplásica de Fanconi, nos quais um dos irmãos apresenta a tríade completa de anemia, malformações esqueléticas e quebras cromossômicas e, o outro, apenas as quebras cromossômicas.

  12. Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells

    OpenAIRE

    Raya, Ángel; Rodríguez-Pizà, Ignasi; Guenechea, Guillermo; Vassena, Rita; Navarro, Susana; Barrero, María José; Consiglio, Antonella; Castellà, Maria; Río, Paula; Sleep, Eduard; González, Federico; Tiscornia, Gustavo; Garreta, Elena; Aasen, Trond; Veiga, Anna

    2009-01-01

    The generation of induced pluripotent stem (iPS) cells has enabled the derivation of patient-specific pluripotent cells and provided valuable experimental platforms to model human disease. Patient-specific iPS cells are also thought to hold great therapeutic potential, although direct evidence for this is still lacking. Here we show that, on correction of the genetic defect, somatic cells from Fanconi anaemia patients can be reprogrammed to pluripotency to generate patient-specific iPS cells....

  13. Carnitine Profile and Effect of Suppletion in Children with Renal Fanconi Syndrome due to Cystinosis

    OpenAIRE

    Besouw, M.; Cornelissen, E.; Cassiman, D.; Kluijtmans, L.; L. van den Heuvel; Levtchenko, E

    2014-01-01

    Background: Cystinosis is an autosomal recessive disorder marked by intralysosomal cystine accumulation. Patients present with generalized proximal tubular dysfunction called renal Fanconi syndrome. Urinary carnitine loss results in plasma and muscle carnitine deficiency, but no clinical signs of carnitine deficiency have been described. Also, the optimal dose of carnitine supplementation is undefined. This study aimed to determine whether currently recommended carnitine doses result in adequ...

  14. Modern Views on de Toni — Debre — Fanconi Syndrome: the Literature Data and Case Report

    Directory of Open Access Journals (Sweden)

    I.S. Lembryk

    2013-11-01

    Full Text Available Introduction. In the article features of clinical course of de Toni — Debre — Fanconi disease (syndrome in children of different age, depending on form of the disease are represented. The objective of investigation was to study clinical peculiarities of the syndrome in childhood. Materials and Methods. Data of foreign literature on this problem for the last 5–10 years are shown. Case report of the disease in 16-year-old patient is described. Results and Discussion. It was proved that this syndrome has autosomal-recessive pattern of inheritance. It is rare in population, and injures mostly bone tissues, kidneys. This condition, in turn, has significant influence at the development and height of the child in general. Clinical features of the syndrome, besides signs of rickets, include: polyuria, polydypsia, growth inhibition, and different degrees of dehydration. Laboratory findings in children with de Toni — Debre — Fanconi syndrome demonstrates presence of proteinuria, hypophosphatemia, hypokalemia and metabolic acidosis. Treatment involves replacement therapy depending on the metabolic imbalance, as well as administration of diuretics and vitamin D metabolites. In our case, the patient received an adequate dose of vitamin D for therapeutic purposes, metabolic products, as well as a course of massage and physical therapy. Conclusions. De Toni — Debre — Fanconi syndrome is a rare enzymopathy, mainly affecting bone, spine, kidneys. Knowledge of the characteristics of the disease in different age periods greatly help the clinician in establishing diagnosis, involvement of highly specialized doctor, developing an adequate treatment strategy.

  15. Terapia génica dirigida en una nuevo "sitio seguro" en células progenitoras hematopoyéticas humanas para su aplicación en anemia de Fanconi

    OpenAIRE

    Rodríguez Fornés, Fátima

    2016-01-01

    La anemia de Fanconi es una enfermedad hereditaria de baja prevalencia, descrita por primera vez por el pediatra Guido Fanconi en 1927. Esta enfermedad se produce como consecuencia de mutaciones en cualquiera de los 19 genes de Fanconi descritos hasta la actualidad, y que participan en la ruta de Fanconi/BRCA. Esta ruta se encarga de la reparación de enlaces intercatenarios del ADN y de coordinar los distintos mecanismos de reparación de las dobles roturas en el ADN. La anemia de Fanconi está...

  16. Terapia génica dirigida en una nuevo "sitio seguro" en células progenitoras hematopoyéticas humanas para su aplicación en anemia de Fanconi

    OpenAIRE

    Rodríguez Fornés, Fátima

    2016-01-01

    La anemia de Fanconi es una enfermedad hereditaria de baja prevalencia, descrita por primera vez por el pediatra Guido Fanconi en 1927. Esta enfermedad se produce como consecuencia de mutaciones en cualquiera de los 19 genes de Fanconi descritos hasta la actualidad, y que participan en la ruta de Fanconi/BRCA. Esta ruta se encarga de la reparación de enlaces intercatenarios del ADN y de coordinar los distintos mecanismos de reparación de las dobles roturas en el ADN. La anemia de Fanconi está...

  17. Nephrogenic diabetes insipidus with idiopathic Fanconi's syndrome in a child who presented as vitamin D resistant rickets.

    Science.gov (United States)

    Patra, Soumya; Nadri, Gulnaz; Chowdhary, Harish; Pemde, Harish K; Singh, Varinder; Chandra, Jagdish

    2011-10-01

    Fanconi's syndrome is a complex of multiple tubular dysfunctions of proximal tubular cells occurring alone or in association with a variety of inherited (primary) or acquired (secondary) disorders. It is characterized by aminoaciduria, normoglycaemic glycosuria, tubular proteinuria without hematuria, metabolic acidosis without anion gap and excessive urinary excretion of phosphorous, calcium, uric acid, bicarbonate, sodium, potassium, and magnesium. Whereas diabetes insipidus is a disease of collecting tubules and child mainly presents with dehydration and hypernatremia. Though all the cases published till date were secondary to drugs, myeloma, hematological disorders, etc., we are reporting the first case of idiopathic Fanconi's syndrome along with nephrogenic diabetes insipidus in a child who presented to us as resistant rickets. Medline search did not reveal any case of nephrogenic diabetes insipidus associated with idiopathic Fanconi syndrome. We hypothesized that the NDI may be due to of severe hypokalemia induced tubular dysfunction.

  18. Inhibition of sodium intestinal transport and mucosal (Na+-K+)-ATPase in experimental Fanconi syndrome.

    Science.gov (United States)

    Wapnir, R A; Exeni, R A; McVicar, M; De Rosas, R J; Lifshitz, F

    1975-11-01

    The administration of 1.5 or 9.0 mmoles/kg ip of maleate to rats induced, in addition to renal alterations similar to those occurring in the Fanconi syndrome, a decline in the intestinal mucosa (Na+-K+)-ATPase with a simultaneous decrease in sodium intestinal transport and an increase in potassium absorption. Further differences in the behavior of the two electrolytes were observed when the concentration of sodium in the perfusates was altered. No changes occurred in amino acid or glucose transport in experimental animals.

  19. Endocytic receptor LRP2/megalin-of holoprosencephaly and renal Fanconi syndrome.

    Science.gov (United States)

    Willnow, Thomas E; Christ, Annabel

    2017-08-01

    Megalin (or LRP2) is an endocytic receptor that plays a central role in embryonic development and adult tissue homeostasis. Loss of this receptor in congenital or acquired diseases results in multiple organ dysfunctions, including forebrain malformation (holoprosencephaly) and renal reabsorption defects (renal Fanconi syndrome). Here, we describe current concepts of the mode of receptor action that include co-receptors and a repertoire of different ligands, and we discuss how these interactions govern functional integrity of the kidney and the brain, and cause disease when defective.

  20. Severe hypophosphatemic osteomalacia with Fanconi syndrome, renal tubular acidosis, vitamin D deficiency and primary biliary cirrhosis.

    Science.gov (United States)

    Bando, Hironori; Hashimoto, Naoko; Hirota, Yushi; Sakaguchi, Kazuhiko; Hisa, Itoko; Inoue, Yoshifumi; Imanishi, Yasuo; Seino, Susumu; Kaji, Hiroshi

    2009-01-01

    A 49-year-old woman was admitted to our hospital for back pain with marked thoracic and extremity deformities leading to bed-rest for three years. She was diagnosed with hypophosphatemic osteomalacia based on her symptoms, X-ray and bone scintigram, high serum alkaline phosphatase level, and low serum levels of both phosphorus and 1,25 dihydroxyvitamin D(3) with inhibition of phosphorus reabsorption. Fanconi syndrome with renal tubular acidosis, vitamin D deficiency and primary biliary cirrhosis were related to the pathogenesis of osteomalacia in this case. Several causal diseases may be concomitantly responsible for acceleration of the severity of osteomalacia in this patient.

  1. Management of dental extraction in a female patient with fanconi anemia.

    Directory of Open Access Journals (Sweden)

    Andre Peisker

    2014-10-01

    Full Text Available Oral surgery in patients with bleeding disorders is associated with a high risk of bleeding during and after surgery. This article is aimed to present the case of an eight-year-old girl suffering from severe Fanconi anemia with pancytopenia who underwent a dental extraction. The hemostatic effect of local administration of tranexamic acid in combination with a primary suture seems to be extremely helpful in order to reduce the necessity of blood products and the risk of postoperative bleeding.

  2. The Fanconi Anemia BRCA Pathway as a Predictor of Benefit from Bevacizumab in a Large Phase-3 Clinical Trial in Ovarian Cancer

    Science.gov (United States)

    2014-10-01

    1 AWARD NUMBER: W81XWH-13-1-0421 TITLE: The Fanconi Anemia BRCA Pathway as a Predictor of Benefit from Bevacizumab in a Large Phase III Clinical...Annual report 3. DATES COVERED 30 Sep 2013 - 29 Sep 2014 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER The Fanconi Anemia BRCA Pathway as a Predictor of...BRCA2 (BRCA1/2) occur in 13-18% of all ovarian carcinomas. BRCA1/2 are involved in the Fanconi anemia (FA) DNA repair pathway and BRCA2 is a FA

  3. Analysis of the G2/M Checkpoint in fanconi anemia cells via examinating chromosomal instability during G2-phase and mitosis

    OpenAIRE

    Sauer, Rica

    2013-01-01

    Fanconi anemia is a genetical and phenotypical heterogenous disease, characterized through loss of one of the 15 identified genes of the Fanconi anemia pathway what causes congenital anomalies, bone marrow failure and solid tumors. In this work the G2/M checkpoint is analysed by use of the phosphatase inhibitor Calyculin A to examine the chromosomal instability, which is typical for fanconi anemia cells, not only in mitoses but also in the G2 phase of the cell cycle. It is proved that the che...

  4. The Fanconi Anemia BRCA Pathway as a Predictor of Benefit from Bevacizumab in a Large Phase 3 Clinical Trial in Ovarian Cancer

    Science.gov (United States)

    2014-12-01

    1 AWARD NUMBER: W81XWH-13-1-0421 TITLE: The Fanconi Anemia BRCA Pathway as a Predictor of Benefit from Bevacizumab in a Large Phase III Clinical...DATES COVERED 30Sep2013 - 29Sep2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-13-1-0421 The Fanconi Anemia BRCA Pathway as a Predictor of...another upfront clinical trial GOG262. We found that germline or somatic mutations in the BRCA-Fanconi anemia pathway was significantly associated with

  5. A male newborn with VACTERL association and Fanconi anemia with a FANCB deletion detected by array comparative genomic hybridization (aCGH).

    Science.gov (United States)

    Umaña, Luis A; Magoulas, Pilar; Bi, Weimin; Bacino, Carlos A

    2011-12-01

    We report on a male newborn with multiple congenital abnormalities consistent with the diagnosis of VACTERL association (vertebral, anal, cardiac, tracheo-esophageal fistula, renal, and limb anomalies), who had Fanconi anemia (complementation group B) recognized by the detection of a deletion in chromosome Xp22.2 using an oligonucleotide array. The diagnosis of Fanconi anemia was confirmed by increased chromosomal breakage abnormalities observed in cultured cells that were treated with cross-linking agents. This is the first report in the literature of Fanconi anemia complementation group B detected by oligonucleotide array testing postnatally.

  6. Cytoplasmic localization of a functionally active Fanconi anemia group A green fluorescent protein chimera in human 293 cells

    NARCIS (Netherlands)

    Kruyt, FAE; Waisfisz, Q; Dijkmans, LM; Hermsen, M.A.; Youssoufian, H; Arwert, F; Joenje, H

    1997-01-01

    Hypersensitivity to cross-linking agents and predisposition to malignancy are characteristic of the genetically heterogeneous inherited bone marrow failure syndrome, Fanconi anemia (FA). The protein encoded by the recently cloned FA complementation group A gene, FAA, has been expected to localize in

  7. Scintigraphic and Radiologic Findings of Pancake Kidney in a Patient with Fanconi Aplastic Anemia

    Directory of Open Access Journals (Sweden)

    Adem Maman

    2016-06-01

    Full Text Available In this case, we have presented that a patient has fankoni aplastic anemia with pancakes kidney in scintigraphy and ultrasonography. The patient is 10 years old and a girl who fanconi aplastic anemia had been diagnosed since three years. In physical examination her general status is good. There was not left hand thumb and she had double the distal phalanx in his right hand thumb in her inspection. We observed 2/6 sistolic murmur in cardiovascular system examınation. Other systems were natural. Abdominal ultrasonography was observed that both the kidney were ectopic location and fused view in the left lower quadrant. Similarly in Tc-99m DTPA and DMSA renal scintigraphy, both kidneys were fused and in the left hemipelvis. The right kidney function were significantly lower by comparison with the left kidney functions. Radiological imaging is necessary in patients with Fanconi aplastic anemia without present clinical symptoms. The renal ultrasonography is important for determining pancakes. In addition, static and dynamic renal scintigraphy plays an important role in revealing the functional status of the kidneys

  8. Glycogen accumulation in the pars recta of the proximal tubule in Fanconi syndrome.

    Science.gov (United States)

    Bendon, R W; Hug, G

    1986-01-01

    We reviewed the renal pathology in 10 cases of renal Fanconi syndrome. Five cases showed the Armanni-Ebstein lesion, i.e., clear glycogen-filled cells limited to the pars recta of the proximal tubules. The 5 cases included 2 siblings with a unique syndrome characterized by death in infancy, severe Fanconi syndrome, severe rickets, carnitine deficiency, and atrophy of the exocrine pancreas. Two other siblings had glycogen storage disease type XI. One of 4 cases of putative tyrosinemia had the lesion. The ultrastructure was studied in 2 cases. The Armanni-Ebstein lesion in these cases was morphologically indistinguishable from that seen in diabetic patients dying after prolonged hyperglycemia. Glycosuria is the only common factor in both diabetic hyperglycemia and the varied proximal tubular diseases studied. The mechanism of the glycogen accumulation in this short parts recta segment of the proximal renal tubule was further investigated by reviewing the renal histology in cases of glycogen storage disease types I, II, III, and VIII. None showed the Armanni-Ebstein lesion, but type I showed glycogen deposition throughout the proximal tubule. Thus, the Armanni-Ebstein lesion is not the result of an enzymatic deficiency for glycogen synthesis in the convoluted tubules.

  9. Interstitial lung disease in an adult with Fanconi anemia: Clues to the pathogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Rubinstein, W.S.; Wenger, S.L.; Hoffman, R.M. [Univ. of Pittsburgh, PA (United States)] [and others

    1997-03-31

    We have studied a 38-year-old man with a prior diagnosis of Holt-Oram syndrome, who presented with diabetes mellitus. He had recently taken prednisone for idiopathic interstitial lung disease and trimethoprim-sulfamethoxazole for sinusitis. Thrombocytopenia progressed to pancytopenia. The patient had skeletal, cardiac, renal, cutaneous, endocrine, hepatic, neurologic, and hematologic manifestations of Fanconi anemia (FA). Chest radiographs showed increased interstitial markings at age 25, dyspnea began in his late 20s, and he stopped smoking at age 32. At age 38, computerized tomography showed bilateral upper lobe fibrosis, lower lobe honeycombing, and bronchiectasis. Pulmonary function tests, compromised at age 29, showed a moderately severe obstructive and restrictive pattern by age 38. Serum alpha-1 antitrypsin level was 224 (normal 85-213) mg/dL and PI phenotype was M1. Karyotype was 46,X-Y with a marked increase in chromosome aberrations induced in vitro by diepoxybutane. The early onset and degree of pulmonary disease in this patient cannot be fully explained by environmental or known genetic causes. The International Fanconi Anemia Registry (IFAR) contains no example of a similar pulmonary presentation. Gene-environment (ecogenetic) interactions in FA seem evident in the final phenotype. The pathogenic mechanism of lung involvement in FA may relate to oxidative injury and cytokine anomalies. 49 refs., 2 figs., 1 tab.

  10. Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells.

    Science.gov (United States)

    Raya, Angel; Rodríguez-Pizà, Ignasi; Guenechea, Guillermo; Vassena, Rita; Navarro, Susana; Barrero, María José; Consiglio, Antonella; Castellà, Maria; Río, Paula; Sleep, Eduard; González, Federico; Tiscornia, Gustavo; Garreta, Elena; Aasen, Trond; Veiga, Anna; Verma, Inder M; Surrallés, Jordi; Bueren, Juan; Izpisúa Belmonte, Juan Carlos

    2009-07-02

    The generation of induced pluripotent stem (iPS) cells has enabled the derivation of patient-specific pluripotent cells and provided valuable experimental platforms to model human disease. Patient-specific iPS cells are also thought to hold great therapeutic potential, although direct evidence for this is still lacking. Here we show that, on correction of the genetic defect, somatic cells from Fanconi anaemia patients can be reprogrammed to pluripotency to generate patient-specific iPS cells. These cell lines appear indistinguishable from human embryonic stem cells and iPS cells from healthy individuals. Most importantly, we show that corrected Fanconi-anaemia-specific iPS cells can give rise to haematopoietic progenitors of the myeloid and erythroid lineages that are phenotypically normal, that is, disease-free. These data offer proof-of-concept that iPS cell technology can be used for the generation of disease-corrected, patient-specific cells with potential value for cell therapy applications.

  11. Fanconi syndrome and chronic renal failure in a chronic hepatitis B monoinfected patient treated with tenofovir

    Directory of Open Access Journals (Sweden)

    Pedro Magalhães-Costa

    Full Text Available Tenofovir disoproxil fumarate (TDF is one of the first-line treatment options in chronic hepatitis B (CHB. Despite its efficacy in suppressing viral load and a high resistance barrier, long life maintenance therapy is required. Registration studies demonstrated TDF to be a safe drug. However, post-marketing experience reported cases of serious nephrotoxicity associated with hypophosphatemia, osteomalacia and, even more recently, Fanconi syndrome associated with TDF therapy in CHB monoinfected patients. Here the authors report a case of a 40 year-old male, with a CHB monoinfection, that, three years after TDF therapy, developed a progressive chronic kidney disease with a serious hypophosphatemia and a secondary osteomalacia that was manifested by bone pain and multiple bone fractures. Further investigational analyses unveiled a proximal renal tubular dysfunction, which fulfilled most of the diagnostic criteria for a Fanconi syndrome. After TDF withdrawal and oral supplementation with phosphate and calcitriol, his renal function stabilized (despite not returning to normal, proximal renal tubular dysfunction abnormalities resolved as well as osteomalacia. In conclusion, physicians should be aware that, in CHB monoinfected patients under TDF therapy, serious renal damage is possible and preventable by timely monitoring serum creatinine and phosphate.

  12. Assessment of single nucleotide polymorphisms in screening 52 DNA repair and cell cycle control genes in Fanconi anemia patients

    Directory of Open Access Journals (Sweden)

    Petrović Sandra

    2015-01-01

    Full Text Available Fanconi anemia (FA is a rare genetically heterogeneous disorder associated with bone marrow failure, birth defects and cancer susceptibility. Apart from the disease- causing mutations in FANC genes, the identification of specific DNA variations, such as single nucleotide polymorphisms (SNPs, in other candidate genes may lead to a better clinical description of this condition enabling individualized treatment with improvement of the prognosis. In this study, we have assessed 95 SNPs located in 52 key genes involved in base excision repair (BER, nucleotide excision repair (NER, mismatch repair (MMR, double strand break (DSB repair and cell cycle control using a DNA repair chip (Asper Biotech, Estonia which includes most of the common variants for the candidate genes. The SNP genotyping was performed in five FA-D2 patients and in one FA-A patient. The polymorphisms studied were synonymous (n=10, nonsynonymous (missense (n=52 and in non-coding regions of the genome (introns and 5 ‘and 3’ untranslated regions (UTR (n=33. Polymorphisms found at the homozygous state are selected for further analysis. Our results have shown a significant inter-individual variability among patients in the type and the frequency of SNPs and also elucidate the need for further studies of polymorphisms located in ATM, APEX APE 1, XRCC1, ERCC2, MSH3, PARP4, NBS1, BARD1, CDKN1B, TP53 and TP53BP1 which may be of great importance for better clinical description of FA. In addition, the present report recommends the use of SNPs as predictive and prognostic genetic markers to individualize therapy of FA patients. [Projekat Ministarstva nauke Republike Srbije, br. 173046

  13. Frequency of Fanconi anemia in Brazil and efficacy of screening for the FANCA 3788-3790del mutation

    Directory of Open Access Journals (Sweden)

    N. Magdalena

    2005-05-01

    Full Text Available Fanconi anemia (FA is an autosomal recessive genetic disease characterized by progressive bone marrow failure, susceptibility to cancer and multiple congenital anomalies. There is important clinical variability among patients and the knowledge of factors which might predict outcome would greatly help the decision making regarding the choices of treatment and the appropriate time to start it. Future studies of the possible correlation between specific mutations with specific clinical presentations will provide the answer to one of these factors. At our Center we standardized a rapid and precise screening test using a mismatch PCR assay for a specific mutation (3788-3790del in exon 38 of gene FANCA in Brazilian FA patients. We present the results obtained after screening 80 non-consanguineous FA patients referred from all regions of Brazil with a clinical diagnosis of FA supported by cellular hypersensitivity to diepoxybutane. We were able to detect the 3788-3790del allele in 24 of the 80 (30% FA patients studied. Thirteen of the 80 (16.25% were homozygotes and 11 of the 80 (13.75% were compound heterozygotes, thus confirming the high frequency of the FANCA 3788-3790del mutation in Brazilian FA patients. The identification of patients with specific mutations in the FA genes may lead to a better clinical description of this condition, also providing data for genotype-phenotype correlations, to a better understanding of the interaction of this specific mutation with other mutations in compound heterozygote patients, and ultimately to the right choices of treatment for each patient with improvement of the prognosis on future studies.

  14. Clinical heterogeneity and chromosome breakage in Iranian patients suspicious of Fanconi anemia

    Directory of Open Access Journals (Sweden)

    Ghasemi Firoozabadi S

    2007-10-01

    Full Text Available Background: Fanconi anemia (FA is a rare autosomal recessive disorder characterized by short stature, skeletal anomalies, increased incidence of solid tumors and leukemia, and bone marrow failure (aplastic anemia. FA has been reported in all races and ethnic groups and affects men and women in an equal proportion. The frequency of FA has been estimated at approximately 1 per 360,000 live births. In some populations, including Ashkenazi Jews, Turks, Saudi Arabians and Iranians, this frequency appears to be higher, probably as a result of the founder effect and consanguineous marriage. Because of extensive genetic and clinical heterogeneity (the age of onset, clinical manifestations and survival, diagnosis of FA on the basis of clinical data alone is unreliable and its molecular diagnosis is difficult. The diagnosis of FA exploits the hypersensitivity of FA lymphocytes and fibroblasts to bifunctional alkylating agents such as mitomycin C (MMC, diepoxybutane (DEB and nitrogen mustard and differentiates it from idiopathic aplastic anemia. In this study, in addition to the patients' clinical profiles, a cytogenetic test using MMC was implemented for an accurate diagnosis of Fanconi anemia.Methods: In this study, the lymphocytes of 20 patients referred for FA, and those of their normal sex-matched controls, were treated with three different concentrations of mitomycin C (20, 30, 40 ng/ml. Slides were prepared and solid stained. In order to determine the number and kind of chromosome abnormalities, 50 metaphase spreads from each culture were analyzed. Clinical information was obtained from patient files.Results: Five patients manifested increased chromosome breakage with MMC, confirming the FA diagnosis. Two different concentrations of MMC (30, 40 ng/ml were most effective.Conclusion: The chromosomal breakage test is important for the accurate diagnosis of Fanconi anemia. DNA crosslinking agents used to treat idiopathic aplastic anemia may be

  15. Preleukemia in Fanconi's anemia: hematopoietic cell multinuclearity, membrane duplication, and dysgranulogenesis.

    Science.gov (United States)

    Barton, J C; Parmley, R T; Carroll, A J; Huang, S T; Goodnough, L T; Findley, H W; Ragab, A H

    1987-04-01

    A 25-year-old male had Fanconi's anemia characterized by small stature, the onset of pancytopenia in the first decade of life, a high spontaneous breakage rate of the chromosomes, and the development of acute myeloblastic leukemia. In the preleukemic phase, marrow erythroblasts were multinucleated, and had duplicated nuclear and cytoplasmic membranes with frequent nuclear pockets and cytoplasmic vacuoles, respectively. All neutrophilic and eosinophilic granulocytes had severe quantitative and qualitative defects of granulogenesis; autophagy and nuclear pockets were also observed in the majority of granulocytic cells. Platelets had decreased granulation and extremely dilated canaliculi. Decreased titration scores with anti-I and anti-i were observed with the patient's erythrocytes and those of his clinically normal mother. The unusual morphologic and serologic findings in this patient appear to have resulted from a membrane abnormality affecting the cells of several hematopoietic lines and their organelles.

  16. How SUMOylation Fine-Tunes the Fanconi Anemia DNA Repair Pathway

    Directory of Open Access Journals (Sweden)

    Kate eColeman

    2016-04-01

    Full Text Available Fanconi Anemia (FA is a rare human genetic disorder characterized by developmental defects, bone marrow failure and cancer predisposition, primarily due to a deficiency in the repair of DNA interstrand crosslinks (ICLs. ICL repair through the FA DNA repair pathway is a complicated multi-step process, involving at least 19 FANC proteins and coordination of multiple DNA repair activities, including homologous recombination (HR, nucleotide excision repair (NER and translesion synthesis (TLS. SUMOylation is a critical regulator of several DNA repair pathways, however, the role of this modification in controlling the FA pathway is poorly understood. Here, we summarize recent advances in the fine-tuning of the FA pathway by SUMO-targeted ubiquitin ligases (STUbLs and other SUMO-related interactions, and discuss the implications of these findings in the design of novel therapeutics for alleviating FA-associated condition, including cancer.

  17. X ray sensitivity of diploid skin fibroblasts from patients with Fanconi's anemia

    Science.gov (United States)

    Kale, Ranjini

    1989-01-01

    Experiments were performed on Fanconi's anemia and normal human fibroblast cell lines growing in culture in an attempt to correlate cell cycle kinetics with genomic damage and determine their bearing on the mechanism of chromosome aberration induction. FA fibroblasts showed a significantly increased susceptibility to chromosomal breakage by x rays in the G2 phase of the cell cycle. No such response was observed in fibroblasts irradiated in the G0 phase. The observed increases in achromatic lesions and in chromatid deletions in FA cells as compared with normal cells appear to indicate that FA cells are deficient in strand break repair and also possibly in base damage excision repair. Experiments are now in progress to further elucidate the mechanisms involved.

  18. The Fanconi anaemia components UBE2T and FANCM are functionally linked to nucleotide excision repair.

    Directory of Open Access Journals (Sweden)

    Ian R Kelsall

    Full Text Available The many proteins that function in the Fanconi anaemia (FA monoubiquitylation pathway initiate replicative DNA crosslink repair. However, it is not clear whether individual FA genes participate in DNA repair pathways other than homologous recombination and translesion bypass. Here we show that avian DT40 cell knockouts of two integral FA genes--UBE2T and FANCM are unexpectedly sensitive to UV-induced DNA damage. Comprehensive genetic dissection experiments indicate that both of these FA genes collaborate to promote nucleotide excision repair rather than translesion bypass to protect cells form UV genotoxicity. Furthermore, UBE2T deficiency impacts on the efficient removal of the UV-induced photolesion cyclobutane pyrimidine dimer. Therefore, this work reveals that the FA pathway shares two components with nucleotide excision repair, intimating not only crosstalk between the two major repair pathways, but also potentially identifying a UBE2T-mediated ubiquitin-signalling response pathway that contributes to nucleotide excision repair.

  19. Fanconi Syndrome Associated with Hyponatremia in Two Patients with Legionella Pneumonia

    Science.gov (United States)

    Ryuge, Akihiro; Ito, Yasuhiko; Yamakawa, Taishi; Tanaka, Hitoshi; Yasui, Hirotoshi; Mashimo, Shuko; Watanabe, Kenshi; Nomura, Rie; Suganuma, Nobukazu; Maruyama, Shoichi

    2016-01-01

    Legionella pneumophila is a cause of community-acquired pneumonia that is reported to induce electrolyte disorders, including hyponatremia, hypokalemia, and hypophosphatemia. We herein report two Japanese men with Legionella pneumonia and hyponatremia and hypophosphatemia. These findings were associated with an elevation of urinary low-molecular-weight tubular protein, including urinary β2-microglobulin, N-acetyl-β-D-glucosaminidase, the fractional excretion of phosphate and uric acid, and the presence of glycosuria and panaminoaciduria, suggesting that their electrolyte disorders had been caused by Fanconi syndrome. In these two cases, hyponatremia was probably due to salt wasting. Electrolyte disorders caused by Legionella pneumonia are corrected by treatment of the primary disease and fluid administration. PMID:27904113

  20. Non-Hodgkin's Lymphoma Primarily Presenting with Fanconi Syndrome and Acute Kidney Injury

    Institute of Scientific and Technical Information of China (English)

    Wen-ling Ye; Bing Han; Bing-yan Liu; Chan Meng; Wei Ye; Yu-bing Wen; Hang Li; Xue-mei Li

    2010-01-01

    @@ KIDNEY involvement is common in non-Hodg-kin's lymphoma (NHL) with incidence up to 30%-40% in autopsy studies. However, it us-ually occurs late in the course of the disease and is clinically silent. Clinically overt renal disease in-cluding acute kidney injury (AKI) as its primary manifes-tation is rarely reported, moreover, Fanconi syndrome (FS) is extremely rare as the main manifestation in NHL. In this report, we presented a case of NHL primarily presenting with FS and AKI due to diffuse interstitial infiltration of NHL cells and emphasized the important role of renal biopsy, especially renal immunohistochemical analysis in the di-agnosis of renal diffuse lymphoma.

  1. Fanconi's Anemia Effect or Sickle Cell Anemia Effect: That is the Question.

    Science.gov (United States)

    Unal, Sule; Chui, David H K; Gumruk, Fatma

    2015-01-01

    A 16-year-old boy who was diagnosed to have sickle cell anemia was referred to our center. The parental consanguinity, growth retardation and dysmorphic features prompted a search for possible Fanconi's Anemia (FA). The diepoxybutane (DEB) test was positive, confirming FA. The interaction of both diseases might account for his relatively mild phenotype in terms of both sickle cell anemia (or Hb S, HBB: c.20A > T) and FA. The high Hb F level that might be related to concomitant FA, may have caused a milder phenotype of sickle cell anemia, whereas nitric oxide (NO) depletion as a consequence of sickle cell anemia, may have caused a delay in the bone marrow failure of FA.

  2. Carcinoma de células escamosas em língua pós-transplante de medula óssea por Anemia de Fanconi Squamous cell carcinoma of the tongue due to Fanconi's Anemia after bone marrow transplantation

    Directory of Open Access Journals (Sweden)

    Ricardo Pasquini

    2003-01-01

    Full Text Available Anemia Fanconi (AF é uma síndrome autossômica recessiva, caracterizada por pancitopenia progressiva com hipoplasia de MO, em associação com várias anormalidades constitucionais, tendo como único recurso terapêutico com possibilidade potencial de cura o transplante de medula óssea, e sendo tais pacientes propensos ao desenvolvimento de malignidades hematológicas e carcinoma de células escamosas (CEC em diversos locais: reto, vagina, cérvice, esôfago, cavidade bucal, faringe ou pele, mas especialmente em cabeça e pescoço. Relatamos aqui três casos de pacientes portadores de AF, que após TMO desenvolveram CEC em língua. Além disso, mencionamos fatores de risco relatados para tal evento, como diagnóstico de AF, condicionamento pré-transplante (quimioterápicos e irradiação, terapia com drogas imunossupressoras para tratamento de doença enxerto contra hospedeiro (DECH aguda ou crônica, sexo e idade avançada. Além do que, discorremos sobre a existência de três mecanismos postulados que predispõem indivíduos com AF ao desenvolvimento de neoplasia: (1 defeito na reparação do DNA; (2 defeito na detoxificação de radicais de oxigênio; e (3 imunodeficiência.Fanconi's Anemia, first described in 1927, is a rare autonomic recessive disease characterized by progressive pancytopenia, congenital malformations, spontaneous or chemically induced chromosome breakage and increased incidence of leukemia and other cancers. The onset of bone marrow hypoplasia and its hematological manifestations is usually in the 3 - 7 year age range. The disease has traditionally been managed clinically through administration of blood products, treatment of infections and prolonged administration of androgens, growth factors and more recently with gene therapy. The value of bone marrow transplantation in correcting the hematological manifestations of Fanconi's anemia has been established. Alkilanting agents and radiation have been utilized as a

  3. The Fanconi anemia pathway: Repairing the link between DNA damage and squamous cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Romick-Rosendale, Lindsey E. [Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children' s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229 (United States); Lui, Vivian W.Y.; Grandis, Jennifer R. [Department of Otolaryngology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Wells, Susanne I., E-mail: Susanne.Wells@cchmc.org [Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children' s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229 (United States)

    2013-03-15

    Fanconi anemia (FA) is a rare inherited recessive disease caused by mutations in one of fifteen genes known to encode FA pathway components. In response to DNA damage, nuclear FA proteins associate into high molecular weight complexes through a cascade of post-translational modifications and physical interactions, followed by the repair of damaged DNA. Hematopoietic cells are particularly sensitive to the loss of these interactions, and bone marrow failure occurs almost universally in FA patients. FA as a disease is further characterized by cancer susceptibility, which highlights the importance of the FA pathway in tumor suppression, and will be the focus of this review. Acute myeloid leukemia is the most common cancer type, often subsequent to bone marrow failure. However, FA patients are also at an extreme risk of squamous cell carcinoma (SCC) of the head and neck and gynecological tract, with an even greater incidence in those individuals who have received a bone marrow transplant and recovered from hematopoietic disease. FA tumor suppression in hematopoietic versus epithelial compartments could be mechanistically similar or distinct. Definition of compartment specific FA activities is now critical to assess the effects of today's bone marrow failure treatments on tomorrow's solid tumor development. It is our hope that current therapies can then be optimized to decrease the risk of malignant transformation in both hematopoietic and epithelial cells. Here we review our current understanding of the mechanisms of action of the Fanconi anemia pathway as it contributes to stress responses, DNA repair and squamous cell carcinoma susceptibility.

  4. Pancitopenia por anemia de Fanconi: presentación de un caso clínico.

    Directory of Open Access Journals (Sweden)

    Miguel Zúñiga

    2009-01-01

    Full Text Available La anemia de Fanconi es una patología genética caracterizada por una alteración en la reparación del ADN que se expresa con alteraciones físicas y hematológicas. Es una enfermedad congénita rara y corresponde a la primera causa de anemia aplásica en la infancia. Tiene un curso desfavorable tanto por el deterioro de sus parámetros sanguíneos, así como también por el riesgo aumentado de malignización hematológica. Su único tratamiento curativo es el trasplante de médula ósea. Se presenta el caso de un niño de 3 años, hijo de padres judíos, portador de malformaciones mayores y menores, que presentó un cuadro infeccioso por Mycoplasma pneumoniae que evolucionó a una pancitopenia severa. En el estudio del caso se buscaron etiologías que abarcaron desde las infecciosas e inmunológicas hasta las que involucraban a la medula ósea Una vez que los exámenes realizados descartaron patologías linfoproliferativas, la clínica y la persistencia del cuadro orientaron a buscar alguna condición genética que explicara esta situación. Dentro de este planteamiento se realizó un estudio de fragilidad cromosómica en linfocitos T que permitió confirmar la presencia de una anemia de Fanconi. Actualmente el paciente tiene 4 años, permanece en condiciones relativamente estables, requiriendo transfusiones en forma periódica, mientras se encuentra en evaluación para su trasplante de células madre hematopoyéticas.

  5. Dearth and Delayed Maturation of Testicular Germ Cells in Fanconi Anemia E Mutant Male Mice

    Science.gov (United States)

    Fu, Chun; Begum, Khurshida; Jordan, Philip W.; He, Yan; Overbeek, Paul A.

    2016-01-01

    After using a self-inactivating lentivirus for non-targeted insertional mutagenesis in mice, we identified a transgenic family with a recessive mutation that resulted in reduced fertility in homozygous transgenic mice. The lentiviral integration site was amplified by inverse PCR. Sequencing revealed that integration had occurred in intron 8 of the mouse Fance gene, which encodes the Fanconi anemia E (Fance) protein. Fanconi anemia (FA) proteins play pivotal roles in cellular responses to DNA damage and Fance acts as a molecular bridge between the FA core complex and Fancd2. To investigate the reduced fertility in the mutant males, we analyzed postnatal development of testicular germ cells. At one week after birth, most tubules in the mutant testes contained few or no germ cells. Over the next 2–3 weeks, germ cells accumulated in a limited number of tubules, so that some tubules contained germ cells around the full periphery of the tubule. Once sufficient numbers of germ cells had accumulated, they began to undergo the later stages of spermatogenesis. Immunoassays revealed that the Fancd2 protein accumulated around the periphery of the nucleus in normal developing spermatocytes, but we did not detect a similar localization of Fancd2 in the Fance mutant testes. Our assays indicate that although Fance mutant males are germ cell deficient at birth, the extant germ cells can proliferate and, if they reach a threshold density, can differentiate into mature sperm. Analogous to previous studies of FA genes in mice, our results show that the Fance protein plays an important, but not absolutely essential, role in the initial developmental expansion of the male germ line. PMID:27486799

  6. Fanconi Syndrome Secondary to Deferasirox in Diamond-Blackfan Anemia: Case Series and Recommendations for Early Diagnosis.

    Science.gov (United States)

    Papneja, Koyelle; Bhatt, Mihir D; Kirby-Allen, Melanie; Arora, Steven; Wiernikowski, John T; Athale, Uma H

    2016-08-01

    Deferasirox is an oral iron chelator used to treat patients with transfusion-related iron overload. We report, from two institutions, two children with Diamond-Blackfan anemia who developed Fanconi syndrome secondary to deferasirox administration, along with a review of the literature. The current recommendation for the laboratory monitoring of patients receiving deferasirox does not include serum electrolytes or urine analysis. Thus, despite routine clinic visits and bloodwork, these two patients presented with life-threatening electrolyte abnormalities requiring hospitalization. Hence, we propose the inclusion of serum electrolytes and urine analysis as part of routine monitoring to facilitate the early diagnosis of Fanconi syndrome in the context of high doses of deferasirox therapy.

  7. Fanconi anemia in brothers initially diagnosed with VACTERL association with hydrocephalus, and subsequently with Baller-Gerold syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Rossbach, H.C.; Granan, N.H.; Rossi, A.R.; Barbosa, J.L. [Univ. of South Florida, St. Petersburg, FL (United States)] [and others

    1996-01-02

    Two brothers with presumed Baller-Gerold syndrome, one of whom was previously diagnosed with the association of vertebral, cardiac, renal, limb anomalies, anal atresia, tracheo-esophageal fistula (VACTERL) association with hydrocephalus, were evaluated for chromosome breakage because of severe thrombo cytopenia in one of them. Spontaneous and clastogen-induced breakage was markedly increased in both patients as compared to control individuals. Clinical manifestations and chromosome breakage, consistent with Fanconi anemia, in patients with a prior diagnosis of either Baller-Gerold syndrome, reported earlier in one other patient, or with VACTERL association with hydrocephalus, recently reported in 3 patients, underline the clinical heterogeneity of Fanconi anemia and raise the question of whether these syndromes are distinct disorders or phenotypic variations of the same disease. 12 refs., 3 figs., 1 tab.

  8. Abacavir-induced reversible Fanconi syndrome with nephrogenic diabetes insipidus in a patient with acquired immunodeficiency syndrome

    Directory of Open Access Journals (Sweden)

    Ahmad M

    2006-01-01

    Full Text Available There are several reports of Fanconi syndrome (FS with or without nephrogenic diabetes insipidus (NDI in patients with human immunodeficiency virus (HIV infection, treated with various antiretroviral medications like cidofovir, adefovir, didenosine and tenofovir. But neither FS nor NDI has been documented with abacavir therapy. We are reporting the first case of abacavir-induced reversible FS with NDI in a patient with acquired immunodeficiency syndrome, who recovered completely with supportive treatment and discontinuation of abacavir.

  9. Fanconi anemia

    Science.gov (United States)

    ... PA: Elsevier Saunders; 2016:chap 27. Dror Y, Freedman MH. Inherited forms of bone marrow failure. In: ... Philadelphia, PA: Elsevier; 2013:chap 27. Dror Y, Freedman MH. The inherited pancytopenias. In: Kliegman RM, Stanton ...

  10. Genomic amplification of Fanconi anemia complementation group A (FancA) in head and neck squamous cell carcinoma (HNSCC): Cellular mechanisms of radioresistance and clinical relevance.

    Science.gov (United States)

    Hess, Julia; Unger, Kristian; Orth, Michael; Schötz, Ulrike; Schüttrumpf, Lars; Zangen, Verena; Gimenez-Aznar, Igor; Michna, Agata; Schneider, Ludmila; Stamp, Ramona; Selmansberger, Martin; Braselmann, Herbert; Hieber, Ludwig; Drexler, Guido A; Kuger, Sebastian; Klein, Diana; Jendrossek, Verena; Friedl, Anna A; Belka, Claus; Zitzelsberger, Horst; Lauber, Kirsten

    2017-02-01

    Radio (chemo) therapy is a crucial treatment modality for head and neck squamous cell carcinoma (HNSCC), but relapse is frequent, and the underlying mechanisms remain largely elusive. Therefore, novel biomarkers are urgently needed. Previously, we identified gains on 16q23-24 to be associated with amplification of the Fanconi anemia A (FancA) gene and to correlate with reduced progression-free survival after radiotherapy. Here, we analyzed the effects of FancA on radiation sensitivity in vitro, characterized the underlying mechanisms, and evaluated their clinical relevance. Silencing of FancA expression in HNSCC cell lines with genomic gains on 16q23-24 resulted in significantly impaired clonogenic survival upon irradiation. Conversely, overexpression of FancA in immortalized keratinocytes conferred increased survival accompanied by improved DNA repair, reduced accumulation of chromosomal translocations, but no hyperactivation of the FA/BRCA-pathway. Downregulation of interferon signaling as identified by microarray analyses, enforced irradiation-induced senescence, and elevated production of the senescence-associated secretory phenotype (SASP) appeared to be candidate mechanisms contributing to FancA-mediated radioresistance. Data of the TCGA HNSCC cohort confirmed the association of gains on 16q24.3 with FancA overexpression and impaired overall survival. Importantly, transcriptomic alterations similar to those observed upon FancA overexpression in vitro strengthened the clinical relevance. Overall, FancA amplification and overexpression appear to be crucial for radiotherapeutic failure in HNSCC.

  11. Idiopathic Fanconi's syndrome with nephrogenic diabetes insipidus in a child who presented as vitamin D resistant rickets--a case report and review of literature.

    Science.gov (United States)

    Patra, Soumya; Nadri, Gulnaz; Chowdhary, Harish; Pemde, Harish K; Singh, Varinder; Chandra, Jagdish

    2011-01-01

    Fanconi's syndrome is a complex of multiple tubular dysfunctions of proximal tubular cells occurring alone or in association with a variety of inherited (primary) or acquired (secondary) disorders. It is characterized by aminoaciduria, normoglycemic glycosuria, tubular proteinuria without hematuria, metabolic acidosis without anion gap and excessive urinary excretion of phosphorous, calcium, uric acid, bicarbonate, sodium, potassium and magnesium. Diabetes insipidus is a disease of collecting tubules and a child mainly presents with dehydration and hypernatremia. We report the first case of idiopathic Fanconi's syndrome along with nephrogenic diabetes insipidus (NDI) in a child who presented to us as resistant rickets. Medline search did not reveal any case of nephrogenic diabetes insipidus associated with idiopathic Fanconi's syndrome. We hypothesized that the NDI may be due to severe hypokalemia induced tubular dysfunction. The child was treated for hypophosphatemic rickets with severe metabolic acidosis and the treatment for NDI was also given. Now he has healed rickets and normal blood pH, sodium and osmolarity.

  12. A case report of nephrogenic diabetes insipidus with idiopathic Fanconi syndrome in a child who presented with vitamin D resistant rickets.

    Science.gov (United States)

    Patra, Soumya; Nadri, Gulnaz; Chowdhary, Harish; Pemde, Harish K; Singh, Varinder; Chandra, Jagdish

    2014-05-01

    Fanconi syndrome is a complex of multiple tubular dysfunctions of proximal tubular cells, occurring alone or in association with a variety of inherited (primary) or acquired (secondary) disorders. It is characterized by aminoaciduria, normoglycemic glycosuria, tubular proteinuria without hematuria, metabolic acidosis without anion gap and excessive urinary excretion of phosphorous, calcium, uric acid, bicarbonate, sodium, potassium and magnesium. Diabetes insipidus is a disease of collecting tubules and children mainly present with dehydration and hypernatremia. We are reporting the first case of idiopathic Fanconi's syndrome along with nephrogenic diabetes insipidus in a child who presented to us with vitamin D resistant rickets. Medline search did not reveal any case of nephrogenic diabetes insipidus (NDI) associated with idiopathic Fanconi syndrome. We hypothesized that the NDI may be due to to severe hypokalemia induced tubular dysfunction.

  13. The Fanconi Anemia Pathway Protects Genome Integrity from R-loops.

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    María L García-Rubio

    2015-11-01

    Full Text Available Co-transcriptional RNA-DNA hybrids (R loops cause genome instability. To prevent harmful R loop accumulation, cells have evolved specific eukaryotic factors, one being the BRCA2 double-strand break repair protein. As BRCA2 also protects stalled replication forks and is the FANCD1 member of the Fanconi Anemia (FA pathway, we investigated the FA role in R loop-dependent genome instability. Using human and murine cells defective in FANCD2 or FANCA and primary bone marrow cells from FANCD2 deficient mice, we show that the FA pathway removes R loops, and that many DNA breaks accumulated in FA cells are R loop-dependent. Importantly, FANCD2 foci in untreated and MMC-treated cells are largely R loop dependent, suggesting that the FA functions at R loop-containing sites. We conclude that co-transcriptional R loops and R loop-mediated DNA damage greatly contribute to genome instability and that one major function of the FA pathway is to protect cells from R loops.

  14. Correction of Fanconi Anemia Group C Hematopoietic Stem Cells Following Intrafemoral Gene Transfer

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    Ouassila Habi

    2010-01-01

    Full Text Available The main cause of morbidity and mortality in Fanconi anemia patients is the development of bone marrow (BM failure; thus correction of hematopoietic stem cells (HSCs through gene transfer approaches would benefit FA patients. However, gene therapy trials for FA patients using ex vivo transduction protocols have failed to provide long-term correction. In addition, ex vivo cultures have been found to be hazardous for FA cells. To circumvent negative effects of ex vivo culture in FA stem cells, we tested the corrective ability of direct injection of recombinant lentiviral particles encoding FancC-EGFP into femurs of FancC−/− mice. Using this approach, we show that FancC−/− HSCs were efficiently corrected. Intrafemoral gene transfer of the FancC gene prevented the mitomycin C-induced BM failure. Moreover, we show that intrafemoral gene delivery into aplastic marrow restored the bone marrow cellularity and corrected the remaining HSCs. These results provide evidence that targeting FA-deficient HSCs directly in their environment enables efficient and long-term correction of BM defects in FA.

  15. Sonic Hedgehog, VACTERL, and Fanconi anemia: Pathogenetic connections and therapeutic implications.

    Science.gov (United States)

    Lubinsky, Mark

    2015-11-01

    Three systems with VACTERL association findings- mutations of the Sonic Hedgehog (SHH) signaling pathway in mice, murine adriamycin teratogenicity, and human Fanconi anemia (FA) pathway mutations, may all involve a similar mechanism. SHH is up-regulated in irradiated cells, and DNA breaks common with radiation damage in the adriamycin and FA systems are plausible signals for such effects, which would affect development. Since FA related DNA breakage occurs throughout life, SHH disturbances may account for later FA related findings involving hematopoietic and malignancy issues. In support, androgen, a standard treatment for FA hematologic failure, down-regulates SHH, and common FA malignancies such as squamous cell carcinomas and acute myeloid leukemia have been linked to enhanced SHH function. This suggests that interventions lowering SHH levels may be useful therapeutically. Also supporting a connection between pre- and post- natal findings, the frequency and number of VACTERL anomalies with FA correlate with the severity and onset of hematopoietic and malignancy issues. In FA, radial anomalies are the most common of these defects, followed by renal findings, while vertebral and gastrointestinal anomalies are relatively uncommon, a pattern that differs from observations of the VACTERL association. Genes with more severe effects also show a greatly increased incidence of brain abnormalities, and a paucity of such findings with other FA genes suggests that brain development is relatively refractory to SHH related effects, accounting for the rarity of such findings with the association.

  16. The Fanconi Anemia C Protein Binds to and Regulates Stathmin-1 Phosphorylation.

    Science.gov (United States)

    Magron, Audrey; Elowe, Sabine; Carreau, Madeleine

    2015-01-01

    The Fanconi anemia (FA) proteins are involved in a signaling network that assures the safeguard of chromosomes. To understand the function of FA proteins in cellular division events, we investigated the interaction between Stathmin-1 (STMN1) and the FA group C (FANCC) protein. STMN1 is a ubiquitous cytosolic protein that regulates microtubule dynamics. STMN1 activities are regulated through phosphorylation-dephosphorylation mechanisms that control assembly of the mitotic spindle, and dysregulation of STMN1 phosphorylation is associated with mitotic aberrancies leading to chromosome instability and cancer progression. Using different biochemical approaches, we showed that FANCC interacts and co-localizes with STMN1 at centrosomes during mitosis. We also showed that FANCC is required for STMN1 phosphorylation, as mutations in FANCC reduced serine 16- and 38-phosphorylated forms of STMN1. Phosphorylation of STMN1 at serine 16 is likely an event dependent on a functional FA pathway, as it is reduced in FANCA- and FANCD2-mutant cells. Furthermore, FA-mutant cells exhibited mitotic spindle anomalies such as supernumerary centrosomes and shorter mitotic spindles. These results suggest that FA proteins participate in the regulation of cellular division via the microtubule-associated protein STMN1.

  17. The Fanconi Anemia C Protein Binds to and Regulates Stathmin-1 Phosphorylation.

    Directory of Open Access Journals (Sweden)

    Audrey Magron

    Full Text Available The Fanconi anemia (FA proteins are involved in a signaling network that assures the safeguard of chromosomes. To understand the function of FA proteins in cellular division events, we investigated the interaction between Stathmin-1 (STMN1 and the FA group C (FANCC protein. STMN1 is a ubiquitous cytosolic protein that regulates microtubule dynamics. STMN1 activities are regulated through phosphorylation-dephosphorylation mechanisms that control assembly of the mitotic spindle, and dysregulation of STMN1 phosphorylation is associated with mitotic aberrancies leading to chromosome instability and cancer progression. Using different biochemical approaches, we showed that FANCC interacts and co-localizes with STMN1 at centrosomes during mitosis. We also showed that FANCC is required for STMN1 phosphorylation, as mutations in FANCC reduced serine 16- and 38-phosphorylated forms of STMN1. Phosphorylation of STMN1 at serine 16 is likely an event dependent on a functional FA pathway, as it is reduced in FANCA- and FANCD2-mutant cells. Furthermore, FA-mutant cells exhibited mitotic spindle anomalies such as supernumerary centrosomes and shorter mitotic spindles. These results suggest that FA proteins participate in the regulation of cellular division via the microtubule-associated protein STMN1.

  18. Regulation of Fanconi anemia protein FANCD2 monoubiquitination by miR-302

    Energy Technology Data Exchange (ETDEWEB)

    Suresh, Bharathi [Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul (Korea, Republic of); College of Medicine, Hanyang University, Seoul (Korea, Republic of); Kumar, A. Madhan [Center of Research Excellence in Corrosion, Research Institute King Fahd University of Petroleum and Minerals, Dhahran (Saudi Arabia); Jeong, Hoe-Su [Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul (Korea, Republic of); Cho, Youl-Hee [College of Medicine, Hanyang University, Seoul (Korea, Republic of); Ramakrishna, Suresh, E-mail: suresh.ramakris@gmail.com [Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul (Korea, Republic of); College of Medicine, Hanyang University, Seoul (Korea, Republic of); Kim, Kye-Seong, E-mail: ks66kim@hanyang.ac.kr [Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul (Korea, Republic of); College of Medicine, Hanyang University, Seoul (Korea, Republic of)

    2015-10-16

    Fanconi anemia (FA) is a recessively inherited multigene disease characterized by congenital defects, progressive bone marrow failure, and heightened cancer susceptibility. Monoubiquitination of the FA pathway member FANCD2 contributes to the repair of replication stalling DNA lesions. However, cellular regulation of FANCD2 monoubiquitination remains poorly understood. In the present study, we identified the miR-302 cluster as a potential regulator of FANCD2 by bioinformatics analysis. MicroRNAs (miRNAs) are the major posttranscriptional regulators of a wide variety of biological processes, and have been implicated in a number of diseases. Expression of the exogenous miR-302 cluster (without miR-367) reduced FANCD2 monoubiquitination and nuclear foci formation. Furthermore, miR-302 cells showed extensive chromosomal breakage upon MMC treatment when compared to mock control cells. Taken together, our results suggest that overexpression of miR-302 plays a critical role in the regulation of FANCD2 monoubiquitination, resulting in characteristic defects in DNA repair within cells. - Highlights: • miR-302 binds to the 3′UTR promoter of the FANCD2 gene to regulate gene expression. • miR-302 cluster down-regulates FANCD2 protein expression. • miR-302 cluster reduces FANCD2 monoubiquitination and nuclear foci formation. • miR-302 exhibits the characteristic defects in DNA repair in cells.

  19. Genotyping of fanconi anemia patients by whole exome sequencing: advantages and challenges.

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    Kerstin Knies

    Full Text Available Fanconi anemia (FA is a rare genomic instability syndrome. Disease-causing are biallelic mutations in any one of at least 15 genes encoding members of the FA/BRCA pathway of DNA-interstrand crosslink repair. Patients are diagnosed based upon phenotypical manifestations and the diagnosis of FA is confirmed by the hypersensitivity of cells to DNA interstrand crosslinking agents. Customary molecular diagnostics has become increasingly cumbersome, time-consuming and expensive the more FA genes have been identified. We performed Whole Exome Sequencing (WES in four FA patients in order to investigate the potential of this method for FA genotyping. In search of an optimal WES methodology we explored different enrichment and sequencing techniques. In each case we were able to identify the pathogenic mutations so that WES provided both, complementation group assignment and mutation detection in a single approach. The mutations included homozygous and heterozygous single base pair substitutions and a two-base-pair duplication in FANCJ, -D1, or -D2. Different WES strategies had no critical influence on the individual outcome. However, database errors and in particular pseudogenes impose obstacles that may prevent correct data perception and interpretation, and thus cause pitfalls. With these difficulties in mind, our results show that WES is a valuable tool for the molecular diagnosis of FA and a sufficiently safe technique, capable of engaging increasingly in competition with classical genetic approaches.

  20. The Fanconi anemia DNA damage repair pathway in the spotlight for germline predisposition to colorectal cancer

    Science.gov (United States)

    Esteban-Jurado, Clara; Franch-Expósito, Sebastià; Muñoz, Jenifer; Ocaña, Teresa; Carballal, Sabela; López-Cerón, Maria; Cuatrecasas, Miriam; Vila-Casadesús, Maria; Lozano, Juan José; Serra, Enric; Beltran, Sergi; Brea-Fernández, Alejandro; Ruiz-Ponte, Clara; Castells, Antoni; Bujanda, Luis; Garre, Pilar; Caldés, Trinidad; Cubiella, Joaquín; Balaguer, Francesc; Castellví-Bel, Sergi

    2016-01-01

    Colorectal cancer (CRC) is one of the most common neoplasms in the world. Fanconi anemia (FA) is a very rare genetic disease causing bone marrow failure, congenital growth abnormalities and cancer predisposition. The comprehensive FA DNA damage repair pathway requires the collaboration of 53 proteins and it is necessary to restore genome integrity by efficiently repairing damaged DNA. A link between FA genes in breast and ovarian cancer germline predisposition has been previously suggested. We selected 74 CRC patients from 40 unrelated Spanish families with strong CRC aggregation compatible with an autosomal dominant pattern of inheritance and without mutations in known hereditary CRC genes and performed germline DNA whole-exome sequencing with the aim of finding new candidate germline predisposition variants. After sequencing and data analysis, variant prioritization selected only those very rare alterations, producing a putative loss of function and located in genes with a role compatible with cancer. We detected an enrichment for variants in FA DNA damage repair pathway genes in our familial CRC cohort as 6 families carried heterozygous, rare, potentially pathogenic variants located in BRCA2/FANCD1, BRIP1/FANCJ, FANCC, FANCE and REV3L/POLZ. In conclusion, the FA DNA damage repair pathway may play an important role in the inherited predisposition to CRC. PMID:27165003

  1. The Fanconi anemia core complex is dispensable during somatic hypermutation and class switch recombination.

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    Peter H L Krijger

    Full Text Available To generate high affinity antibodies during an immune response, B cells undergo somatic hypermutation (SHM of their immunoglobulin genes. Error-prone translesion synthesis (TLS DNA polymerases have been reported to be responsible for all mutations at template A/T and at least a fraction of G/C transversions. In contrast to A/T mutations which depend on PCNA ubiquitination, it remains unclear how G/C transversions are regulated during SHM. Several lines of evidence indicate a mechanistic link between the Fanconi Anemia (FA pathway and TLS. To investigate the contribution of the FA pathway in SHM we analyzed FancG-deficient B cells. B cells deficient for FancG, an essential member of the FA core complex, were hypersensitive to treatment with cross-linking agents. However, the frequencies and nucleotide exchange spectra of SHM remained comparable between wild-type and FancG-deficient B cells. These data indicate that the FA pathway is not involved in regulating the outcome of SHM in mammals. In addition, the FA pathway appears dispensable for class switch recombination.

  2. Long-term Survival, Organ Function, and Malignancy after Hematopoietic Stem Cell Transplantation for Fanconi Anemia.

    Science.gov (United States)

    Bonfim, Carmem; Ribeiro, Lisandro; Nichele, Samantha; Bitencourt, Marco; Loth, Gisele; Koliski, Adriana; Funke, Vaneuza A M; Pilonetto, Daniela V; Pereira, Noemi F; Flowers, Mary E D; Velleuer, Eunike; Dietrich, Ralf; Fasth, Anders; Torres-Pereira, Cassius C; Pedruzzi, Paola; Eapen, Mary; Pasquini, Ricardo

    2016-07-01

    We report on long-term survival in 157 patients with Fanconi anemia (FA) who survived 2 years or longer after their first transplantation with a median follow-up of 9 years. Marrow failure (80%) was the most common indication for transplantation. There were 20 deaths beyond 2 years after transplantation, with 12 of the deaths occurring beyond 5 years after transplantation. Donor chimerism was available for 149 patients: 112 (76%) reported > 95% chimerism, 27 (18%) reported 90% to 95% chimerism, and 8 (5%) reported 20% to 89% donor chimerism. Two patients have < 20% donor chimerism. The 10- and 15-year probabilities of survival were 90% and 79%, respectively. Results of multivariate analysis showed higher mortality risks for transplantations before 2003 (hazard ratio [HR], 7.87; P = .001), chronic graft-versus-host disease (GVHD) (HR, 3.80; P = .004) and squamous cell carcinoma after transplantation (HR, 38.17; P < .0001). The predominant cause of late mortality was squamous cell carcinoma, with an incidence of 8% and 14% at 10 and 15 years after transplantation, respectively, and was more likely to occur in those with chronic GVHD. Other causes of late mortality included chronic GVHD, infection, graft failure, other cancers, and hemorrhage. Although most patients are disease free and functional long term, our data support aggressive surveillance for long periods to identify those at risk for late mortality.

  3. Pancitopenia por anemia de Fanconi: presentación de un caso clínico.

    Directory of Open Access Journals (Sweden)

    Miguel Zúñiga

    2010-08-01

    Full Text Available La anemia de Fanconi es una patología genética caracterizada por una alteración en la reparación del ADN que se expresa con alteraciones físicas y hematológicas. Es una enfermedad congénita rara y corresponde a la primera causa de anemia aplásica en la infancia. Tiene un curso desfavorable tanto por el deterioro de sus parámetros sanguíneos, así como también por el riesgo aumentado de malignización hematológica. Su único tratamiento curativo es el trasplante de médula ósea. Se presenta el caso de un niño de 3 años, hijo de padres judíos, portador de malformaciones mayores y menores, que presentó un cuadro infeccioso por Mycoplasma pneumoniae que evolucionó a una pancitopenia severa. En el  estudio del caso se buscaron etiologías  que abarcaron desde las infecciosas e inmunológicas hasta  las que involucraban a la medula ósea Una vez que los exámenes realizados descartaron patologías linfoproliferativas, la clínica y la persistencia del cuadro orientaron a buscar alguna condición genética que explicara esta situación.

  4. Diagnostic Overlap between Fanconi Anemia and the Cohesinopathies: Roberts Syndrome and Warsaw Breakage Syndrome

    Directory of Open Access Journals (Sweden)

    Petra van der Lelij

    2010-01-01

    Full Text Available Fanconi anemia (FA is a recessively inherited disease characterized by multiple symptoms including growth retardation, skeletal abnormalities, and bone marrow failure. The FA diagnosis is complicated due to the fact that the clinical manifestations are both diverse and variable. A chromosomal breakage test using a DNA cross-linking agent, in which cells from an FA patient typically exhibit an extraordinarily sensitive response, has been considered the gold standard for the ultimate diagnosis of FA. In the majority of FA patients the test results are unambiguous, although in some cases the presence of hematopoietic mosaicism may complicate interpretation of the data. However, some diagnostic overlap with other syndromes has previously been noted in cases with Nijmegen breakage syndrome. Here we present results showing that misdiagnosis may also occur with patients suffering from two of the three currently known cohesinopathies, that is, Roberts syndrome (RBS and Warsaw breakage syndrome (WABS. This complication may be avoided by scoring metaphase chromosomes—in addition to chromosomal breakage—for spontaneously occurring premature centromere division, which is characteristic for RBS and WABS, but not for FA.

  5. A DOG’s View of Fanconi Anemia: Insights from C. elegans

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    Martin Jones

    2012-01-01

    Full Text Available C. elegans provides an excellent model system for the study of the Fanconi Anemia (FA, one of the hallmarks of which is sensitivity to interstrand crosslinking agents. Central to our understanding of FA has been the investigation of DOG-1, the functional ortholog of the deadbox helicase FANCJ. Here we review the current understanding of the unique role of DOG-1 in maintaining stability of G-rich DNA in C. elegans and explore the question of why DOG-1 animals are crosslink sensitive. We propose a dynamic model in which noncovalently linked G-rich structures form and un-form in the presence of DOG-1. When DOG-1 is absent but crosslinking agents are present the G-rich structures are readily covalently crosslinked, resulting in increased crosslinks formation and thus giving increased crosslink sensitivity. In this interpretation DOG-1 is neither upstream nor downstream in the FA pathway, but works alongside it to limit the availability of crosslink substrates. This model reconciles the crosslink sensitivity observed in the absence of DOG-1 function with its unique role in maintaining G-Rich DNA and will help to formulate experiments to test this hypothesis.

  6. Immune thrombocytopenia in two unrelated Fanconi anemia patients – a mere coincidence?

    Directory of Open Access Journals (Sweden)

    Anna eKarastaneva

    2015-06-01

    Full Text Available Thrombocytopenia and pancytopenia, occurring in patients with Fanconi anemia (FA, are interpreted either as progression to bone marrow failure or as developing myelodysplasia. On the other hand, immune thrombocytopenia (ITP represents an acquired and often self-limiting benign hematologic disorder, associated with peripheral, immune-mediated, platelet destruction requiring different management modalities than those used in congenital bone marrow failure syndromes, including FA. Here we describe the clinical course of two independent FA patients with atypical - namely immune - thrombocytopenia. While in one patient belonging to complementation group FA-A, the ITP started at 17 months of age and showed a chronically persisting course with severe purpura, responding well to intravenous immunoglobulins (IVIG and later also danazol, a synthetic androgen, the other patient (of complementation group FA-D2 had a self-limiting course that resolved after one administration of IVIG. No cytogenetic aberrations or bone marrow abnormalities other than FA-typical mild dysplasia were detected. Our data show that acute and chronic ITP may occur in FA patients and impose individual diagnostic and therapeutic challenges in this rare congenital bone marrow failure / tumor predisposition syndrome. The management and a potential context of immune pathogenesis with the underlying marrow disorder are discussed.

  7. The Fanconi anemia pathway and ICL repair: implications for cancer therapy.

    Science.gov (United States)

    Wang, Lily C; Gautier, Jean

    2010-10-01

    Fanconi anemia (FA) is an inherited disease caused by mutations in at least 13 genes and characterized by genomic instability. In addition to displaying strikingly heterogenous clinical phenotypes, FA patients are exquisitely sensitive to treatments with crosslinking agents that create interstrand crosslinks (ICL). In contrast to bacteria and yeast, in which ICLs are repaired through replication-dependent and -independent mechanisms, it is thought that ICLs are repaired primarily during DNA replication in vertebrates. However, recent data indicate that replication-independent ICL repair also operates in vertebrates. While the precise role of the FA pathway in ICL repair remains elusive, increasing evidence suggests that FA proteins function at different steps in the sensing, recognition and processing of ICLs, as well as in signaling from these very toxic lesions, which can be generated by a wide variety of cancer chemotherapeutic drugs. Here, we discuss some of the recent findings that have shed light on the role of the FA pathway in ICL repair, with special emphasis on the implications of these findings for cancer therapy since disruption of FA genes have been associated with cancer predisposition.

  8. Bone marrow transplantation for Fanconi anemia using fludarabine-based conditioning.

    Science.gov (United States)

    Stepensky, Polina; Shapira, Michael Y; Balashov, Dmitry; Trakhtman, Pavel; Skorobogatova, Elena; Rheingold, Lyudmila; Brooks, Rebecca; Revel-Vilk, Shoshana; Weintraub, Michael; Stein, Jerry; Maschan, Alexey; Or, Reuven; Resnick, Igor B

    2011-09-01

    In the mid-1990s, we introduced a fludarabine (Flu)-based conditioning regimen for hematopoietic stem cell transplantation (HSCT) in patients with Fanconi anemia (FA).The aim of this study is to compare Flu-based conditioning to alternative regimens in patients with FA. Forty-one patients with FA (aged 0.5-31, median, 10.3 years) who underwent allogeneic HSCT were included in this retrospective study. Hospital records were reviewed for conditioning regimens, engraftment data, and toxicity. The median (range) follow-up was 32 (0.5-149) months. Flu-based conditioning regimens were used in 24 patients: 17 patients were treated with alternative conditioning regimens including a radiation-based regimen/cyclophosphamide and busulfan regimen. The disease-free survival (DFS) after Flu-based regimens is 83% (20/24) versus 35% (6/17) for the alternative regimens (P = .002). Toxicity was significantly lower in patients who received Flu-based conditioning (modified Bearman toxicity score [P = .001]). Seven patients received transplants from matched unrelated donors without irradiation (5 of whom are currently alive and well). All patients who survived are disease free and in good clinical condition. We conclude that a combination of fludarabine with antithymocyte globulin (ATG) and low-dose cyclophosphamide (Cy) and/or busulfan (Bu) is safe, demonstrates low rejection rates, and is well tolerated by FA patients. Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  9. Hypersensitivities for acetaldehyde and other agents among cancer cells null for clinically relevant Fanconi anemia genes.

    Science.gov (United States)

    Ghosh, Soma; Sur, Surojit; Yerram, Sashidhar R; Rago, Carlo; Bhunia, Anil K; Hossain, M Zulfiquer; Paun, Bogdan C; Ren, Yunzhao R; Iacobuzio-Donahue, Christine A; Azad, Nilofer A; Kern, Scott E

    2014-01-01

    Large-magnitude numerical distinctions (>10-fold) among drug responses of genetically contrasting cancers were crucial for guiding the development of some targeted therapies. Similar strategies brought epidemiological clues and prevention goals for genetic diseases. Such numerical guides, however, were incomplete or low magnitude for Fanconi anemia pathway (FANC) gene mutations relevant to cancer in FANC-mutation carriers (heterozygotes). We generated a four-gene FANC-null cancer panel, including the engineering of new PALB2/FANCN-null cancer cells by homologous recombination. A characteristic matching of FANCC-null, FANCG-null, BRCA2/FANCD1-null, and PALB2/FANCN-null phenotypes was confirmed by uniform tumor regression on single-dose cross-linker therapy in mice and by shared chemical hypersensitivities to various inter-strand cross-linking agents and γ-radiation in vitro. Some compounds, however, had contrasting magnitudes of sensitivity; a strikingly high (19- to 22-fold) hypersensitivity was seen among PALB2-null and BRCA2-null cells for the ethanol metabolite, acetaldehyde, associated with widespread chromosomal breakage at a concentration not producing breaks in parental cells. Because FANC-defective cancer cells can share or differ in their chemical sensitivities, patterns of selective hypersensitivity hold implications for the evolutionary understanding of this pathway. Clinical decisions for cancer-relevant prevention and management of FANC-mutation carriers could be modified by expanded studies of high-magnitude sensitivities.

  10. ¿ENFERMEDAD DE GAUCHER: UNA CAUSA INFRECUENTE DE SÍNDROME DE FANCONI ?

    Directory of Open Access Journals (Sweden)

    Musso CG

    2007-01-01

    Full Text Available La enfermedad de Gaucher es un trastorno genético autosómico recesivo generador de un déficit de la enzima lisosomal glucosilceramida-beta-glucosidasa ácida. Dicha enzima degrada la glucosilceramida, sustancia a partir de la cual se sintetizan muchos esfingo y glucolípidos. La falta de su degradación conduce a su almacenamiento en los macrófagos tisulares con las consiguientes complicaciones mecánicas y funcionales. El compromiso renal es infrecuente en esta enfermedad, pero cuando se presenta lo hace bajo la forma de proteinuria aislada o glomerulonefritis.El sindrome de Fanconi consiste en la disfunción parcial o total de los túbulos proximales renales. Existen diversas entidades que pueden inducir este síndrome, pero no hay hasta ahora informes en la literatura que lo vinculen con la enfermedad de Gaucher.Presentamos un caso clínico en el cual se logró documentar dicha asociación.

  11. Molecular and cellular functions of the FANCJ DNA helicase defective in cancer and in Fanconi Anemia

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    Robert M. Brosh

    2014-10-01

    Full Text Available The FANCJ DNA helicase is mutated in hereditary breast and ovarian cancer as well as the progressive bone marrow failure disorder Fanconi anemia (FA. FANCJ is linked to cancer suppression and DNA double strand break (DSB repair through its direct interaction with the hereditary breast cancer associated gene product, BRCA1. FANCJ also operates in the FA pathway of interstrand cross-link (ICL repair and contributes to homologous recombination (HR. FANCJ collaborates with a number of DNA metabolizing proteins implicated in DNA damage detection and repair, and plays an important role in cell cycle checkpoint control. In addition to its role in the classical FA pathway, FANCJ is believed to have other functions that are centered on alleviating replication stress. FANCJ resolves G-quadruplex (G4 DNA structures that are known to affect cellular replication and transcription, and potentially plays a role in the preservation and functionality of chromosomal structures such as telomeres. Recent studies suggest that FANCJ helps to maintain chromatin structure and preserve epigenetic stability by facilitating smooth progression of the replication fork when it encounters DNA damage or an alternate DNA structure such as a G4. Ongoing studies suggest a prominent but still not well-understood role of FANCJ in transcriptional regulation, chromosomal structure and function, and DNA damage repair to maintain genomic stability. This review will synthesize our current understanding of the molecular and cellular functions of FANCJ that are critical for chromosomal integrity.

  12. The Fanconi anemia associated protein FAAP24 uses two substrate specific binding surfaces for DNA recognition.

    Science.gov (United States)

    Wienk, Hans; Slootweg, Jack C; Speerstra, Sietske; Kaptein, Robert; Boelens, Rolf; Folkers, Gert E

    2013-07-01

    To maintain the integrity of the genome, multiple DNA repair systems exist to repair damaged DNA. Recognition of altered DNA, including bulky adducts, pyrimidine dimers and interstrand crosslinks (ICL), partially depends on proteins containing helix-hairpin-helix (HhH) domains. To understand how ICL is specifically recognized by the Fanconi anemia proteins FANCM and FAAP24, we determined the structure of the HhH domain of FAAP24. Although it resembles other HhH domains, the FAAP24 domain contains a canonical hairpin motif followed by distorted motif. The HhH domain can bind various DNA substrates; using nuclear magnetic resonance titration experiments, we demonstrate that the canonical HhH motif is required for double-stranded DNA (dsDNA) binding, whereas the unstructured N-terminus can interact with single-stranded DNA. Both DNA binding surfaces are used for binding to ICL-like single/double-strand junction-containing DNA substrates. A structural model for FAAP24 bound to dsDNA has been made based on homology with the translesion polymerase iota. Site-directed mutagenesis, sequence conservation and charge distribution support the dsDNA-binding model. Analogous to other HhH domain-containing proteins, we suggest that multiple FAAP24 regions together contribute to binding to single/double-strand junction, which could contribute to specificity in ICL DNA recognition.

  13. BRCA/Fanconi anemia pathway implicates chemoresistance to gemcitabine in biliary tract cancer.

    Science.gov (United States)

    Nakashima, Shinsuke; Kobayashi, Shogo; Nagano, Hiroaki; Tomokuni, Akira; Tomimaru, Yoshito; Asaoka, Tadafumi; Hama, Naoki; Wada, Hiroshi; Kawamoto, Koichi; Marubashi, Shigeru; Eguchi, Hidetoshi; Doki, Yuichiro; Mori, Masaki

    2015-05-01

    The BRCA/Fanconi anemia (FA) pathway plays a key role in the repair of DNA double strand breaks. We focused on this pathway to clarify chemoresistance mechanisms in biliary tract cancer (BTC). We also investigated changes in the CD24(+)/44(+) population that may be involved in chemoresistance, as this population likely includes cancer stem cells. We used three BTC cell lines to establish gemcitabine (GEM)-resistant (GR) cells and evaluated the expression of BRCA/FA pathway components, chemoresistance, and the effect of BRCA/FA pathway inhibition on the CD24(+)/44(+) population. FANCD2 and CD24 expression were evaluated in 108 resected BTC specimens. GR cells highly expressed the BRCA/FA components. The BRCA/FA pathway was upregulated by GEM and cisplatin (CDDP) exposure. Inhibition using siRNA and RAD51 inhibitor sensitized GR cells to GEM or CDDP. The CD24(+)/44(+) population was increased in GR and parent BTC cells treated with GEM or CDDP and highly expressed BRCA/FA genes. FANCD2 was related to CD24 expression in resected BTC specimens. Inhibition of the BRCA/FA pathway under GEM reduced the CD24(+)/44(+) population in MzChA1-GR cells. Thus, high expression of the BRCA/FA pathway is one mechanism of chemoresistance against GEM and/or CDDP and is related to the CD24(+)/44(+) population in BTC.

  14. Finnish Fanconi anemia mutations and hereditary predisposition to breast and prostate cancer.

    Science.gov (United States)

    Mantere, T; Haanpää, M; Hanenberg, H; Schleutker, J; Kallioniemi, A; Kähkönen, M; Parto, K; Avela, K; Aittomäki, K; von Koskull, H; Hartikainen, J M; Kosma, V-M; Laasanen, S-L; Mannermaa, A; Pylkäs, K; Winqvist, R

    2015-07-01

    Mutations in downstream Fanconi anemia (FA) pathway genes, BRCA2, PALB2, BRIP1 and RAD51C, explain part of the hereditary breast cancer susceptibility, but the contribution of other FA genes has remained questionable. Due to FA's rarity, the finding of recurrent deleterious FA mutations among breast cancer families is challenging. The use of founder populations, such as the Finns, could provide some advantage in this. Here, we have resolved complementation groups and causative mutations of five FA patients, representing the first mutation confirmed FA cases in Finland. These patients belonged to complementation groups FA-A (n = 3), FA-G (n = 1) and FA-I (n = 1). The prevalence of the six FA causing mutations was then studied in breast (n = 1840) and prostate (n = 565) cancer cohorts, and in matched controls (n = 1176 females, n = 469 males). All mutations were recurrent, but no significant association with cancer susceptibility was observed for any: the prevalence of FANCI c.2957_2969del and c.3041G>A mutations was even highest in healthy males (1.7%). This strengthens the exclusive role of downstream genes in cancer predisposition. From a clinical point of view, current results provide fundamental information of the mutations to be tested first in all suspected FA cases in Finland. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Carcinoma de células escamosas em língua pós-transplante de medula óssea por Anemia de Fanconi Squamous cell carcinoma of the tongue due to Fanconi's Anemia after bone marrow transplantation

    OpenAIRE

    Ricardo Pasquini; José Z. Neto; Medeiros,Carlos R. de; Marco A. Bitencourt; Carmem M. S. Bonfim; Vaneuza A. Moreira; Setúbal,Daniela C.; Flowers, Mary E.D.; Elcio Kupka; Araújo,Marcos V.

    2003-01-01

    Anemia Fanconi (AF) é uma síndrome autossômica recessiva, caracterizada por pancitopenia progressiva com hipoplasia de MO, em associação com várias anormalidades constitucionais, tendo como único recurso terapêutico com possibilidade potencial de cura o transplante de medula óssea, e sendo tais pacientes propensos ao desenvolvimento de malignidades hematológicas e carcinoma de células escamosas (CEC) em diversos locais: reto, vagina, cérvice, esôfago, cavidade bucal, faringe ou pele, mas espe...

  16. INVESTIGATION OF NEPFROPROTECTIVE EFFECT OF SILYMARIN AGAINST METHOTREXATE AND IFOSFAMIDE INDUCED TOXICITY IN RATS.

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    MANOHAR NAIK K

    2015-01-01

    Full Text Available The present study was undertaken to investigate the Nephroprotective effect of silymarin against Methotrexate (MTX induced nephrotoxicity in rats. In MTX model rats of either sex (n=6 were pre-treated with silymarin (50mg/kg, p.o. for 6 days in MTX model, MTX toxicity was induced by administering MTX (20mg/kg on third day by intra-peritoneal route. The influence of prophylactic treatment was analyzed by quantification of Serum/Urinary biomarkers and antioxidants and histopathological observations. Silymarin treatment in presence of MTX was responsible for significant reduction in Serum; Urea, Creatinine, Aspartate transaminase (AST, Alanine transaminase (ALT and Urinary; Total Protein, Sodium and Potassium compared to MTX control group. Silymarin treatment was also responsible for significant increase in Serum Albumin and antioxidants such as superoxide dismutase (SOD, Glutathione (GSH and Catalase activities in kidney tissue homogenate compared to MTX control group. Similarly, there was an increase in the urine volume and decrease in the kidney weight in the silymarin treated groups compared to the MTX control group. Results were further supported by histopathological studies. Investigation witnessed the administration of silymarin 50mg/kg dose was effective in normalizing the abnormal conditions of kidney induced by MTX. Thus investigational finding conclude that silymarin possess potential benefits in treating animals with nephrotoxicity.

  17. Protective effects of alpha lipoic acid versus N-acetylcysteine on ifosfamide-induced nephrotoxicity.

    Science.gov (United States)

    El-Sisi, Alaa El-Din E; El-Syaad, Magda E; El-Desoky, Karima I; Moussa, Ethar A

    2015-02-01

    Ifosfamide (IFO) is a highly effective chemotherapeutic agent for treating a variety of pediatric solid tumors. However, its use is limited due to its serious side effect on kidneys. The side-chain oxidation of IFO in renal tubular cells produces a reactive toxic metabolite that is believed to be responsible for its nephrotoxic effect. Therefore, this study was carried out to investigate the possible underlying mechanisms that may be involved in IFO-induced nephrotoxicity, including free radical generation and the possible role of alpha lipoic acid (ALA) versus N-acetylcysteine (NAC) in protection against this toxicity. Male albino rats were injected intraperitoneally with saline, IFO (50 mg/kg daily for 5 days), IFO + ALA (100 mg/kg daily for 8 days) and IFO + NAC (200 mg/kg daily for 8 days). Kidney malondialdehyde, nitric oxide and glutathione contents and serum biochemical parameters and histopathological analysis were determined. Both ALA and NAC markedly reduced the severity of renal dysfunction induced by IFO. NAC was more nephroprotective than ALA. This study suggests that oxidative stress is possibly involved in the IFO-induced nephrotoxicity in rats. The study also suggests the potential therapeutic role for ALA and NAC against IFO-induced nephrotoxicity.

  18. Identification and analysis of new proteins involved in the DNA damage response network of Fanconi anemia and Bloom syndrome.

    Science.gov (United States)

    Guo, Rong; Xu, Dongyi; Wang, Weidong

    2009-05-01

    The use of co-immunoprecipitation (co-IP) to purify multi-protein complexes has contributed greatly to our understanding of the DNA damage response network associated with Fanconi anemia (FA), Bloom syndrome (BS) and breast cancer. Four new FA genes and two new protein partners for the Bloom syndrome gene product have been identified by co-IP. Here, we discuss our experience in using co-IP and other techniques to isolate and characterize new FA and BS-related proteins.

  19. Uso da radiação ionizante no diagnóstico da Anemia de Fanconi

    OpenAIRE

    Lima, Suelen Cristina

    2013-01-01

    A Anemia de Fanconi (AF) é uma síndrome genética essencialmente autossômica recessiva, caracterizada clinicamente por anormalidades congênitas, alterações hematológicas e suscetibilidade aumentada ao câncer. Ao nível celular, indivíduos portadores desta síndrome apresentam acentuada fragilidade cromossômica, resultante de falhas no sistema de reparo a lesões no DNA, o que lhes confere hipersensibilidade a agentes clastogênicos. Para o diagnóstico laboratorial, costumase aval...

  20. Alteraciones cromosómicas estructurales inducidas por bioflavonoides de la dieta en linfocitos de anemia de Fanconi

    OpenAIRE

    Galeano, Liliana; Guevara, Gonzalo

    2010-01-01

    Introducción La anemia de Fanconi es una enfermedad genética con herencia autosómica recesiva caracterizada por aplasia medular, predisposición a leucemia mieloide aguda, tumores sólidos y aumento en la inestabilidad cromosómica. Este síndrome puede considerarse como modelo biológico para analizar sustancias naturales con posible efecto genotóxico, difíciles de evaluar en células normales. Los objetivos de este estudio son describir y cuantificar las alteraciones cromosómicas estructurales in...

  1. Defining the molecular interface that connects the Fanconi anemia protein FANCM to the Bloom syndrome dissolvasome.

    Science.gov (United States)

    Hoadley, Kelly A; Xue, Yutong; Ling, Chen; Takata, Minoru; Wang, Weidong; Keck, James L

    2012-03-20

    The RMI subcomplex (RMI1/RMI2) functions with the BLM helicase and topoisomerase IIIα in a complex called the "dissolvasome," which separates double-Holliday junction DNA structures that can arise during DNA repair. This activity suppresses potentially harmful sister chromatid exchange (SCE) events in wild-type cells but not in cells derived from Bloom syndrome patients with inactivating BLM mutations. The RMI subcomplex also associates with FANCM, a component of the Fanconi anemia (FA) core complex that is important for repair of stalled DNA replication forks. The RMI/FANCM interface appears to help coordinate dissolvasome and FA core complex activities, but its precise role remains poorly understood. Here, we define the structure of the RMI/FANCM interface and investigate its roles in coordinating cellular DNA-repair activities. The X-ray crystal structure of the RMI core complex bound to a well-conserved peptide from FANCM shows that FANCM binds to both RMI proteins through a hydrophobic "knobs-into-holes" packing arrangement. The RMI/FANCM interface is shown to be critical for interaction between the components of the dissolvasome and the FA core complex. FANCM variants that substitute alanine for key interface residues strongly destabilize the complex in solution and lead to increased SCE levels in cells that are similar to those observed in blm- or fancm-deficient cells. This study provides a molecular view of the RMI/FANCM complex and highlights a key interface utilized in coordinating the activities of two critical eukaryotic DNA-damage repair machines.

  2. Fanconi anemia core complex gene promoters harbor conserved transcription regulatory elements.

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    Daniel Meier

    Full Text Available The Fanconi anemia (FA gene family is a recent addition to the complex network of proteins that respond to and repair certain types of DNA damage in the human genome. Since little is known about the regulation of this novel group of genes at the DNA level, we characterized the promoters of the eight genes (FANCA, B, C, E, F, G, L and M that compose the FA core complex. The promoters of these genes show the characteristic attributes of housekeeping genes, such as a high GC content and CpG islands, a lack of TATA boxes and a low conservation. The promoters functioned in a monodirectional way and were, in their most active regions, comparable in strength to the SV40 promoter in our reporter plasmids. They were also marked by a distinctive transcriptional start site (TSS. In the 5' region of each promoter, we identified a region that was able to negatively regulate the promoter activity in HeLa and HEK 293 cells in isolation. The central and 3' regions of the promoter sequences harbor binding sites for several common and rare transcription factors, including STAT, SMAD, E2F, AP1 and YY1, which indicates that there may be cross-connections to several established regulatory pathways. Electrophoretic mobility shift assays and siRNA experiments confirmed the shared regulatory responses between the prominent members of the TGF-β and JAK/STAT pathways and members of the FA core complex. Although the promoters are not well conserved, they share region and sequence specific regulatory motifs and transcription factor binding sites (TBFs, and we identified a bi-partite nature to these promoters. These results support a hypothesis based on the co-evolution of the FA core complex genes that was expanded to include their promoters.

  3. The Fanconi anemia/BRCA gene network in zebrafish: Embryonic expression and comparative genomics

    Energy Technology Data Exchange (ETDEWEB)

    Titus, Tom A.; Yan Yilin; Wilson, Catherine; Starks, Amber M.; Frohnmayer, Jonathan D.; Bremiller, Ruth A.; Canestro, Cristian; Rodriguez-Mari, Adriana; He Xinjun [Institute of Neuroscience, University of Oregon, 1425 E. 13th Avenue, Eugene, OR 97403 (United States); Postlethwait, John H., E-mail: jpostle@uoneuro.uoregon.edu [Institute of Neuroscience, University of Oregon, 1425 E. 13th Avenue, Eugene, OR 97403 (United States)

    2009-07-31

    Fanconi anemia (FA) is a genetic disease resulting in bone marrow failure, high cancer risks, and infertility, and developmental anomalies including microphthalmia, microcephaly, hypoplastic radius and thumb. Here we present cDNA sequences, genetic mapping, and genomic analyses for the four previously undescribed zebrafish FA genes (fanci, fancj, fancm, and fancn), and show that they reverted to single copy after the teleost genome duplication. We tested the hypothesis that FA genes are expressed during embryonic development in tissues that are disrupted in human patients by investigating fanc gene expression patterns. We found fanc gene maternal message, which can provide Fanc proteins to repair DNA damage encountered in rapid cleavage divisions. Zygotic expression was broad but especially strong in eyes, central nervous system and hematopoietic tissues. In the pectoral fin bud at hatching, fanc genes were expressed specifically in the apical ectodermal ridge, a signaling center for fin/limb development that may be relevant to the radius/thumb anomaly of FA patients. Hatching embryos expressed fanc genes strongly in the oral epithelium, a site of squamous cell carcinomas in FA patients. Larval and adult zebrafish expressed fanc genes in proliferative regions of the brain, which may be related to microcephaly in FA. Mature ovaries and testes expressed fanc genes in specific stages of oocyte and spermatocyte development, which may be related to DNA repair during homologous recombination in meiosis and to infertility in human patients. The intestine strongly expressed some fanc genes specifically in proliferative zones. Our results show that zebrafish has a complete complement of fanc genes in single copy and that these genes are expressed in zebrafish embryos and adults in proliferative tissues that are often affected in FA patients. These results support the notion that zebrafish offers an attractive experimental system to help unravel mechanisms relevant not only

  4. Monoketone analogs of curcumin, a new class of Fanconi anemia pathway inhibitors

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    Turker Mitchell S

    2009-12-01

    Full Text Available Abstract Background The Fanconi anemia (FA pathway is a multigene DNA damage response network implicated in the repair of DNA lesions that arise during replication or after exogenous DNA damage. The FA pathway displays synthetic lethal relationship with certain DNA repair genes such as ATM (Ataxia Telangectasia Mutated that are frequently mutated in tumors. Thus, inhibition of FANCD2 monoubiquitylation (FANCD2-Ub, a key step in the FA pathway, might target tumor cells defective in ATM through synthetic lethal interaction. Curcumin was previously identified as a weak inhibitor of FANCD2-Ub. The aim of this study is to identify derivatives of curcumin with better activity and specificity. Results Using a replication-free assay in Xenopus extracts, we screened monoketone analogs of curcumin for inhibition of FANCD2-Ub and identified analog EF24 as a strong inhibitor. Mechanistic studies suggest that EF24 targets the FA pathway through inhibition of the NF-kB pathway kinase IKK. In HeLa cells, nanomolar concentrations of EF24 inhibited hydroxyurea (HU-induced FANCD2-Ub and foci in a cell-cycle independent manner. Survival assays revealed that EF24 specifically sensitizes FA-competent cells to the DNA crosslinking agent mitomycin C (MMC. In addition, in contrast with curcumin, ATM-deficient cells are twofold more sensitive to EF24 than matched wild-type cells, consistent with a synthetic lethal effect between FA pathway inhibition and ATM deficiency. An independent screen identified 4H-TTD, a compound structurally related to EF24 that displays similar activity in egg extracts and in cells. Conclusions These results suggest that monoketone analogs of curcumin are potent inhibitors of the FA pathway and constitute a promising new class of targeted anticancer compounds.

  5. Prevalence of breast and colorectal cancer in Ashkenazi Jewish carriers of Fanconi anemia and Bloom syndrome.

    Science.gov (United States)

    Baris, Hagit N; Kedar, Inbal; Halpern, Gabrielle J; Shohat, Tamy; Magal, Nurit; Ludman, Mark D; Shohat, Mordechai

    2007-12-01

    Fanconi anemia complementation group C and Bloom syndrome, rare autosomal recessive disorders marked by chromosome instability, are especially prevalent in the Ashkenazi* Jewish community. A single predominant mutation for each has been reported in Ahshkenazi Jews: c.711+4A-->T (IVS4 +4 A-->T) in FACC and BLM(Ash) in Bloom syndrome. Individuals affected by either of these syndromes are characterized by susceptibility for developing malignancies, and we questioned whether heterozygote carriers have a similarly increased risk. To estimate the cancer rate among FACC and BLM(Ash) carriers and their families over three previous generations in unselected Ashkenazi Jewish individuals. We studied 42 FACC carriers, 28 BLM(Ash) carriers and 43 controls. The control subjects were Ashkenazi Jews participating in our prenatal genetic screening program who tested negative for FACC and BLM(Ash). All subjects filled out a questionnaire regarding their own and a three-generation family history of cancer. The prevalence rates of cancer among relatives of FACC, BLM(Ash) and controls were computed and compared using the chi-square test. In 463 relatives of FACC carriers, 45 malignancies were reported (9.7%) including 10 breast (2.2%) and 13 colon cancers (2.8%). Among 326 relatives of BLM(Ash) carriers there were 30 malignancies (9.2%) including 7 breast (2.1%) and 4 colon cancers (1.2%). Controls consisted of 503 family members with 63 reported malignancies (12.5%) including 11 breast (2.2%) and 11 colon cancers (2.2%). We found no significantly increased prevalence of malignancies among carriers in at least three generations compared to the controls.

  6. Cellular characterization of cells from the Fanconi anemia complementation group, FA-D1/BRCA2

    Energy Technology Data Exchange (ETDEWEB)

    Godthelp, Barbara C. [Department of Toxicogenetics, Leiden University Medical Center, Building 2, Postzone S-6-P, P.O. Box 9600, 2300 RC, Leiden (Netherlands); Buul, Paul P.W. van [Department of Toxicogenetics, Leiden University Medical Center, Building 2, Postzone S-6-P, P.O. Box 9600, 2300 RC, Leiden (Netherlands); Jaspers, Nicolaas G.J. [Department of Cell Biology and Genetics, Erasmus University, P.O. Box 1738, 3000 DR Rotterdam (Netherlands); Elghalbzouri-Maghrani, Elhaam [Department of Toxicogenetics, Leiden University Medical Center, Building 2, Postzone S-6-P, P.O. Box 9600, 2300 RC, Leiden (Netherlands); Duijn-Goedhart, Annemarie van [Department of Toxicogenetics, Leiden University Medical Center, Building 2, Postzone S-6-P, P.O. Box 9600, 2300 RC, Leiden (Netherlands); Arwert, Fre [Department of Clinical Genetics and Human Genetics, Free University Medical Center, Amsterdam (Netherlands); Joenje, Hans [Department of Clinical Genetics and Human Genetics, Free University Medical Center, Amsterdam (Netherlands); Zdzienicka, Malgorzata Z. [Department of Toxicogenetics, Leiden University Medical Center, Building 2, Postzone S-6-P, P.O. Box 9600, 2300 RC, Leiden (Netherlands) and Department of Molecular Cell Genetics, Collegium Medicum, N.Copernicus University, Bydgoszcz (Poland)]. E-mail: M.Z.Zdzienicka@LUMC.nl

    2006-10-10

    Fanconi anemia (FA) is an inherited cancer-susceptibility disorder, characterized by genomic instability and hypersensitivity to DNA cross-linking agents. The discovery of biallelic BRCA2 mutations in the FA-D1 complementation group allows for the first time to study the characteristics of primary BRCA2-deficient human cells. FANCD1/BRCA2-deficient fibroblasts appeared hypersensitive to mitomycin C (MMC), slightly sensitive to methyl methane sulfonate (MMS), and like cells derived from other FA complementation groups, not sensitive to X-ray irradiation. However, unlike other FA cells, FA-D1 cells were slightly sensitive to UV irradiation. Despite the observed lack of X-ray sensitivity in cell survival, significant radioresistant DNA synthesis (RDS) was observed in the BRCA2-deficient fibroblasts but also in the FANCA-deficient fibroblasts, suggesting an impaired S-phase checkpoint. FA-D1/BRCA2 cells displayed greatly enhanced levels of spontaneous as well as MMC-induced chromosomal aberrations (Canada), similar to cells deficient in homologous recombination (HR) and non-D1 FA cells. In contrast to Brca2-deficient rodent cells, FA-D1/BRCA2 cells showed normal sister chromatid exchange (SCE) levels, both spontaneous as well as after MMC treatment. Hence, these data indicate that human cells with biallelic BRCA2 mutations display typical features of both FA- and HR-deficient cells, which suggests that FANCD1/BRCA2 is part of the integrated FA/BRCA DNA damage response pathway but also controls other functions outside the FA pathway.

  7. Cloning and analysis of the mouse Fanconi anemia group a cDNA and an overlapping penta zinc finger cDNA

    NARCIS (Netherlands)

    Wong, JCY; Alon, N; Norga, K; Kruyt, FAE; Youssoufian, H; Buchwald, M

    2000-01-01

    Despite the cloning of four disease-associated genes for Fanconi anemia (FA), the molecular pathogenesis of FA remains largely unknown. To study FA complementation group A using the mouse as a mode I system, we cloned and characterized the mouse homolog of the human FANCA cDNA, The mouse cDNA

  8. De Toni-Debré-Fanconi syndrome in a patient with Kearns-Sayre syndrome: a case report

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    Mihai Cristina

    2009-11-01

    Full Text Available Abstract Introduction Kearns-Sayre syndrome is a mitochondrial myopathy that demonstrates chronic progressive ophthalmoplegia with onset before the age of 20 and pigmentary degeneration of the retina. Case presentation We report the case of an 18-year-old Romanian man with short stature, external ophthalmoplegia, palpebral ptosis, myopathy, sensorineural hearing impairment, cerebellar ataxia, cardiac conduction defect, diabetes mellitus, hypoparathyroidism and hyperaldosteronism. The patient's evolution showed progressive insufficiency of the renal tubule: hyperphosphaturia, hyperaminoaciduria and, later, glucosuria (de Toni-Debré-Fanconi syndrome, a syndrome, to date, rarely diagnosed in association with complete Kearns-Sayre syndrome. The final diagnosis was delayed for several years and was only established when he developed diabetes mellitus. Southern blot analysis and polymerase chain reaction amplification revealed the presence of a deletion in the mitochondrial DNA. Conclusion Despite the rarity of this syndrome, the diagnosis was easily made due to the presence of the classic triad: external ophthalmoplegia, pigmentary retinopathy and onset in a patient younger than 20 years old. In our opinion, a search for Kearns-Sayre syndrome in all patients with de Toni-Debré-Fanconi syndrome is a valuable medical routine.

  9. Fanconi anemia patients are more susceptible to infection with tumor virus SV40.

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    Manola Comar

    Full Text Available Fanconi anemia (FA is a recessive DNA repair disease characterized by a high predisposition to developing neoplasms. DNA tumor polyomavirus simian virus 40 (SV40 transforms FA fibroblasts at high efficiency suggesting that FA patients could be highly susceptible to SV40 infection. To test this hypothesis, the large tumor (LT antigen of SV40, BKV, JCV and Merkel Cell (MC polyomaviruses were tested in blood samples from 89 FA patients and from 82 of their parents. Two control groups consisting of 47 no-FA patients affected by other genetic bone marrow failure diseases and 91 healthy subjects were also evaluated. Although JCV, BKV and MC were not found in any of the FA samples, the prevalence and viral load of SV40 were higher in FA patients (25%; mean viral load: 1.1×10(2 copies/10(5cells as compared with healthy individuals (4.3%; mean viral load: 0.8×10(1 copies/10(5cells and genetic controls (0% (p<0.005. A marked age-dependent frequency of SV40 was found in FA with respect to healthy subjects suggesting that, although acquired early in life, the virus can widespread more easily in specific groups of population. From the analysis of family pedigrees, 60% of the parents of SV40-positive probands were positive for the virus compared to 2% of the parents of the SV40-negative probands (p<0.005. It is worthy of note that the relative frequency of SV40-positive relatives detected in this study was the highest ever reported, showing that asymptomatic FA carriers are also more susceptible to SV40. In conclusion, we favor the hypothesis that SV40 spread could be facilitated by individuals who are genetically more susceptible to infection, such as FA patients. The increased susceptibility to SV40 infection seems to be associated with a specific defect of the immune system which supports a potential interplay of SV40 with an underlying genetic alteration that increases the risk of malignancies.

  10. Non-specific chemical inhibition of the Fanconi anemia pathway sensitizes cancer cells to cisplatin

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    Jacquemont Céline

    2012-04-01

    Full Text Available Abstract Background Platinum compounds such as cisplatin and carboplatin are DNA crosslinking agents widely used for cancer chemotherapy. However, the effectiveness of platinum compounds is often tempered by the acquisition of cellular drug resistance. Until now, no pharmacological approach has successfully overcome cisplatin resistance in cancer treatment. Since the Fanconi anemia (FA pathway is a DNA damage response pathway required for cellular resistance to DNA interstrand crosslinking agents, identification of small molecules that inhibit the FA pathway may reveal classes of chemicals that sensitize cancer cells to cisplatin. Results Through a cell-based screening assay of over 16,000 chemicals, we identified 26 small molecules that inhibit ionizing radiation and cisplatin-induced FANCD2 foci formation, a marker of FA pathway activity, in multiple human cell lines. Most of these small molecules also compromised ionizing radiation-induced RAD51 foci formation and homologous recombination repair, indicating that they are not selective toward the regulation of FANCD2. These compounds include known inhibitors of the proteasome, cathepsin B, lysosome, CHK1, HSP90, CDK and PKC, and several uncharacterized chemicals including a novel proteasome inhibitor (Chembridge compound 5929407. Isobologram analyses demonstrated that half of the identified molecules sensitized ovarian cancer cells to cisplatin. Among them, 9 demonstrated increased efficiency toward FA pathway-proficient, cisplatin-resistant ovarian cancer cells. Six small molecules, including bortezomib (proteasome inhibitor, CA-074-Me (cathepsin B inhibitor and 17-AAG (HSP90 inhibitor, synergized with cisplatin specifically in FA-proficient ovarian cancer cells (2008 + FANCF, but not in FA-deficient isogenic cells (2008. In addition, geldanamycin (HSP90 inhibitor and two CHK1 inhibitors (UCN-01 and SB218078 exhibited a significantly stronger synergism with cisplatin in FA

  11. Paternal or Maternal Uniparental Disomy of Chromosome 16 Resulting in Homozygosity of a Mutant Allele Causes Fanconi Anemia.

    Science.gov (United States)

    Donovan, Frank X; Kimble, Danielle C; Kim, Yonghwan; Lach, Francis P; Harper, Ursula; Kamat, Aparna; Jones, MaryPat; Sanborn, Erica M; Tryon, Rebecca; Wagner, John E; MacMillan, Margaret L; Ostrander, Elaine A; Auerbach, Arleen D; Smogorzewska, Agata; Chandrasekharappa, Settara C

    2016-05-01

    Fanconi anemia (FA) is a rare inherited disorder caused by pathogenic variants in one of 19 FANC genes. FA patients display congenital abnormalities, and develop bone marrow failure, and cancer susceptibility. We identified homozygous mutations in four FA patients and, in each case, only one parent carried the obligate mutant allele. FANCA and FANCP/SLX4 genes, both located on chromosome 16, were the affected recessive FA genes in three and one family respectively. Genotyping with short tandem repeat markers and SNP arrays revealed uniparental disomy (UPD) of the entire mutation-carrying chromosome 16 in all four patients. One FANCA patient had paternal UPD, whereas FA in the other three patients resulted from maternal UPD. These are the first reported cases of UPD as a cause of FA. UPD indicates a reduced risk of having another child with FA in the family and has implications in prenatal diagnosis.

  12. Role of Fanconi Anemia FANCG in Preventing Double-Strand Breakage and Chromosomal Rearrangement during DNA Replication

    Energy Technology Data Exchange (ETDEWEB)

    Tebbs, R S; Hinz, J M; Yamada, N A; Wilson, J B; Jones, N J; Salazar, E P; Thomas, C B; Jones, I M; Thompson, L H

    2003-10-04

    The Fanconi anemia (FA) proteins overlap with those of homologous recombination through FANCD1/BRCA2, but the biochemical functions of other FA proteins are unknown. By constructing and characterizing a null fancg mutant of hamster CHO cells, we present several new insights for FA. The fancg cells show a broad sensitivity to genotoxic agents, not supporting the conventional concept of sensitivity to only DNA crosslinking agents. The aprt mutation rate is normal, but hprt mutations are reduced, which we ascribe to the lethality of large deletions. CAD and dhfr gene amplification rates are increased, implying excess chromosomal breakage during DNA replication, and suggesting amplification as a contributing factor to cancer-proneness in FA patients. In S-phase cells, both spontaneous and mutagen-induced Rad51 nuclear foci are elevated. These results support a model in which FancG protein helps to prevent collapse of replication forks by allowing translesion synthesis or lesion bypass through homologous recombination.

  13. A case of Fanconi syndrome accompanied by crystal depositions in tubular cells in a patient with multiple myeloma

    Directory of Open Access Journals (Sweden)

    Do Hee Kim

    2014-06-01

    Full Text Available Fanconi syndrome (FS is a rare condition that is characterized by defects in the proximal tubular function. A 48-year-old woman was admitted for evaluation of proteinuria. The patient showed normal anion gap acidosis, normoglycemic glycosuria, hypophosphatemia, and hypouricemia. Thus, her condition was compatible with FS. The M peak was found behind the beta globulin region in urine protein electrophoresis. Upon bone marrow examination, we found that 24% of cells were CD138+ plasma cells with kappa restriction. From a kidney biopsy, we found crystalline inclusions within proximal tubular epithelial cells. Thereafter, she was diagnosed with FS accompanied by multiple myeloma. The patient received chemotherapy and autologous stem cell transplantation, and obtained very good partial hematologic response. However, proximal tubular dysfunction was persistent until 1 year after autologous stem cell transplantation. In short, we report a case of FS accompanied by multiple myeloma, demonstrating crystalline inclusion in proximal tubular cells on kidney biopsy.

  14. Systems Biology-Based Identification of Crosstalk between E2F Transcription Factors and the Fanconi Anemia Pathway

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    Moe Tategu

    2007-01-01

    Full Text Available Fanconi anemia (FA is an autosomal recessive disorder characterized by congenital abnormalities, bone marrow failure, chromosome fragility, and cancer susceptibility. At least eleven members of the FA gene family have been identified using complementation experiments. Ubiquitin-proteasome has been shown to be a key regulator of FA proteins and their involvement in the repair of DNA damage. Here, we identifi ed a novel functional link between the FA/BRCA pathway and E2F-mediated cell cycle regulome. In silico mining of a transcriptome database and promoter analyses revealed that a significant number of FA gene members were regulated by E2F transcription factors, known to be pivotal regulators of cell cycle progression – as previously described for BRCA1. Our findings suggest that E2Fs partly determine cell fate through the FA/BRCA pathway.

  15. Alternaria alternata invasive fungal infection in a patient with Fanconi's anemia after an unrelated bone marrow transplant.

    Science.gov (United States)

    Ferreira, Isabelina de Sousa; Teixeira, Gilda; Abecasis, Manuel

    2013-02-01

    Alternaria spp. have emerged as opportunistic pathogens particularly in immunosuppressed patients, such as bone marrow transplant recipients. The authors present a case of Alternaria alternata in a patient with Fanconi's anemia, who received antifungal prophylaxis with posaconazole after an unrelated bone marrow transplantation, followed by empirical antifungal treatment with caspofungin when persistent fever emerged until cutaneous lesions eventually appeared. At that time there were clinical reasons to assume that the patient had an infection with an emerging fungus. This consideration triggered a change of the antifungal therapy from caspofungin to liposomal amphotericin B. After collecting sufficient evidence for the presence of an invasive fungal infection by A. alternata and given the severity of neutropenia and other immunosuppression, oral posaconazole was added to liposomal amphotericin B. The course of disease in this case suggests a possibly synergistic interaction between liposomal amphotericin B and posaconazole when administered simultaneously to treat an invasive systemic infection by Alternaria spp. in immunocompromised patients.

  16. In-vivo assessment of DNA ligation efficiency and fidelity in cells from patients with Fanconi's anemia and other cancer-prone hereditary disorders.

    Science.gov (United States)

    Rünger, T M; Sobotta, P; Dekant, B; Möller, K; Bauer, C; Kraemer, K H

    1993-04-01

    We developed a host cell DNA ligation assay, in which we transfected linearized plasmid pZ189 into human lymphoblasts or fibroblasts in order to assess the efficiency and accuracy of DNA ligation within these host cells. We used cell lines from patients with Fanconi's anemia and other chromosome breakage or instability syndromes (Bloom's syndrome, ataxia telangiectasia, Werner's syndrome). With the Fanconi's anemia lymphoblast line GM8010 we did not find a reduced, but a slightly hypermutable DNA ligation. Mutation analysis revealed a unique 7.9-12.5-fold increase in insertions or complex mutations. With cells from the other chromosome breakage/instability syndromes we also found a hypermutable and/or reduced DNA ligation. An impaired DNA ligation might be a common molecular mechanism of genetic instability in these disorders.

  17. Cells Deficient in the Fanconi Anemia Protein FANCD2 are Hypersensitive to the Cytotoxicity and DNA Damage Induced by Coffee and Caffeic Acid

    Science.gov (United States)

    Burgos-Morón, Estefanía; Calderón-Montaño, José Manuel; Orta, Manuel Luis; Guillén-Mancina, Emilio; Mateos, Santiago; López-Lázaro, Miguel

    2016-01-01

    Epidemiological studies have found a positive association between coffee consumption and a lower risk of cardiovascular disorders, some cancers, diabetes, Parkinson and Alzheimer disease. Coffee consumption, however, has also been linked to an increased risk of developing some types of cancer, including bladder cancer in adults and leukemia in children of mothers who drink coffee during pregnancy. Since cancer is driven by the accumulation of DNA alterations, the ability of the coffee constituent caffeic acid to induce DNA damage in cells may play a role in the carcinogenic potential of this beverage. This carcinogenic potential may be exacerbated in cells with DNA repair defects. People with the genetic disease Fanconi Anemia have DNA repair deficiencies and are predisposed to several cancers, particularly acute myeloid leukemia. Defects in the DNA repair protein Fanconi Anemia D2 (FANCD2) also play an important role in the development of a variety of cancers (e.g., bladder cancer) in people without this genetic disease. This communication shows that cells deficient in FANCD2 are hypersensitive to the cytotoxicity (clonogenic assay) and DNA damage (γ-H2AX and 53BP1 focus assay) induced by caffeic acid and by a commercial lyophilized coffee extract. These data suggest that people with Fanconi Anemia, or healthy people who develop sporadic mutations in FANCD2, may be hypersensitive to the carcinogenic activity of coffee. PMID:27399778

  18. Cells Deficient in the Fanconi Anemia Protein FANCD2 are Hypersensitive to the Cytotoxicity and DNA Damage Induced by Coffee and Caffeic Acid

    Directory of Open Access Journals (Sweden)

    Estefanía Burgos-Morón

    2016-07-01

    Full Text Available Epidemiological studies have found a positive association between coffee consumption and a lower risk of cardiovascular disorders, some cancers, diabetes, Parkinson and Alzheimer disease. Coffee consumption, however, has also been linked to an increased risk of developing some types of cancer, including bladder cancer in adults and leukemia in children of mothers who drink coffee during pregnancy. Since cancer is driven by the accumulation of DNA alterations, the ability of the coffee constituent caffeic acid to induce DNA damage in cells may play a role in the carcinogenic potential of this beverage. This carcinogenic potential may be exacerbated in cells with DNA repair defects. People with the genetic disease Fanconi Anemia have DNA repair deficiencies and are predisposed to several cancers, particularly acute myeloid leukemia. Defects in the DNA repair protein Fanconi Anemia D2 (FANCD2 also play an important role in the development of a variety of cancers (e.g., bladder cancer in people without this genetic disease. This communication shows that cells deficient in FANCD2 are hypersensitive to the cytotoxicity (clonogenic assay and DNA damage (γ-H2AX and 53BP1 focus assay induced by caffeic acid and by a commercial lyophilized coffee extract. These data suggest that people with Fanconi Anemia, or healthy people who develop sporadic mutations in FANCD2, may be hypersensitive to the carcinogenic activity of coffee.

  19. Anemia aplásica adquirida e anemia de Fanconi - Diretrizes Brasileiras em Transplante de Células-Tronco Hematopoéticas Acquired aplastic anemia and Fanconi anemia - Brazilian Guidelines in Hematopoietic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Larissa A. Medeiros

    2010-05-01

    Full Text Available As diretrizes apresentadas neste trabalho foram elaboradas e aprovadas na I Reunião de Diretrizes Brasileiras em Transplante de Células-Tronco Hematopoéticas (TCTH realizada no Rio de Janeiro, entre os dias 19 e 21 de julho de 2009. O evento foi promovido pela SBTMO (Sociedade Brasileira de Transplante de Medula Óssea. Neste artigo, tratamos da anemia aplásica severa (AAS, considerada uma urgência hematológica, que, identificada e manejada de forma precoce, apresenta grande possibilidade de recuperação da hematopoese seja através de transplante de medula óssea ou terapia imunossupressora. Objetiva-se nortear o manejo terapêutico no contexto do transplante e indicar formas de condicionamento, de acordo com as características clínicas dos pacientes, como o número de transfusões, com intuito de minimizar a rejeição primária e secundária, garantindo a melhora da sobrevida global e livre de doença (observadas pela literatura e já validadas por resultados na população brasileira. No que concerne à anemia de Fanconi, o transplante é a única modalidade curativa para o componente aplásico de medula óssea; embora não modificando as outras características da síndrome também demanda perícia e agilidade na busca de um doador com resultados expressivos de sobrevida.The guidelines presented in this article have been prepared and approved in the I Meeting of Brazilian Guidelines in Hematopoietic Stem Cell Transplantation (HSCT - Rio de Janeiro, July 19-21, 2009. The event was sponsored by SBTMO (Brazilian Society of Bone Marrow Transplantation. In this paper, we treat the severe aplastic anemia (SAA, considered a hematological emergency, that when identified and medically treated early, shows a great chance of recovery of the hematopoiesis, either through bone marrow transplantation or immunosuppressive therapy. Its objective is to guide the management of the transplantation, and indicate methods of conditioning, according to

  20. Defective homing is associated with altered Cdc42 activity in cells from patients with Fanconi anemia group A

    Science.gov (United States)

    Zhang, Xiaoling; Shang, Xun; Guo, Fukun; Murphy, Kim; Kirby, Michelle; Kelly, Patrick; Reeves, Lilith; Smith, Franklin O.; Williams, David A.

    2008-01-01

    Previous studies showed that Fanconi anemia (FA) murine stem cells have defective reconstitution after bone marrow (BM) transplantation. The mechanism underlying this defect is not known. Here, we report defective homing of FA patient BM progenitors transplanted into mouse models. Using cells from patients carrying mutations in FA complementation group A (FA-A), we show that when transplanted into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) recipient mice, FA-A BM cells exhibited impaired homing activity. FA-A cells also showed defects in both cell-cell and cell-matrix adhesion. Complementation of FA-A deficiency by reexpression of FANCA readily restored adhesion of FA-A cells. A significant decrease in the activity of the Rho GTPase Cdc42 was found associated with these defective functions in patient-derived cells, and expression of a constitutively active Cdc42 mutant was able to rescue the adhesion defect of FA-A cells. These results provide the first evidence that FA proteins influence human BM progenitor homing and adhesion via the small GTPase Cdc42-regulated signaling pathway. PMID:18565850

  1. Xpf and not the Fanconi anaemia proteins or Rev3 accounts for the extreme resistance to cisplatin in Dictyostelium discoideum.

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    Xiao-Yin Zhang

    2009-09-01

    Full Text Available Organisms like Dictyostelium discoideum, often referred to as DNA damage "extremophiles", can survive exposure to extremely high doses of radiation and DNA crosslinking agents. These agents form highly toxic DNA crosslinks that cause extensive DNA damage. However, little is known about how Dictyostelium and the other "extremophiles" can tolerate and repair such large numbers of DNA crosslinks. Here we describe a comprehensive genetic analysis of crosslink repair in Dictyostelium discoideum. We analyse three gene groups that are crucial for a replication-coupled repair process that removes DNA crosslinks in higher eukarya: The Fanconi anaemia pathway (FA, translesion synthesis (TLS, and nucleotide excision repair. Gene disruption studies unexpectedly reveal that the FA genes and the TLS enzyme Rev3 play minor roles in tolerance to crosslinks in Dictyostelium. However, disruption of the Xpf nuclease subcomponent results in striking hypersensitivity to crosslinks. Genetic interaction studies reveal that although Xpf functions with FA and TLS gene products, most Xpf mediated repair is independent of these two gene groups. These results suggest that Dictyostelium utilises a distinct Xpf nuclease-mediated repair process to remove crosslinked DNA. Other DNA damage-resistant organisms and chemoresistant cancer cells might adopt a similar strategy to develop resistance to DNA crosslinking agents.

  2. Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia.

    Science.gov (United States)

    Kashiyama, Kazuya; Nakazawa, Yuka; Pilz, Daniela T; Guo, Chaowan; Shimada, Mayuko; Sasaki, Kensaku; Fawcett, Heather; Wing, Jonathan F; Lewin, Susan O; Carr, Lucinda; Li, Tao-Sheng; Yoshiura, Koh-ichiro; Utani, Atsushi; Hirano, Akiyoshi; Yamashita, Shunichi; Greenblatt, Danielle; Nardo, Tiziana; Stefanini, Miria; McGibbon, David; Sarkany, Robert; Fassihi, Hiva; Takahashi, Yoshito; Nagayama, Yuji; Mitsutake, Norisato; Lehmann, Alan R; Ogi, Tomoo

    2013-05-02

    Cockayne syndrome (CS) is a genetic disorder characterized by developmental abnormalities and photodermatosis resulting from the lack of transcription-coupled nucleotide excision repair, which is responsible for the removal of photodamage from actively transcribed genes. To date, all identified causative mutations for CS have been in the two known CS-associated genes, ERCC8 (CSA) and ERCC6 (CSB). For the rare combined xeroderma pigmentosum (XP) and CS phenotype, all identified mutations are in three of the XP-associated genes, ERCC3 (XPB), ERCC2 (XPD), and ERCC5 (XPG). In a previous report, we identified several CS cases who did not have mutations in any of these genes. In this paper, we describe three CS individuals deficient in ERCC1 or ERCC4 (XPF). Remarkably, one of these individuals with XP complementation group F (XP-F) had clinical features of three different DNA-repair disorders--CS, XP, and Fanconi anemia (FA). Our results, together with those from Bogliolo et al., who describe XPF alterations resulting in FA alone, indicate a multifunctional role for XPF. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  3. Elucidation of the Fanconi Anemia Protein Network in Meoisis and Its Function in the Regulation of Histone Modifications

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    Kris G. Alavattam

    2016-10-01

    Full Text Available Precise epigenetic regulation of the sex chromosomes is vital for the male germline. Here, we analyze meiosis in eight mouse models deficient for various DNA damage response (DDR factors, including Fanconi anemia (FA proteins. We reveal a network of FA and DDR proteins in which FA core factors FANCA, FANCB, and FANCC are essential for FANCD2 foci formation, whereas BRCA1 (FANCS, MDC1, and RNF8 are required for BRCA2 (FANCD1 and SLX4 (FANCP accumulation on the sex chromosomes during meiosis. In addition, FA proteins modulate distinct histone marks on the sex chromosomes: FA core proteins and FANCD2 regulate H3K9 methylation, while FANCD2 and RNF8 function together to regulate H3K4 methylation independently of FA core proteins. Our data suggest that RNF8 integrates the FA-BRCA pathway. Taken together, our study reveals distinct functions for FA proteins and illuminates the male sex chromosomes as a model to dissect the function of the FA-BRCA pathway.

  4. Clinical and biochemical signs in Fleckvieh cattle with genetically confirmed Fanconi-Bickel syndrome (cattle homozygous for Fleckvieh haplotype 2).

    Science.gov (United States)

    Burgstaller, Johann; Url, Angelika; Pausch, Hubert; Schwarzenbacher, Hermann; Egerbacher, Monika; Wittek, Thomas

    2016-01-01

    Fanconi-Bickel Syndrome (FBS) is an autosomal recessive disorder of the carbohydrate metabolism, which has been reported in human and some animals (OMIA 000366-9913). In Fleckvieh cattle it is caused by mutations in SLC2A2, a gene encoding for glucose transporter protein 2 (GLUT2), which is primarily expressed in liver, kidney, pancreas and intestines. The causal mutation resides in a previously reported Fleckvieh Haplotype 2 (FH-2). FH-2 homozygous individuals are rare, but due to widespread use of heterozygous bulls in artificial insemination, heterozygous animals are likely to be present in a larger number in the cattle population. Two clinical cases of Fleckvieh cattle with a syndrome resembling the phenotypic appearance of FBS are presented in the present study describing the association between the clinical manifestations of FBS and the postulated frameshift mutation in bovine SLC2A2. Clinical examination showed poor growth, retarded development, polyuria, and polydipsia. Laboratory analyses showed an increased plasma glucose but normal insulin concentration and increased renal glucose excretion. Histopathological examination of kidney and liver samples revealed massively increased liver glycogen storage and nephrosis. Sires of both cases were tested positive for being heterozygous carriers for the same frameshift mutation in SLC2A2 as was originally reported in Fleckvieh cattle. DNA of both cases described was analyzed and Sanger sequencing confirmed homozygosity for the frameshift mutation in SLC2A2.

  5. Carcinoma de células escamosas da hipofaringe em mulher jovem com anemia de Fanconi Squamous cell carcinoma of the hypopharynx in a young woman with Fanconi’s anemia

    OpenAIRE

    Henrique de Lins e Horta; Fernando Fernandes Guimarães; Luiz Otávio Savassi Rocha; Roberto Eustáquio Santos Guimarães; Eugênia Ribeiro Valadares

    2006-01-01

    A anemia de Fanconi é um raro distúrbio autossômico recessivo caracterizado por malformações congênitas, aplasia da medula óssea e instabilidade genômica, com predisposição ao desenvolvimento de neoplasias malignas, em especial as leucemias e os tumores do trato aerodigestivo alto. Em razão de características inerentes à síndrome em questão, o tratamento de tais neoplasias é particularmente difícil. Relata-se o caso de anemia de Fanconi uma jovem de 24 anos, que desenvolveu carcinoma de célul...

  6. Maternal serum alpha-fetoprotein levels are normal in Fanconi anemia: Can it be a lack of postnatal inhibition of AFP gene resulting in the elevation?

    Science.gov (United States)

    Aslan, Deniz; Karabacak, Recep Onur; Aslan, Oner Deniz

    2017-04-01

    We investigated the feasibility of using serum alpha-fetoprotein (AFP) levels as a screening test for prenatal diagnosis of Fanconi anemia (FA). Serial measurements in maternal serum were recorded. Parents, both heterozygous for FA, had declined prenatal molecular testing. The infant was born with no somatic abnormalities, and FA was confirmed by postnatal molecular analysis. Maternal serum AFP levels during each trimester of pregnancy were normal indicating that these levels cannot be used as a screening test in prenatal diagnosis. Three-year follow-up after birth showed constantly elevated serum levels in the patient from the start, suggesting a lack of postnatal inhibition on AFP gene.

  7. Low-Dose Total-Body Irradiation and Fludarabine Phosphate Followed by Unrelated Donor Stem Cell Transplant in Treating Patients With Fanconi Anemia

    Science.gov (United States)

    2016-03-01

    Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndromes; Fanconi Anemia; Previously Treated Myelodysplastic Syndromes

  8. Carcinoma de células escamosas em língua pós-transplante de medula óssea por Anemia de Fanconi

    OpenAIRE

    Pasquini Ricardo; Neto José Z.; Medeiros Carlos R.; Bitencourt Marco A.; Bonfim Carmem M. S.; Moreira Vaneuza A.; Setúbal Daniela C.; Flowers Mary E. D.; Kupka Elcio; Araújo Marcos V.

    2003-01-01

    Anemia Fanconi (AF) é uma síndrome autossômica recessiva, caracterizada por pancitopenia progressiva com hipoplasia de MO, em associação com várias anormalidades constitucionais, tendo como único recurso terapêutico com possibilidade potencial de cura o transplante de medula óssea, e sendo tais pacientes propensos ao desenvolvimento de malignidades hematológicas e carcinoma de células escamosas (CEC) em diversos locais: reto, vagina, cérvice, esôfago, cavidade bucal, faringe ou pele, mas espe...

  9. Fatores sociais, comportamentais e microbiológicos associados à saúde bucal de crianças e adolescentes com Anemia de Fanconi

    OpenAIRE

    Lyko, Karine Fatima

    2012-01-01

    Resumo: A Anemia de Fanconi (AF) é uma desordem genética de fenótipo variado sendo o mais importante a falência medular progressiva. O único recurso terapêutico com possibilidade de cura das complicações hematológicas é o transplante de células tronco hematopoéticas (TCTH). O regime de condicionamento terapêutico antes e após o TCTH pode provocar alterações da microbiota bucal em pacientes com AF aumentando o risco de problemas bucais e agravando o quadro clínico geral. O propósito deste estu...

  10. Manifestações bucais compatíveis com doença do enxerto contra o hospedeiro em pacientes com anemia de Fanconi

    OpenAIRE

    Cavalcanti, Laura Grein

    2014-01-01

    Resumo: A anemia de Fanconi é uma doença genética rara caracterizada por anomalias congênitas, falência medular progressiva e maior susceptibilidade ao desenvolvimento de neoplasias malignas. O único tratamento com perspectiva de cura hematológica é o transplante de células-tronco hematopoiéticas (TCTH). Uma das complicações relacionadas a este procedimento é o desenvolvimento da doença do enxerto contra o hospedeiro crônica (DECHc), a qual pode desencadear dor, impedimento funcional e reduçã...

  11. DNA cross-link-dependent RAD50/MRE11/NBS1 subnuclear assembly requires the Fanconi anemia C protein.

    Science.gov (United States)

    Pichierri, Pietro; Averbeck, Dietrich; Rosselli, Filippo

    2002-10-01

    Fanconi anemia (FA) is a cancer-predisposition syndrome characterized by hypersensitivity to interstrand-cross-link (ICL) inducers. FA hypersensitivity to ICL has been correlated with alterations in homologous recombination, non-homologous end-joining, telomere maintenance, DNA-damage assessment and checkpoint regulation, processes in which the components of the RAD50/MRE11/NBS1 (RMN) complex are involved. To better characterize the mechanisms by which ICL are processed in human cells and to gain insight into their toxicity in FA, we examined (i). the RMN complex assembling in response to the ICL inducers mitomycin C (MMC) and photoactivated 8-methoxypsoralen and (ii). the proficiency of FA cells to perform RMN activation in response to ICL inducers. We show here that ICL activates the assembly of the RMN proteins into subnuclear foci, and that their formation proceeds independently of ICL incision, a step mainly dependent on XP-F/ERCC1 heterodimer activity. Interestingly, FA cells were unable to form RMN foci in response to either ICL inducer. Analysis by pulsed-field gel electrophoresis and single-cell gel electrophoresis of MMC-treated cells showed that FA cells from complementation group C (FA-C cells, defective in the FANCC gene) form double-strand breaks and unhook MMC-induced ICL similarly to FANCC wild-type cells. These observations imply that the absence of RMN assembly in FA-C cells is not simply due to the absence of DNA ends produced as intermediates of ICL processing, and indicates a direct role for FANCC in RMN focus assembly in response to ICL inducers. Moreover, we show that the formation of foci, including BRCA1 and/or RAD51 proteins, is significantly delayed in FA cells. These alterations in the assembly of DNA-repair proteins in FA provide an interpretation for the DNA-damage processing anomalies observed in FA cells and for the genetic instability and the cancer predisposition of the syndrome.

  12. Ouabain, a cardiac glycoside, inhibits the Fanconi anemia/BRCA pathway activated by DNA interstrand cross-linking agents.

    Directory of Open Access Journals (Sweden)

    Dong Wha Jun

    Full Text Available Modulation of the DNA repair pathway is an emerging target for the development of anticancer drugs. DNA interstrand cross-links (ICLs, one of the most severe forms of DNA damage caused by anticancer drugs such as cisplatin and mitomycin C (MMC, activates the Fanconi anemia (FA/BRCA DNA repair pathway. Inhibition of the FA/BRCA pathway can enhance the cytotoxic effects of ICL-inducing anticancer drugs and can reduce anticancer drug resistance. To find FA/BRCA pathway inhibitory small molecules, we established a cell-based high-content screening method for quantitating the activation of the FA/BRCA pathway by measuring FANCD2 foci on DNA lesions and then applied our method to chemical screening. Using commercial LOPAC1280 chemical library screening, ouabain was identified as a competent FA/BRCA pathway inhibitory compound. Ouabain, a member of the cardiac glycoside family, binds to and inhibits Na(+/K(+-ATPase and has been used to treat heart disease for many years. We observed that ouabain, as well as other cardiac glycoside family members--digitoxin and digoxin--down-regulated FANCD2 and FANCI mRNA levels, reduced monoubiquitination of FANCD2, inhibited FANCD2 foci formation on DNA lesions, and abrogated cell cycle arrest induced by MMC treatment. These inhibitory activities of ouabain required p38 MAPK and were independent of cellular Ca(2+ ion increase or the drug uptake-inhibition effect of ouabain. Furthermore, we found that ouabain potentiated the cytotoxic effects of MMC in tumor cells. Taken together, we identified an additional effect of ouabain as a FA/BRCA pathway-inhibiting chemosensitization compound. The results of this study suggest that ouabain may serve as a chemosensitizer to ICL-inducing anticancer drugs.

  13. Analysis of baseline and cisplatin-inducible gene expression in Fanconi anemia cells using oligonucleotide-based microarrays

    Directory of Open Access Journals (Sweden)

    Liu Johnson M

    2002-11-01

    Full Text Available Abstract Background Patients with Fanconi anemia (FA suffer from multiple defects, most notably of the hematological compartment (bone marrow failure, and susceptibility to cancer. Cells from FA patients show increased spontaneous chromosomal damage, which is aggravated by exposure to low concentrations of DNA cross-linking agents such as mitomycin C or cisplatin. Five of the identified FA proteins form a nuclear core complex. However, the molecular function of these proteins remains obscure. Methods Oligonucleotide microarrays were used to compare the expression of approximately 12,000 genes from FA cells with matched controls. Expression profiles were studied in lymphoblastoid cell lines derived from three different FA patients, one from the FA-A and two from the FA-C complementation groups. The isogenic control cell lines were obtained by either transfecting the cells with vectors expressing the complementing cDNAs or by using a spontaneous revertant cell line derived from the same patient. In addition, we analyzed expression profiles from two cell line couples at several time points after a 1-hour pulse treatment with a discriminating dose of cisplatin. Results Analysis of the expression profiles showed differences in expression of a number of genes, many of which have unknown function or are difficult to relate to the FA defect. However, from a selected number of proteins involved in cell cycle regulation, DNA repair and chromatin structure, Western blot analysis showed that p21waf1/Cip1 was significantly upregulated after low dose cisplatin treatment in FA cells specifically (as well as being expressed at elevated levels in untreated FA cells. Conclusions The observed increase in expression of p21waf1/Cip1 after treatment of FA cells with crosslinkers suggests that the sustained elevated levels of p21waf1/Cip1 in untreated FA cells detected by Western blot analysis likely reflect increased spontaneous damage in these cells.

  14. Allogeneic hematopoietic cell transplantation for fanconi anemia in patients with pretransplantation cytogenetic abnormalities, myelodysplastic syndrome, or acute leukemia.

    Science.gov (United States)

    Ayas, Mouhab; Saber, Wael; Davies, Stella M; Harris, Richard E; Hale, Gregory A; Socie, Gerard; LeRademacher, Jennifer; Thakar, Monica; Deeg, H Joachim J; Al-Seraihy, Amal; Battiwalla, Minoo; Camitta, Bruce M; Olsson, Richard; Bajwa, Rajinder S; Bonfim, Carmem M; Pasquini, Ricardo; Macmillan, Margaret L; George, Biju; Copelan, Edward A; Wirk, Baldeep; Al Jefri, Abdullah; Fasth, Anders L; Guinan, Eva C; Horn, Biljana N; Lewis, Victor A; Slavin, Shimon; Stepensky, Polina; Bierings, Marc; Gale, Robert Peter

    2013-05-01

    Allogeneic hematopoietic cell transplantation (HCT) can cure bone marrow failure in patients with Fanconi anemia (FA). Data on outcomes in patients with pretransplantation cytogenetic abnormalities, myelodysplastic syndrome (MDS), or acute leukemia have not been separately analyzed. We analyzed data on 113 patients with FA with cytogenetic abnormalities (n = 54), MDS (n = 45), or acute leukemia (n = 14) who were reported to the Center for International Blood and Marrow Transplant Research from 1985 to 2007. Neutrophil recovery occurred in 78% and 85% of patients at days 28 and 100, respectively. Day 100 cumulative incidences of acute graft-versus-host disease grades B to D and C to D were 26% (95% CI, 19% to 35%) and 12% (95% CI, 7% to 19%), respectively. Survival probabilities at 1, 3, and 5 years were 64% (95% CI, 55% to 73%), 58% (95% CI, 48% to 67%), and 55% (95% CI, 45% to 64%), respectively. In univariate analysis, younger age was associated with superior 5-year survival (≤ v > 14 years: 69% [95% CI, 57% to 80%] v 39% [95% CI, 26% to 53%], respectively; P = .001). In transplantations from HLA-matched related donors (n = 82), younger patients (≤ v > 14 years: 78% [95% CI, 64% to 90%] v 34% [95% CI, 20% to 50%], respectively; P < .001) and patients with cytogenetic abnormalities only versus MDS/acute leukemia (67% [95% CI, 52% to 81%] v 43% [95% CI, 27% to 59%], respectively; P = .03) had superior 5-year survival. Our analysis indicates that long-term survival for patients with FA with cytogenetic abnormalities, MDS, or acute leukemia is achievable. Younger patients and recipients of HLA-matched related donor transplantations who have cytogenetic abnormalities only have the best survival.

  15. Molecular analysis of the most prevalent mutations of the FANCA and FANCC genes in Brazilian patients with Fanconi anaemia

    Directory of Open Access Journals (Sweden)

    David Enrique Aguilar Rodriguez

    2005-01-01

    Full Text Available Fanconi anaemia (FA is a recessive autosomal disease determined by mutations in genes of at least eleven complementation groups, with distinct distributions in different populations. As far as we know, there are no reports regarding the molecular characterisation of the disease in unselected FA patients in Brazil. OBECTIVE: This study aimed to investigate the most prevalent mutations of FANCA and FANCC genes in Brazilian patients with FA. METHODS: Genomic DNA obtained from 22 racially and ethnically diverse unrelated FA patients (mean age ± SD: 14.0 ± 7.8 years; 10 male, 12 female; 14 white, 8 black was analysed by polymerase chain reaction and restriction site assays for identification of FANCA (delta3788-3790 and FANCC (delta322G, IVS4+4A -> T, W22X, L496R, R548X, Q13X, R185X, and L554P gene mutations. RESULTS: Mutations in FANCA and FANCC genes were identified in 6 (27.3% and 14 (63.6% out of 22 patients, respectively. The disease could not be attributed to the tested mutations in the two remaining patients enrolled in the study (9.1%. The registry of the two most prevalent gene abnormalities (delta3788-3790 and IVS4 + 4 -> T revealed that they were present in 18.2% and 15.9% of the FA alleles, respectively. Additional FANCC gene mutations were found in the study, with the following prevalence: delta322G (11.4%, W22X (9.1%, Q13X (2.3%, L554P (2.3%, and R548X (2.3% of total FA alleles. CONCLUSION: These results suggest that mutations of FANCA and FANCC genes are the most prevalent mutations among FA patients in Brazil.

  16. Inducibility of nuclear Rad51 foci after DNA damage distinguishes all Fanconi anemia complementation groups from D1/BRCA2

    Energy Technology Data Exchange (ETDEWEB)

    Godthelp, Barbara C. [Department of Toxicogenetics, Leiden University Medical Center, Wassenaarseweg 72, NL-2333 AL Leiden (Netherlands); Wiegant, Wouter W. [Department of Toxicogenetics, Leiden University Medical Center, Wassenaarseweg 72, NL-2333 AL Leiden (Netherlands); Waisfisz, Quinten [Department of Clinical Genetics and Human Genetics, Free University Medical Center, Van der Boechorststraat 7, NL-1081 BT Amsterdam (Netherlands); Medhurst, Annette L. [Department of Clinical Genetics and Human Genetics, Free University Medical Center, Van der Boechorststraat 7, NL-1081 BT Amsterdam (Netherlands); Arwert, Fre [Department of Clinical Genetics and Human Genetics, Free University Medical Center, Van der Boechorststraat 7, NL-1081 BT Amsterdam (Netherlands); Joenje, Hans [Department of Clinical Genetics and Human Genetics, Free University Medical Center, Van der Boechorststraat 7, NL-1081 BT Amsterdam (Netherlands); Zdzienicka, Malgorzata Z. [Department of Toxicogenetics, Leiden University Medical Center, Wassenaarseweg 72, NL-2333 AL Leiden (Netherlands) and Department of Molecular Cell Genetics, Collegium Medicum, N. Copernicus University, Bydgoszcz (Poland)]. E-mail: m.z.zdzienicka@lumc.nl

    2006-02-22

    Fanconi anemia (FA) is a cancer susceptibility disorder characterized by chromosomal instability and hypersensitivity to DNA cross-linking agents. So far 11 complementation groups have been identified, from which only FA-D1/BRCA2 and FA-J are defective downstream of the central FANCD2 protein as cells from these groups are capable of monoubiquitinating FANCD2. In this study we show that cells derived from patients from the new complementation groups, FA-I, FA-J and FA-L are all proficient in DNA damage induced Rad51 foci formation, making the cells from FA-D1/BRCA2 patients that are defective in this process the sole exception. Although FA-B patient HSC230 was previously reported to also have biallelic BRCA2 mutations, we found normal Rad51 foci formation in cells from this patient, consistent with the recent identification of an X-linked gene being mutated in four unrelated FA-B patients. Thus, our data show that none of the FA proteins, except BRCA2, are required to sequester Rad51 into nuclear foci. Since cells from the FA-D1 and FA-J patient groups are both able to monoubiquitinate FANCD2, the 'Rad51 foci phenotype' provides a convenient assay to distinguish between these two groups. Our results suggest that FANCJ and FANCD1/BRCA2 are part of the integrated FANC/BRCA DNA damage response pathway or, alternatively, that they represent sub-pathways in which only FANCD1/BRCA2 is directly connected to the process of homologous recombination.

  17. Deficiency of UBE2T, the E2 Ubiquitin Ligase Necessary for FANCD2 and FANCI Ubiquitination, Causes FA-T Subtype of Fanconi Anemia

    Directory of Open Access Journals (Sweden)

    Kimberly A. Rickman

    2015-07-01

    Full Text Available Fanconi anemia (FA is a rare bone marrow failure and cancer predisposition syndrome resulting from pathogenic mutations in genes encoding proteins participating in the repair of DNA interstrand crosslinks (ICLs. Mutations in 17 genes (FANCA-FANCS have been identified in FA patients, defining 17 complementation groups. Here, we describe an individual presenting with typical FA features who is deficient for the ubiquitin-conjugating enzyme (E2, UBE2T. UBE2T is known to interact with FANCL, the E3 ubiquitin-ligase component of the multiprotein FA core complex, and is necessary for the monoubiquitination of FANCD2 and FANCI. Proband fibroblasts do not display FANCD2 and FANCI monoubiquitination, do not form FANCD2 foci following treatment with mitomycin C, and are hypersensitive to crosslinking agents. These cellular defects are complemented by expression of wild-type UBE2T, demonstrating that deficiency of the protein UBE2T can lead to Fanconi anemia. UBE2T gene gains an alias of FANCT.

  18. Lung Cancer Cell Line Screen Links Fanconi Anemia/BRCA Pathway Defects to Increased Relative Biological Effectiveness of Proton Radiation

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Qi; Ghosh, Priyanjali; Magpayo, Nicole [Laboratory of Cellular and Molecular Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Testa, Mauro; Tang, Shikui [Division of Radiation Physics, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Gheorghiu, Liliana [Laboratory of Cellular and Molecular Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Biggs, Peter; Paganetti, Harald [Division of Radiation Physics, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Efstathiou, Jason A. [Laboratory of Cellular and Molecular Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Lu, Hsiao-Ming [Division of Radiation Physics, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Held, Kathryn D. [Laboratory of Cellular and Molecular Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Willers, Henning, E-mail: hwillers@mgh.harvard.edu [Laboratory of Cellular and Molecular Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States)

    2015-04-01

    Purpose: Growing knowledge of genomic heterogeneity in cancer, especially when it results in altered DNA damage responses, requires re-examination of the generic relative biological effectiveness (RBE) of 1.1 of protons. Methods and Materials: For determination of cellular radiosensitivity, we irradiated 17 lung cancer cell lines at the mid-spread-out Bragg peak of a clinical proton beam (linear energy transfer, 2.5 keV/μm). For comparison, 250-kVp X rays and {sup 137}Cs γ-rays were used. To estimate the RBE of protons relative to {sup 60}Co (Co60eq), we assigned an RBE(Co60Eq) of 1.1 to X rays to correct the physical dose measured. Standard DNA repair foci assays were used to monitor damage responses. FANCD2 was depleted using RNA interference. Results: Five lung cancer cell lines (29.4%) exhibited reduced clonogenic survival after proton irradiation compared with X-irradiation with the same physical doses. This was confirmed in a 3-dimensional sphere assay. Corresponding proton RBE(Co60Eq) estimates were statistically significantly different from 1.1 (P≤.05): 1.31 to 1.77 (for a survival fraction of 0.5). In 3 of these lines, increased RBE was correlated with alterations in the Fanconi anemia (FA)/BRCA pathway of DNA repair. In Calu-6 cells, the data pointed toward an FA pathway defect, leading to a previously unreported persistence of proton-induced RAD51 foci. The FA/BRCA-defective cells displayed a 25% increase in the size of subnuclear 53BP1 foci 18 hours after proton irradiation. Conclusions: Our cell line screen has revealed variations in proton RBE that are partly due to FA/BRCA pathway defects, suggesting that the use of a generic RBE for cancers should be revisited. We propose that functional biomarkers, such as size of residual 53BP1 foci, may be used to identify cancers with increased sensitivity to proton radiation.

  19. Generation of an induced pluripotent stem cell line that mimics the disease phenotypes from a patient with Fanconi anemia by conditional complementation

    Directory of Open Access Journals (Sweden)

    Sumitha Prameela Bharathan

    2017-04-01

    Full Text Available Generation of Fanconi anemia (FA patient-specific induced pluripotent stem cells (iPSCs has been reported to be technically challenging due to the defects in the FA-pathway in the patients' somatic cells. By inducible complementation of FA-pathway, we successfully reprogrammed the fibroblasts of an FA patient to iPSCs. CSCR19i-indCFANCA, one of the iPSC lines generated by the inducible complementation of FA-pathway, was extensively characterized for its pluripotency and karyotype. In the absence of doxycycline (DOX and FANCA expression, this line showed the cellular phenotypes of FA, suggesting it is an excellent tool for FA disease modeling and drug screening.

  20. Repair pathways independent of the Fanconi anemia nuclear core complex play a predominant role in mitigating formaldehyde-induced DNA damage

    Energy Technology Data Exchange (ETDEWEB)

    Noda, Taichi [Department of Biology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Department of Dermatology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Takahashi, Akihisa [Department of Biology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Kondo, Natsuko [Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, Kumatori-cho, Sennan-gun, Osaka 590-0494 (Japan); Mori, Eiichiro [Department of Biology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Okamoto, Noritomo [Department of Otorhinolaryngology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Nakagawa, Yosuke [Department of Oral and Maxillofacial Surgery, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Ohnishi, Ken [Department of Biology, Ibaraki Prefectual University of Health Sciences, 4669-2 Ami, Ami-mati, Inasiki-gun, Ibaraki 300-0394 (Japan); Zdzienicka, Malgorzata Z. [Department of Molecular Cell Genetics, Collegium Medicum in Bydgoszcz, Nicolaus-Copernicus-University in Torun, ul. Sklodowskiej-Curie 9, 85-094 Bydgoszcz (Poland); Thompson, Larry H. [Biosciences and Biotechnology Division, L452, Lawrence Livermore National Laboratory, P.O. Box 808, Livermore, CA 94551-0808 (United States); Helleday, Thomas [Gray Institute for Radiation Oncology and Biology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford, OX3 7DQ (United Kingdom); Department of Genetics, Microbiology and Toxicology Stockholm University, SE-106 91 Stockholm (Sweden); Asada, Hideo [Department of Dermatology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); and others

    2011-01-07

    The role of the Fanconi anemia (FA) repair pathway for DNA damage induced by formaldehyde was examined in the work described here. The following cell types were used: mouse embryonic fibroblast cell lines FANCA{sup -/-}, FANCC{sup -/-}, FANCA{sup -/-}C{sup -/-}, FANCD2{sup -/-} and their parental cells, the Chinese hamster cell lines FANCD1 mutant (mt), FANCGmt, their revertant cells, and the corresponding wild-type (wt) cells. Cell survival rates were determined with colony formation assays after formaldehyde treatment. DNA double strand breaks (DSBs) were detected with an immunocytochemical {gamma}H2AX-staining assay. Although the sensitivity of FANCA{sup -/-}, FANCC{sup -/-} and FANCA{sup -/-}C{sup -/-} cells to formaldehyde was comparable to that of proficient cells, FANCD1mt, FANCGmt and FANCD2{sup -/-} cells were more sensitive to formaldehyde than the corresponding proficient cells. It was found that homologous recombination (HR) repair was induced by formaldehyde. In addition, {gamma}H2AX foci in FANCD1mt cells persisted for longer times than in FANCD1wt cells. These findings suggest that formaldehyde-induced DSBs are repaired by HR through the FA repair pathway which is independent of the FA nuclear core complex. -- Research highlights: {yields} We examined to clarify the repair pathways of formaldehyde-induced DNA damage. Formaldehyde induces DNA double strand breaks (DSBs). {yields} DSBs are repaired through the Fanconi anemia (FA) repair pathway. {yields} This pathway is independent of the FA nuclear core complex. {yields} We also found that homologous recombination repair was induced by formaldehyde.

  1. What Is Fanconi Anemia?

    Science.gov (United States)

    ... Living With Clinical Trials Links Related Topics Anemia Aplastic Anemia Blood and Bone Marrow Transplant Congenital Heart Defects ... red blood cells. FA is a type of aplastic anemia . In aplastic anemia, the bone marrow stops making ...

  2. Fanconi's anaemia and anaesthesia

    African Journals Online (AJOL)

    Adele

    Clinical manifestations. Approximately a third of these ... stature, which in some cases may be related to superimposed ... FA is the commonest type of inherited bone marrow failure ... transplantation), renal ultrasound, hearing tests and cardiac.

  3. Somatic, hematologic phenotype, long-term outcome, and effect of hematopoietic stem cell transplantation. An analysis of 97 Fanconi anemia patients from the Italian national database on behalf of the Marrow Failure Study Group of the AIEOP (Italian Association of Pediatric Hematology-Oncology).

    Science.gov (United States)

    Svahn, Johanna; Bagnasco, Francesca; Cappelli, Enrico; Onofrillo, Daniela; Caruso, Silvia; Corsolini, Fabio; De Rocco, Daniela; Savoia, Anna; Longoni, Daniela; Pillon, Marta; Marra, Nicoletta; Ramenghi, Ugo; Farruggia, Piero; Locasciulli, Anna; Addari, Carmen; Cerri, Carla; Mastrodicasa, Elena; Casazza, Gabriella; Verzegnassi, Federico; Riccardi, Francesca; Haupt, Riccardo; Barone, Angelica; Cesaro, Simone; Cugno, Chiara; Dufour, Carlo

    2016-07-01

    We analyzed 97 Fanconi anemia patients from a clinic/biological database for genotype, somatic, and hematologic phenotype, adverse hematological events, solid tumors, and treatment. Seventy-two patients belonged to complementation group A. Eighty percent of patients presented with mild/moderate somatic phenotype and most with cytopenia. No correlation was seen between somatic/hematologic phenotype and number of missense mutations of FANCA alleles. Over follow-up, 33% of patients improved or maintained mild/moderate cytopenia or normal blood count, whereas remaining worsened cytopenia. Eleven patients developed a hematological adverse event (MDS, AML, pathological cytogenetics) and three developed solid tumors. 10 years cumulative risk of death of the whole cohort was 25.6% with median follow-up 5.8 years. In patients eligible to hematopoietic stem cell transplantation because of moderate cytopenia, mortality was significantly higher in subjects transplanted from matched unrelated donor over nontransplanted subjects, whereas there was no significant difference between matched sibling donor transplants and nontransplanted patients. In patients eligible to transplant because of severe cytopenia and clonal disease, mortality risk was not significantly different in transplanted from matched unrelated versus matched sibling donor versus nontransplanted subjects. The decision to transplant should rely on various elements including, type of donor, HLA matching, patient comorbidities, impairment, and clonal evolution of hematopoiesis. Am. J. Hematol. 91:666-671, 2016. © 2016 Wiley Periodicals, Inc.

  4. Crystal structure of a Fanconi anemia-associated nuclease homolog bound to 5' flap DNA: basis of interstrand cross-link repair by FAN1

    Energy Technology Data Exchange (ETDEWEB)

    Gwon, Gwang Hyeon; Kim, Youngran; Liu, Yaqi; Watson, Adam T.; Jo, Aera; Etheridge, Thomas J.; Yuan, Fenghua; Zhang, Yanbin; Kim, YoungChang; Carr, Anthony M.; Cho, Yunje

    2014-10-15

    Fanconi anemia (FA) is an autosomal recessive genetic disorder caused by defects in any of 15 FA genes responsible for processing DNA interstrand cross-links (ICLs). The ultimate outcome of the FA pathway is resolution of cross-links, which requires structure-selective nucleases. FA-associated nuclease 1 (FAN1) is believed to be recruited to lesions by a monoubiquitinated FANCI–FANCD2 (ID) complex and participates in ICL repair. Here, we determined the crystal structure of Pseudomonas aeruginosa FAN1 (PaFAN1) lacking the UBZ (ubiquitin-binding zinc) domain in complex with 5' flap DNA. All four domains of the right-hand-shaped PaFAN1 are involved in DNA recognition, with each domain playing a specific role in bending DNA at the nick. The six-helix bundle that binds the junction connects to the catalytic viral replication and repair (VRR) nuclease (VRR nuc) domain, enabling FAN1 to incise the scissile phosphate a few bases distant from the junction. The six-helix bundle also inhibits the cleavage of intact Holliday junctions. PaFAN1 shares several conserved features with other flap structure-selective nucleases despite structural differences. A clamping motion of the domains around the wedge helix, which acts as a pivot, facilitates nucleolytic cleavage. The PaFAN1 structure provides insights into how archaeal Holliday junction resolvases evolved to incise 5' flap substrates and how FAN1 integrates with the FA complex to participate in ICL repair.

  5. A High-Throughput Screening Strategy to Identify Protein-Protein Interaction Inhibitors That Block the Fanconi Anemia DNA Repair Pathway.

    Science.gov (United States)

    Voter, Andrew F; Manthei, Kelly A; Keck, James L

    2016-07-01

    Induction of the Fanconi anemia (FA) DNA repair pathway is a common mechanism by which tumors evolve resistance to DNA crosslinking chemotherapies. Proper execution of the FA pathway requires interaction between the FA complementation group M protein (FANCM) and the RecQ-mediated genome instability protein (RMI) complex, and mutations that disrupt FANCM/RMI interactions sensitize cells to DNA crosslinking agents. Inhibitors that block FANCM/RMI complex formation could be useful therapeutics for resensitizing tumors that have acquired chemotherapeutic resistance. To identify such inhibitors, we have developed and validated high-throughput fluorescence polarization and proximity assays that are sensitive to inhibitors that disrupt interactions between the RMI complex and its binding site on FANCM (a peptide referred to as MM2). A pilot screen of 74,807 small molecules was performed using the fluorescence polarization assay. Hits from the primary screen were further tested using the proximity assay, and an orthogonal proximity assay was used to assess inhibitor selectivity. Direct physical interaction between the RMI complex and the most selective inhibitor identified through the screening process was measured by surface plasmon resonance and isothermal titration calorimetry. Observation of direct binding by this small molecule validates the screening protocol.

  6. Fanconi anaemia, BRCA2 mutations and childhood cancer: a developmental perspective from clinical and epidemiological observations with implications for genetic counselling.

    Science.gov (United States)

    Meyer, Stefan; Tischkowitz, Marc; Chandler, Kate; Gillespie, Alan; Birch, Jillian M; Evans, D Gareth

    2014-02-01

    Fanconi anaemia (FA) is an inherited condition characterised by congenital and developmental abnormalities and a strong cancer predisposition. In around 3-5% of cases FA is caused by biallelic mutations in the BRCA2 gene. Individuals heterozygous for BRCA2 mutations have an increased risk of inherited breast and ovarian cancer. We reviewed the mutation spectrum in BRCA2-associated FA, and the spectrum and frequency of BRCA2 mutations in distinct populations. The rarity of FA due to biallelic BRCA2 mutations supports a fundamental role of BRCA2 for prevention of malignant transformation during development. The spectrum of malignancies seen associated with FA support the concept of a tissue selectivity of BRCA2 mutations for development of FA-associated cancers. This specificity is illustrated by the distinct FA-associated BRCA2 mutations that appear to predispose to specific brain or haematological malignancies. For some populations, the number of FA-patients with biallelic BRCA2 disruption is smaller than that expected from the carrier frequency, and this implies that some pregnancies with biallelic BRCA2 mutations do not go to term. The apparent discrepancy between expected and observed incidence of BRCA2 mutation-associated FA in high-frequency carrier populations has important implications for the genetic counselling of couples with recurrent miscarriages from high-risk populations.

  7. Bone marrow failure in Fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells.

    Science.gov (United States)

    Ceccaldi, Raphael; Parmar, Kalindi; Mouly, Enguerran; Delord, Marc; Kim, Jung Min; Regairaz, Marie; Pla, Marika; Vasquez, Nadia; Zhang, Qing-Shuo; Pondarre, Corinne; Peffault de Latour, Régis; Gluckman, Eliane; Cavazzana-Calvo, Marina; Leblanc, Thierry; Larghero, Jérôme; Grompe, Markus; Socié, Gérard; D'Andrea, Alan D; Soulier, Jean

    2012-07-01

    Fanconi anemia (FA) is an inherited DNA repair deficiency syndrome. FA patients undergo progressive bone marrow failure (BMF) during childhood, which frequently requires allogeneic hematopoietic stem cell transplantation. The pathogenesis of this BMF has been elusive to date. Here we found that FA patients exhibit a profound defect in hematopoietic stem and progenitor cells (HSPCs) that is present before the onset of clinical BMF. In response to replicative stress and unresolved DNA damage, p53 is hyperactivated in FA cells and triggers a late p21(Cdkn1a)-dependent G0/G1 cell-cycle arrest. Knockdown of p53 rescued the HSPC defects observed in several in vitro and in vivo models, including human FA or FA-like cells. Taken together, our results identify an exacerbated p53/p21 "physiological" response to cellular stress and DNA damage accumulation as a central mechanism for progressive HSPC elimination in FA patients, and have implications for clinical care.

  8. The Fanconi anemia/BRCA pathway is involved in DNA interstrand cross-link repair of adriamycin-resistant leukemia cells.

    Science.gov (United States)

    Yao, Chenjiao; Du, Wei; Chen, Haibing; Xiao, Sheng; Huang, Lihua; Chen, Fangping

    2015-03-01

    The Fanconi anemia/BRCA (FA/BRCA) pathway plays a vital role in DNA damage repair induced by DNA cross-linking agents and is closely related to drug response in cancer treatment. Here we demonstrate that the FA/BRCA pathway contributes to acquired drug resistance in adriamycin (ADR)-resistant leukemia cell lines, and disruption of this pathway partially reverses the drug resistance. We observed that ADR-resistant cells have reduced DNA interstrand cross-links (ICL) compared with ADR-sensitive cells. Western blot studies demonstrated enhanced FA protein expression in ADR-resistant cells. Using siRNA to knock down FANCF in K562/R drug-resistant cells showed increases in sensitivity to ADR and ADR-induced DNA damage, and demonstrated a direct relationship between the FA/BRCA pathway and drug sensitivity. Overexpression of FANCF in K562 drug-sensitive cells partially reproduced the drug-resistant phenotype. These results show that the FA/BRCA pathway is involved in acquired ADR resistance of leukemia cells. The FA/BRCA pathway may be a new target to reverse ADR resistance in leukemia treatment.

  9. The nuclease hSNM1B/Apollo is linked to the Fanconi anemia pathway via its interaction with FANCP/SLX4.

    Science.gov (United States)

    Salewsky, Bastian; Schmiester, Maren; Schindler, Detlev; Digweed, Martin; Demuth, Ilja

    2012-11-15

    The recessive genetic disorder Fanconi anemia (FA) is clinically characterized by congenital defects, bone marrow failure and an increased incidence of cancer. Cells derived from FA patients exhibit hypersensitivity to DNA interstrand crosslink (ICL)-inducing agents. We have earlier reported a similar cellular phenotype for human cells depleted of hSNM1B/Apollo (siRNA). In fact, hSNM1B/Apollo has a dual role in the DNA damage response and in generation and maintenance of telomeres, the latter function involving interaction with the shelterin protein TRF2. Here we find that ectopically expressed hSNM1B/Apollo co-immunoprecipitates with SLX4, a protein recently identified as a new FA protein, FANCP, and known to interact with several structure-specific nucleases. As shown by immunofluorescence analysis, FANCP/SLX4 depletion (siRNA) resulted in a significant reduction of hSNM1B/Apollo nuclear foci, supporting the functional relevance of this new protein interaction. Interestingly, as an additional consequence of FANCP/SLX4 depletion, we found a reduction of cellular TRF2, in line with its telomere-related function. Finally, analysis of human cells following double knockdown of hSNM1B/Apollo and FANCP/SLX4 indicated that they function epistatically. These findings further substantiate the role of hSNM1B/Apollo in a downstream step of the FA pathway during the repair of DNA ICLs.

  10. Factors Influencing the Decision-Making Process and Long-Term Interpersonal Outcomes for Parents Who Undergo Preimplantation Genetic Diagnosis for Fanconi Anemia: a Qualitative Investigation.

    Science.gov (United States)

    Haude, K; McCarthy Veach, P; LeRoy, B; Zierhut, H

    2017-06-01

    Fanconi anemia (FA) is characterized by congenital malformations, progressive bone marrow failure, and predisposition to malignancy. Hematopoietic stem cell transplantation is used to treat FA, and best results are attained with sibling donors who are human leukocyte antigen (HLA) identical matches. Preimplantation genetic diagnosis (PGD) offers parents of an affected child the opportunity to have an unaffected child who is an HLA match. While some research has investigated parents' experiences during the PGD process, no published studies specifically address factors influencing their decision-making process and long-term interpersonal outcomes. The aims of this study are to: (1) examine parents' expectations and the influence of media, bioethics, and religion on their decision to undergo PGD; (2) examine parents' social support and emotional experiences during their PGD process; and (3) characterize long-term effects of PGD on relationship dynamics (partner, family, friends), others' attitudes, and parental regret. Nine parents participated in semi-structured interviews. Thematic analysis revealed their decision to use PGD was variously influenced by media, bioethics, and religion, in particular, affecting parents' initial confidence levels. Moreover, the PGD process was emotionally complex, with parents desiring varying amounts and types of support from different sources at different times. Parents reported others' attitudes towards them were similar or no different than before PGD. Parental regret regarding PGD was negligible. Results of this study will promote optimization of long-term care for FA families.

  11. Allogeneic hematopoietic stem cell transplantation from an alternative stem cell source in Fanconi anemia patients: analysis of 47 patients from a single institution

    Directory of Open Access Journals (Sweden)

    C.R. de Medeiros

    2006-10-01

    Full Text Available We transplanted 47 patients with Fanconi anemia using an alternative source of hematopoietic cells. The patients were assigned to the following groups: group 1, unrelated bone marrow (N = 15; group 2, unrelated cord blood (N = 17, and group 3, related non-sibling bone marrow (N = 15. Twenty-four patients (51% had complete engraftment, which was not influenced by gender (P = 0.87, age (P = 0.45, dose of cyclophosphamide (P = 0.80, nucleated cell dose infused (P = 0.60, or use of anti-T serotherapy (P = 0.20. Favorable factors for superior engraftment were full HLA compatibility (independent of the source of cells; P = 0.007 and use of a fludarabine-based conditioning regimen (P = 0.046. Unfavorable factors were > or = 25 transfusions pre-transplant (P = 0.011 and degree of HLA disparity (P = 0.007. Intensity of mucositis (P = 0.50 and use of androgen prior to transplant had no influence on survival (P = 0.80. Acute graft-versus-host disease (GVHD grade II-IV and chronic GVHD were diagnosed in 47 and 23% of available patients, respectively, and infections prevailed as the main cause of death, associated or not with GVHD. Eighteen patients are alive, the Kaplan-Meyer overall survival is 38% at ~8 years, and the best results were obtained with related non-sibling bone marrow patients. Three recommendations emerged from the present study: fludarabine as part of conditioning, transplant in patients with <25 transfusions and avoidance of HLA disparity. In addition, an extended family search (even when consanguinity is not present seeking for a related non-sibling donor is highly recommended.

  12. Fanconi Bickel Syndrome: Novel Mutations in GLUT 2 Gene Causing a Distinguished Form of Renal Tubular Acidosis in Two Unrelated Egyptian Families

    Directory of Open Access Journals (Sweden)

    Mohammad Al-Haggar

    2011-01-01

    Full Text Available Background. Fanconi-Bickel syndrome (FBS is an autosomal recessive disorder caused by defects in facilitative glucose transporter 2 (GLUT2 or SLC2A2 gene mapped on chromosome 3q26.1-26.3, that codes for the glucose transporter protein 2. Methods. Two unrelated Egyptian families having suspected cases of FBS were enrolled after taking a written informed consent; both had positive consanguinity, and index cases had evidences of proximal renal tubular defects with hepatomegaly; they were subjected to history taking, signs of rickets as well as anthropometric measurements. Laboratory workup included urinalysis, renal and liver function tests including fasting and postprandial blood sugar; serum calcium, phosphorus, alkaline phosphatase, sodium and potassium, lipid profile, and detailed blood gas. Imaging including bone survey and abdominal ultrasound, and liver biopsy were done to confirm diagnosis. Molecular analysis of the GLUT2 gene was done for DNA samples extracted from peripheral blood leukocyte. All coding sequences, including flanking introns in GLUT2 gene, were amplified using PCR followed by direct sequencing. Results. Two new mutations had been detected, one in each family, in exon 3 two bases (GA were deleted (c.253 254delGA and in exon 6 in the second family, G-to-C substitution at position-1 of the splicing acceptor site (c.776-1G>C or IVS5-1G>A. Conclusion. FBS is a rare disease due to mutation in GLUT2 gene; many mutations were reported, about half were novel mutations; yet none of these mutations is more frequent. A more extensive survey for the most frequent mutations among FBS has to be contemplated to allow for use of molecular screening tests like ARMS.

  13. Fanconi's anemia and clinical radiosensitivity. Report on two adult patients with locally advanced solid tumors treated by radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Bremer, M.; Karstens, J.H. [Hannover Medical School, Hannover (Germany). Dept. of Radiation Oncology; Schindler, D.; Gross, M. [Univ. Wuerzburg (Germany). Inst. of Human Genetics; Doerk, T. [Hannover Medical School, Hannover (Germany). Dept. of Obstetrics and Gynecology; Morlot, S. [Hannover Medical School, Hannover (Germany). Inst. of Human Genetics

    2003-11-01

    Background: Patients with Fanconi's anemia (FA) may exhibit an increased clinical radiosensitivity of various degree, although detailed clinical data are scarce. We report on two cases to underline the possible challenges in the radiotherapy of FA patients. Case Report and Results: Two 24- and 32-year-old male patients with FA were treated by definitive radiotherapy for locally advanced squamous cell head and neck cancers. In the first patient, long-term tumor control could be achieved after delivery of 67 Gy with a - in part - hyperfractionated split-course treatment regimen and, concurrently, one course of carboplatin followed by salvage neck dissection. Acute toxicity was marked, but no severe treatment-related late effects occurred. 5 years later, additional radiotherapy was administered due to a second (squamous cell carcinoma of the anus) and third (squamous cell carcinoma of the head and neck) primary, which the patient succumbed to. By contrast, the second patient experienced fatal acute hematologic toxicity after delivery of only 8 Gy of hyperfractionated radiotherapy. While the diagnosis FA could be based on flow cytometric analysis of a lymphocyte culture in the second patient, the diagnosis in the first patient had to be confirmed by hypersensitivity to mitomycin of a fibroblast cell line due to complete somatic lymphohematopoietic mosaicism. In this patient, phenotype complementation and molecular genetic analysis revealed a pathogenic mutation in the FANCA gene. The first patient has not been considered to have FA until he presented with his second tumor. Conclusion: FA has to be considered in patients presenting at young age with squamous cell carcinoma of the head and neck or anus. The diagnosis FA is of immediate importance for guiding the optimal choice of treatment. Radiotherapy or even radiochemotherapy seems to be feasible and effective in individual cases. (orig.)

  14. A YAC contig spanning the nevoid basal cell carcinoma syndrome, Fanconi anaemia group C, and xeroderma pigmentosum group A loci on chromosome 9q

    Energy Technology Data Exchange (ETDEWEB)

    Morris, D.J.; Reis, A. [Freie Universtiaet, Berlin (Germany)

    1994-09-01

    Nevoid basal cell carcinoma syndrome (NBCCS, Gorlin syndrome) is an autosomal dominant disorder, characterized primarily by multiple basal cell carcinomas, epithelium-lined jaw cysts, and palmar and plantar pits, as well as various other features. Loss of heterozygosity studies and linkage analysis have mapped the NBCCS gene to chromosome 9q and suggested that it is a tumor suppressor. The apparent sensitivity of NBCCS patients to UV and X-irradiation raises the possibility of hypersensitivity to DNA-damaging reagents or defective DNA repair being etiological in the disorder. The recent mapping of the Fanconi anaemia group C (FACC) and xeroderma pigmentosum complementing group A (XPAC) genes to the same region on 9q has led us to begin the molecular dissection of the 9q22-q31 region. PCR analysis of the presence or absence of 10 microsatellite markers and exons 3 and 4 of the XPAC and FACC genes, respectively, allowed us to order 12 YACs into an overlapping contig and to order the markers as follows: D9S151/D9S12P1-D9S12P2-D9S197-D9S196-D9S280-FACC-D9S287/XPAC-D9S180-D9S6-D9S176. Sizing of the YACs has provided an initial estimate of the size of the NBCCS candidate region between D9S12 and D9S180 to be less than 1.65 Mb. 45 refs., 1 fig., 1 tab.

  15. Fanconi Bickel Syndrome: Novel Mutations in GLUT 2 Gene Causing a Distinguished Form of Renal Tubular Acidosis in Two Unrelated Egyptian Families.

    Science.gov (United States)

    Al-Haggar, Mohammad; Sakamoto, Osamu; Shaltout, Ali; El-Hawary, Amany; Wahba, Yahya; Abdel-Hadi, Dina

    2011-01-01

    Background. Fanconi-Bickel syndrome (FBS) is an autosomal recessive disorder caused by defects in facilitative glucose transporter 2 (GLUT2 or SLC2A2) gene mapped on chromosome 3q26.1-26.3, that codes for the glucose transporter protein 2. Methods. Two unrelated Egyptian families having suspected cases of FBS were enrolled after taking a written informed consent; both had positive consanguinity, and index cases had evidences of proximal renal tubular defects with hepatomegaly; they were subjected to history taking, signs of rickets as well as anthropometric measurements. Laboratory workup included urinalysis, renal and liver function tests including fasting and postprandial blood sugar; serum calcium, phosphorus, alkaline phosphatase, sodium and potassium, lipid profile, and detailed blood gas. Imaging including bone survey and abdominal ultrasound, and liver biopsy were done to confirm diagnosis. Molecular analysis of the GLUT2 gene was done for DNA samples extracted from peripheral blood leukocyte. All coding sequences, including flanking introns in GLUT2 gene, were amplified using PCR followed by direct sequencing. Results. Two new mutations had been detected, one in each family, in exon 3 two bases (GA) were deleted (c.253 254delGA) and in exon 6 in the second family, G-to-C substitution at position-1 of the splicing acceptor site (c.776-1G>C or IVS5-1G>A). Conclusion. FBS is a rare disease due to mutation in GLUT2 gene; many mutations were reported, about half were novel mutations; yet none of these mutations is more frequent. A more extensive survey for the most frequent mutations among FBS has to be contemplated to allow for use of molecular screening tests like ARMS.

  16. Carcinoma de células escamosas da hipofaringe em mulher jovem com anemia de Fanconi Squamous cell carcinoma of the hypopharynx in a young woman with Fanconi’s anemia

    Directory of Open Access Journals (Sweden)

    Henrique de Lins e Horta

    2006-12-01

    Full Text Available A anemia de Fanconi é um raro distúrbio autossômico recessivo caracterizado por malformações congênitas, aplasia da medula óssea e instabilidade genômica, com predisposição ao desenvolvimento de neoplasias malignas, em especial as leucemias e os tumores do trato aerodigestivo alto. Em razão de características inerentes à síndrome em questão, o tratamento de tais neoplasias é particularmente difícil. Relata-se o caso de anemia de Fanconi uma jovem de 24 anos, que desenvolveu carcinoma de células escamosas da hipofaringe, na ausência de fatores de risco como o tabagismo e o alcoolismo, e faz-se uma revisão sumária da literatura a respeito do tema.Fanconi’s anemia is a rare autosomal recessive disorder characterized by congenital malformation, bone marrow failure and genomic instability, with a predisposition to develop malignancies, especially the leukemias and upper aerodigestive tract tumors. Due to inherent characteristics to this syndrome, the treatment of such neoplasms is particularly difficult. In this paper we report the case of a 24-year-old woman with Fanconi’s anemia who developed a squamous cell carcinoma of the hypopharynx; she had none of the traditional risk factors, such as smoking and alcohol abuse. We also briefly review the literature about this topic

  17. Stem cell transplantation from HLA-matched related donor for Fanconi's anaemia: a retrospective review of the multicentric Italian experience on behalf of AIEOP-GITMO.

    Science.gov (United States)

    Dufour, C; Rondelli, R; Locatelli, F; Miano, M; Di Girolamo, G; Bacigalupo, A; Messina, C; Porta, F; Balduzzi, A; Iorio, A P; Buket, E; Madon, E; Pession, A; Dini, G; Di Bartolomeo, P

    2001-03-01

    Twenty-seven consecutive Italian patients with Fanconi's anaemia (FA) underwent stem cell transplantation (SCT) from an HLA-matched related donor in 10 Italian centres of the Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP), Gruppo Italiano di Trapianto di Midollo Osseo (GITMO). Twenty-two patients (81.5%) were conditioned with low-dose (median 20 mg/kg) cyclophosphamide (Cy) and thoraco-abdominal or total body irradiation (median dose 500 cGy), five patients (18.5%) with high-dose Cy (median 120 mg/kg). Graft-vs.-host disease (GVHD) prophylaxis was carried out with cyclosporin A in 26 cases; methotrexate (MTX) was added in eight cases. One patient received MTX alone. The median follow-up was 36 months. Ninety-two percent of patients (25 out of 27) engrafted, grade II and III acute GVHD occurred in 28% and 8% of patients, respectively, with chronic GVHD in 12.5%. Conditioning-related toxicity was mild: 4% of patients had grade III mucositis, 7.4% had grade II haemorrhagic cystitis, 14.8% had grade III liver toxicity and 11.1% had grade III renal toxicity. Transplant-related mortality at 12 months was 19.2%, survival at 36 months was 81.5%, with a median Karnofsky score of 100%. No late tumours occurred after a mean follow-up of the survivors of 5 years. None of the studied variables significantly affected the survival, including conditioning regimen, acute GVHD and clinical non-haematological phenotype. Among the studied variables, only conditioning regimens containing high-dose Cy and the presence of genital abnormalities were significantly (P < 0.05) associated with an increased rate of acute GVHD. Our study demonstrates that the Italian FA patients undergoing SCT from an HLA-matched related donor have a very good outcome. These patients, when compared with others of different ethnic origin who underwent allogeneic bone marrow transplantation, showed a less severe non-haematological phenotype, raising the possibility that this milder phenotype may

  18. 低磷骨软化症为突出表现的范可尼综合征1例报告并文献复习%Fanconi syndrome with hypophosphatemic osteomalacia: a case report an literature review

    Institute of Scientific and Technical Information of China (English)

    李欣; 刘芳; 丁致民

    2012-01-01

    目的 分析范可尼综合征(Fanconi syndrome,FS)的病因、发病机制、临床表现及治疗.方法 采用病例回顾的方式,讨论FS的临床特征、实验室诊断标准及治疗.结果 本例无明显先天疾病可查,成年后起病,且无家族史,以多发性骨痛为突出表现,伴有明显身高缩短及低磷骨软化症的临床表现,辅助检查提示低血钾、低分子蛋白尿、肾性糖尿、氨基酸尿、尿酸化实验提示Ⅱ型肾小管酸中毒,故考虑继发性FS.结论 FS病因多种,成人起病的FS以继发性多见,应早期发现、早期防治.%Objective To review the etiologies, pathogenesis, clinical manifestations and treatment of Fanconi syn-drome(FS). Methods Through revisting a case.we further discussed the clinical characteristic,diagnosis criteria and treatment of FS. Results We reported a 45 years old woman with multiple bone pain,short stature and the features of hypophosphatemic osteomalacia. Laboratory test showed hypokalemia, low-molecular-weight proteinuria, renal glucosuria.aminoaciduria and proximal renal tubular acidosis. All these accorded with the diagnosis of FS. We consid-ered the diagnosis of secondary FS because of deficiency of congenital diseases. Conclusion The etiology of FS is va-rious. In adults,the acquired forms are the main cause of FS.

  19. How Is Fanconi Anemia Treated?

    Science.gov (United States)

    ... make more blood cells for a limited time. Screening and Short-Term Treatment Even if you or ... to the esophagus, which carries food to the stomach. This can cause serious breathing, swallowing, and eating ...

  20. Clinical features of adefovir dipivoxil-induced Fanconi syndrome and hypophosphatemic osteomalacia%阿德福韦酯相关Fanconi综合征、低磷性骨软化症的临床分析

    Institute of Scientific and Technical Information of China (English)

    李晓静; 蒋玲; 张燕燕; 张晓黎; 侯新国

    2014-01-01

    Adefovir dipivoxil (ADV) is commonly used as an anti-viral agent in the treatment of chronic hepatitis B,with a dose-and time-dependent nephrotoxicity.Clinical analysis was made in 4 patients with chronic hepatitis B who developed Fanconi syndrome and hypophosphatemic osteomalacia after long-term use of ADV (10 mg/d).%阿德福韦酯(ADV)是临床常用的一种抗乙型肝炎病毒药物,其肾毒性具有剂量和时间依赖性.本研究对4例长期应用小剂量ADV(10 mg/d)后出现Fanconi综合征、低磷性骨软化症乙肝患者的临床表现、治疗转归进行总结,并结合相关文献就其临床特点、发病机制等方面进行分析.

  1. Analysis of 133 meioses places the genes for nevoid basal cell carcinoma (gorlin) syndrome and fanconi anemia group C in a 2.6-cM interval and contributes to the fine map of 9q22.3

    Energy Technology Data Exchange (ETDEWEB)

    Farndon, P.A.; Hardy, C.; Kilpatrick, M.W. [Birmingham Maternity Hospital, Edgbaston (United Kingdom)] [and others

    1994-09-15

    Four disease genes (NBCCS, ESS1, XPAC, FACC) map to 9q22.3-q31. A fine map of this region was produced by linkage and haplotype analysis using 12 DNA markers. The gene for nevoid basal cell carcinoma syndrome (NBCCS, Gorlin) has an important role in congenital malformations and carcinogenesis. Phase-known recombinants in a study of 133 meioses place NBCCS between (D9S12/D9S151) and D9S176. Haplotype analysis in a two-generation family suggests that NBCCS lies in a smaller interval of 2.6 cM centromeric to D9S287. These flanking markers will be useful clinically for gene tracking. Recombinants also map FACC (Fanconi anemia, group C) to the same region, between (D9S12/D9S151) and D9S287. The recombination rate between (D9S12/D9S151) and D9S53 in males is 8.3% and 13.2% in females, giving a sex-specific male:female ratio of 1:1.6 and a sex-averaged map distance of 10.4 cM. No double recombinants were detected, in agreement with the apparently complete level of interference predicted from the male chiasmata map. 19 refs., 2 figs., 1 tab.

  2. An experimental renal acidification defect in patients with hereditary fructose intolerance. II. Its distinction from classic renal tubular acidosis; its resemblance to the renal acidification defect associated with the Fanconi syndrome of children with cystinosis.

    Science.gov (United States)

    Morris, R C

    1968-07-01

    In adult patients with hereditary fructose intolerance (HFI) fructose induces a renal acidification defect characterized by (a) a 20-30% reduction in tubular reabsorption of bicarbonate (T HCO(3) (-)) at plasma bicarbonate concentrations ranging from 21-31 mEq/liter, (b) a maximal tubular reabsorption of bicarbonate (Tm HCO(3) (-)) of approximately 1.9 mEq/100 ml of glomerular filtrate, (c) disappearance of bicarbonaturia at plasma bicarbonate concentrations less than 15 mEq/liter, and (d) during moderately severe degrees of acidosis, a sustained capacity to maintain urinary pH at normal minima and to excrete acid at normal rates. In physiologic distinction from this defect, the renal acidification defect of patients with classic renal tubular acidosis is characterized by (a) just less than complete tubular reabsorption of bicarbonate at plasma bicarbonate concentrations of 26 mEq/liter or less, (b) a normal Tm HCO(3) (-) of approximately 2.8 mEq/100 ml of glomerular filtrate, and (c) during acidosis of an even severe degree, a quantitatively trivial bicarbonaturia, as well as (d) a urinary pH of greater than 6. That the fructose-induced renal acidification defect involves a reduced H(+) secretory capacity of the proximal nephron is supported by the magnitude of the reduction in T HCO(3) (-) (20-30%) and the simultaneous occurrence and the persistence throughout administration of fructose of impaired tubular reabsorption of phosphate, alpha amino nitrogen and uric acid.A reduced H(+) secretory capacity of the proximal nephron also appears operative in two unrelated children with hyperchloremic acidosis, Fanconi's syndrome, and cystinosis. In both, T HCO(3) (-) was reduced 20-30% at plasma bicarbonate concentrations ranging from 20-30 mEq/liter. The bicarbonaturia disappeared at plasma bicarbonate concentrations ranging from 15-18 mEq/liter, and during moderate degrees of acidosis, urinary pH decreased to less than 6, and the excretion rate of acid was normal.

  3. Expression of hHR21sp gene by peripheral blood and hematopoietic cells of normal subjects and Fanconi anemia patients%FA贫血病人造血细胞hHR21sp基因表达的研究

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective The radiation sensitive gene rad 21 of Schizosaccharomyces pombe is involved in the repair of double-stranded breaks in DNA and is essential for mitotic growth. The hHR21sp gene is its human homologue. In an attempt to investigate the role of hHR21sp in DNA repair, we studied the effects of UV and γ-ray irradiation on hHR21sp gene expression in normal human peripheral blood cells, and non-iradiated peripheral and bone marrow cells from Fanconi anemia (FA) patients who have shown DNA repair deficiency.Methods Total steady state RNA was extracted from peripheral blood cells and bone marrow. RNA transcripts were quantified after RT-PCR and Southern blot, phosphoimmage and autoradiogram analysis. The results were compared with control groups. Results hHR21sp expression was significantly increased from 3h to 9h after UV irradiation in peripheral blood cells from normal subjects at doses of 40-80j/m2 (P<0.05). hHR21sp was also up-regulated by γ-ray irradiation at 6h to 9h at dose of 1 to 5Gy (P<0.01), which was more significant than the UV irradiation. In the non-irradiated FA patient group, hHR21sp expression was decreased in bone marrow hematopoietic cells (P<0.05). After activation by PHA and IL-2, there was still a significant depression in expression by the FA patients peripheral blood cells compared with control groups (P<0.05). Conclusion hHR21sp was up-regulated at doses and times irradiated at the range tested in normal peripheral blood cells, and is more affected by γ-ray irradiation than UV irradiation. FA patient bone marrow hematopoietic cells and peripheral blood mononuclear cells showed down-regulation of hHR21sp expression. The results imply that defects in DNA repair via hHR21sp expression may play an important role in the pathogenesis of FA syndrome.%目的检测UV和γ辐射对正常人外周血单核细胞的hHR21sp基因转录表达水平及hHR21sp在范可尼贫血(Fanconis Anemia FA)骨髓造血细胞和激活后的外周血单核

  4. 1例阿德福韦酯致范可尼综合征并继发低磷性骨软化症的药学监护%Pharmaceutical Care of One Case of Hypophosphatemic Osteomalacia Secondary by Fanconi Syndrome Caused by Adefovir

    Institute of Scientific and Technical Information of China (English)

    赵俊; 辛晓玮; 赵杉杉; 姚文; 隋忠国

    2015-01-01

    Objective:To summarize the feature of one case of hypophosphatemic osteomalacia secondary to Fanconi syndrome caused by adefovir and discuss the key points of pharmaceutical care of these patients.Methods:The correct phosphorus supplement and monitoring of relevant indexes in patients with hypophosphatemic osteomala-cia caused by adefovir were guided by combination of the clinical situation of a patients and the relevant data in re-cent years.Results:The patient got eusemia after withdrawal of adefovir or substitution with other antiviral drugs as well as symptomatic treatment including the supplements of phosphorus, calcium and vitamin D.Conclusion:All the patients receiving adefovir ester, regardless of the dosage, needed the relevant inspection regularly. Once Fan-coni syndrome occurred, other antiviral drugs should be used immediately instead of adefpvor ester.%目的:对1例阿德福韦酯致范可尼综合征并继发低磷性骨软化症患者的病例特点进行总结,并结合文献资料,探讨该类患者的药学监护要点。方法:检索近年来国内外有关阿德福韦酯引起低磷性骨软化症的相关文献,并结合临床中1例患者的诊疗情况,指导该类患者进行正确的补磷以及相关指标的监测。结果:通过停用阿德福韦酯或换用其他抗病毒药物,并予以补磷、补钙、补维生素D等对症治疗,可以达到良好的预后。结论:凡服用阿德福韦酯的患者,无论剂量大小,均需定期进行相关检查,以监测是否发生范可尼综合征。一旦发生,应立即换用其他抗病毒药物。

  5. Controversies and research agenda in nephropathic cystinosis: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference.

    Science.gov (United States)

    Langman, Craig B; Barshop, Bruce A; Deschênes, Georges; Emma, Francesco; Goodyer, Paul; Lipkin, Graham; Midgley, Julian P; Ottolenghi, Chris; Servais, Aude; Soliman, Neveen A; Thoene, Jess G; Levtchenko, Elena N

    2016-06-01

    Nephropathic cystinosis is an autosomal recessive metabolic, lifelong disease characterized by lysosomal cystine accumulation throughout the body that commonly presents in infancy with a renal Fanconi syndrome and, if untreated, leads to end-stage kidney disease (ESKD) in the later childhood years. The molecular basis is due to mutations in CTNS, the gene encoding for the lysosomal cystine-proton cotransporter, cystinosin. During adolescence and adulthood, extrarenal manifestations of cystinosis develop and require multidisciplinary care. Despite substantial improvement in prognosis due to cystine-depleting therapy with cysteamine, no cure of the disease is currently available. Kidney Disease: Improving Global Outcomes (KDIGO) convened a Controversies Conference on cystinosis to review the state-of-the-art knowledge and to address areas of controversies in pathophysiology, diagnostics, monitoring, and treatment in different age groups. More importantly, promising areas of investigation that may lead to optimal outcomes for patients afflicted with this lifelong, systemic disease were discussed with a research agenda proposed for the future.

  6. Quality improvement.

    Science.gov (United States)

    2014-10-30

    Ready to Lead at tinyurl.com/pd9mmuy is a collection of a short series of articles by senior improvement manager at Healthcare Improvement Scotland Steven Wilson. The collection is aimed at drawing out some of the key behaviours, skills and attributes necessary for successful quality improvement leadership. It is not intended as a comprehensive examination, but offers some alternative and creative ideas about what makes effective quality improvement leaders.

  7. 表现为范可尼综合征的阿德福韦酯相关慢性肾脏病15例分析%Analysis of 15 cases with adefovir dipivoxil related chronic kidney disease as fanconi syndrome

    Institute of Scientific and Technical Information of China (English)

    王晓今; 傅青春; 臧祖胜; 施莉琴; 李震宇; 周丰; 李莉; 陈华丽; 陈成伟

    2014-01-01

    目的:对15例长期服用阿德福韦酯(ADV)引起的慢性肾脏病合并范可尼综合征进行分析,并对早期发现ADV 的肾毒性和避免引发范可尼综合征提出监测和防治措施。方法研究对象为2011年4月至2013年9月在解放军第八五医院南京军区上海肝病研究中心因长期服用 ADV 而确诊为范可尼综合征的15例患者,服药剂量均为10 mg/d,平均服药时间4.72年,平均服药至症状出现时间为3.22年。结果患者临床表现为进行性全身多处骨及关节疼痛,4例伴夜尿增多。所有患者血磷均有不同程度的下降;12例存在低尿酸血症,12例肾小球滤过率降低,9例血清碱性磷酸酶增高;4例患者进行了血半胱氨酸蛋白酶抑制剂 C(Cys-C)检测,3例增高;7例患者出现尿蛋白阳性,8例尿糖阳性;11例患者双能 X 线吸收测定法检测骨密度提示骨质疏松。转归:确诊后均停用 ADV,改用恩替卡韦0.5 mg/d 继续抗病毒治疗。所有患者骨痛均在2~8个月后明显缓解;5例停药后2~12个月血磷恢复正常;12例血尿酸降低的患者中有6例在1~11个月恢复正常;9例碱性磷酸酶增高者有2例分别于1、12个月恢复正常,其余较停药前明显下降;7例尿蛋白阳性患者中2例分别在停药后4、19个月蛋白尿消失;8例尿糖阳性的患者有2例分别于停药后4、7个月转阴。结论与以往的文献报道不同,ADV 除可引起程度不同的低磷血症、低尿酸血症等近端肾小管联合功能缺陷所致的范可尼综合征外,尚可引起肾小球损伤。对 ADV 应用超过1年的患者,要定期监测血磷、肌酐、尿酸、Cys-C 及 GFR。应用 ADV 治疗者应避免同时应用其他具有肾毒性的药物,一旦出现肾损伤,要及时更换为其他抗病毒药物或者根据 GFR 水平延长用药间隔时间。%Objective To analyze 15 cases of Fanconi syndrome caused by long

  8. Adefovir dipivoxil-induced Fanconi syndrome and hypophosphatemic osteomalacia associated with muscular weakness in a patient with chronic hepatitis B%阿德福韦酯致Fanconi综合征和低磷性骨软化症并进行性肌无力1例

    Institute of Scientific and Technical Information of China (English)

    李玲; 董光富; 张晓; 谢悦胜

    2011-01-01

    Adefovir dipivoxil is commonly used for treatment of chronic hepatitis B. The renal toxicity of adefovir dipivoxil is dose- and time-related, occurring often in patients with a daily dose over 30 mg and those with impaired renal function. We report a case of chronic hepatitis B with a history of taking adefovir dipivoxil at 10 mg/day for 4 years. The patient complained of lumbosacral and joint pain and had the diagnosis of ankylosing spondylitis (AS) or spondyloarthropathy in several hospitals before admission in our hospital. A diagnosis of acquired Fanconi syndrome and hypophosphatemia osteomalacia associated with progressive muscular weakness was made eventually. We reviewed the literature and found reports of only fewer than 10 similar cases. Clinical attention should be given to kidney damage induced by adefovir dipivoxil.%阿德福韦酯是一种常用的治疗慢性乙型病毒性肝炎的药物.阿德福韦酯的肾毒性具有剂量和时间相关性,多见于30 mg/d以上剂量以及有基础肾功能损害的患者.我们报道1例慢性乙肝患者,服用阿德福韦酯10 mg/d共4年,以腰骶部和膝、髋关节疼痛为主诉就诊,曾辗转多家医院均误诊为强直性脊柱炎或脊柱关节病,最终确诊为获得性Fanconi综合征和低磷性骨软化症伴进行性肌无力,查阅国内外文献,类似报道不足10例,阿德福韦酯的肾损害应引起临床医师的重视.

  9. Collaborative Improvement

    DEFF Research Database (Denmark)

    Kaltoft, Rasmus

    The thesis data have been collected in the EU-sponsored project: Collaborative Improvement Tool for the Extended Manufacturing Enterprise, CO-IMPROVE. In this project four universities (Denmark, Ireland, Italy, and The Netherlands), two software vendors (Greece and Sweden) and three companies (De...... learn how to improve operations in (hopefully) a win-win like manner through collaboration.......The thesis data have been collected in the EU-sponsored project: Collaborative Improvement Tool for the Extended Manufacturing Enterprise, CO-IMPROVE. In this project four universities (Denmark, Ireland, Italy, and The Netherlands), two software vendors (Greece and Sweden) and three companies...... (Denmark, Italy and The Netherlands) each with three to five suppliers were involved. The CO-IMPROVE project and the thesis is based on “action research” and “action learning”. The main aim of the whole project is through actual involvement and actions make the researchers, companies and selected suppliers...

  10. Improving Photosynthesis

    Science.gov (United States)

    Evans, John R.

    2013-01-01

    Photosynthesis is the basis of plant growth, and improving photosynthesis can contribute toward greater food security in the coming decades as world population increases. Multiple targets have been identified that could be manipulated to increase crop photosynthesis. The most important target is Rubisco because it catalyses both carboxylation and oxygenation reactions and the majority of responses of photosynthesis to light, CO2, and temperature are reflected in its kinetic properties. Oxygenase activity can be reduced either by concentrating CO2 around Rubisco or by modifying the kinetic properties of Rubisco. The C4 photosynthetic pathway is a CO2-concentrating mechanism that generally enables C4 plants to achieve greater efficiency in their use of light, nitrogen, and water than C3 plants. To capitalize on these advantages, attempts have been made to engineer the C4 pathway into C3 rice (Oryza sativa). A simpler approach is to transfer bicarbonate transporters from cyanobacteria into chloroplasts and prevent CO2 leakage. Recent technological breakthroughs now allow higher plant Rubisco to be engineered and assembled successfully in planta. Novel amino acid sequences can be introduced that have been impossible to reach via normal evolution, potentially enlarging the range of kinetic properties and breaking free from the constraints associated with covariation that have been observed between certain kinetic parameters. Capturing the promise of improved photosynthesis in greater yield potential will require continued efforts to improve carbon allocation within the plant as well as to maintain grain quality and resistance to disease and lodging. PMID:23812345

  11. Improved confinem

    Directory of Open Access Journals (Sweden)

    Ahmed M. El-Kholy

    2016-06-01

    Full Text Available Traditional steel ties reinforcement cannot provide superior confinement for reinforced concrete (RC columns due to the constraints on tie spacing and disturbance of concrete continuity. This paper presents a practical confinement configuration consisting of single Expanded Metal Mesh (EMM layer in additional to regular tie reinforcement. The EMM layer is warped above ties. The proposed transverse reinforcement, with various volumetric ratios of ties, was investigated in sixteen square short RC column specimens categorized in two groups according to their slenderness ratios. The specimens were cast in vertical position simulating the construction field and they were tested under concentric compression till failure. The results indicated that the columns, confined with proposed lateral reinforcement, revealed significant improvement in the strength and ductility. Also, high reduction in ties volumetric ratio with no loss in ultimate load could be achieved by installing the EMM layer.

  12. 阿德福韦酯致范可尼综合征1例及41例不良反应报道汇总分析%Fanconi's Syndrome induced by adefovir:A case report and pooled analysis of 41 cases

    Institute of Scientific and Technical Information of China (English)

    邹羽真; 胡扬; 张波

    2015-01-01

    Objective:To investigate the features of the hypophosphataemic osteomalacia related to adefovir dipivoxil.Methods:Analysis was upon a case of hypophosphataemic osteomalacia developed after administration of adefovir dipivoxil for treatment of chronic hepititis B.Results: The clinical symptoms started after the patient had been taking adefovir dipivoxil (10 mgqd) for 5 years, and alleviated after the patient withdrawn adefovir dipivoxil for 24 days. Also, serum inorganic phosphorus recovered to normal (0.81 mmol·L-1), which lowest level was 0.53 mmol·L-1. Systematic review of the literature showed that decrease in phosphate, glomerular filtration rate and uric acid levels and increase in alkaline phosphatase were noted in Fanconi's syndrome induced by adefovir dipivoxil, with or without reduction in blood calcium and serum creatinine clearance.Conclusion: Those patients with chronic hepitits B who take adefovir dipivoxil are suggested taking periodical examinations including blood phosphate and serum creatinine. It indicates renal tubular injury when hypophosphatemia happens, please use other antivirals instead. If patients with long-term adefovir dipivoxil therapy have a pain in bone, take the possibility of hypophosphatemic osteomalacia a into consideration.%目的:探讨阿德福韦酯致范可尼综合征的临床特征、机制以及分布特点。方法:对1例应用阿德福韦酯治疗慢性乙型肝炎后发生低血磷性骨软化症的病例进行分析,并在全球范围内就其发生情况进行文献复习。结果:1例患者的临床症状出现时间是连续服用阿德福韦酯10 mgqd 5年之后,在停用阿德福韦酯24 d后,临床症状减轻,血磷恢复正常(症状较重时0.53 mmol·L-1,停用阿德福韦酯24 d时升至0.81 mmol·L-1),诊断为阿德福韦酯相关范可尼综合征、低血磷性骨软化症。复习文献发现阿德福韦酯导致的范可尼综合征均有血磷下降,尿酸水平下降,碱性

  13. Fanconi anaemia in black South African patients heterozygous for ...

    African Journals Online (AJOL)

    of FA in this population as 1/476 000 in a case-based ascertainment study. More recently, gene ... Evidence further suggested that the clinical manifestations of FA in this population were .... Jewish and Afrikaner populations. Founder mutations ...

  14. A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome.

    NARCIS (Netherlands)

    Meetei, AR; Sechi, S; Wallisch, M; Yang, D; Young, MK; Joenje, H.; Hoatlin, M.E.

    2003-01-01

    Bloom syndrome (BS) is a genetic disorder associated with dwarfism, immunodeficiency, reduced fertility, and an elevated risk of cancer. To investigate the mechanism of this disease, we isolated from human HeLa extracts three complexes containing the helicase defective in BS, BLM. Interestingly, one

  15. A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome.

    NARCIS (Netherlands)

    Meetei, AR; Sechi, S; Wallisch, M; Yang, D; Young, MK; Joenje, H.; Hoatlin, M.E.

    2003-01-01

    Bloom syndrome (BS) is a genetic disorder associated with dwarfism, immunodeficiency, reduced fertility, and an elevated risk of cancer. To investigate the mechanism of this disease, we isolated from human HeLa extracts three complexes containing the helicase defective in BS, BLM. Interestingly, one

  16. Theme: Laboratory Facilities Improvement.

    Science.gov (United States)

    Miller, Glen M.; And Others

    1993-01-01

    Includes "Laboratory Facilities Improvement" (Miller); "Remodeling Laboratories for Agriscience Instruction" (Newman, Johnson); "Planning for Change" (Mulcahy); "Laboratory Facilities Improvement for Technology Transfer" (Harper); "Facilities for Agriscience Instruction" (Agnew et al.); "Laboratory Facility Improvement" (Boren, Dwyer); and…

  17. CDBG Public Improvements Activity

    Data.gov (United States)

    Department of Housing and Urban Development — CDBG activity related to public improvements, including senior centers, youth centers, parks, street improvements, water/sewer improvements, child care centers, fire...

  18. Improving Paver Implementation.

    Science.gov (United States)

    1984-09-01

    to improved preventive maintenance : Improved decision making: Other: 42. Do you intend to implement PAVER for roads/streets? A. Yes; we plan to...Elimination of a project due to improved preventive maintenance : Improved decision making: Other: 36. Do you intend to implement PAVER for roads/streets? A...Increased funding for pavement projects: Elimination of a project due to improved preventive maintenance : Improved decision making: Other: 39. Do you

  19. Embarking on performance improvement.

    Science.gov (United States)

    Brown, Bobbi; Falk, Leslie Hough

    2014-06-01

    Healthcare organizations should approach performance improvement as a program, not a project. The program should be led by a guidance team that identifies goals, prioritizes work, and removes barriers to enable clinical improvement teams and work groups to realize performance improvements. A healthcare enterprise data warehouse can provide the initial foundation for the program analytics. Evidence-based best practices can help achieve improved outcomes and reduced costs.

  20. Improved technical specifications

    Energy Technology Data Exchange (ETDEWEB)

    Hoffman, D.R.

    1994-12-31

    Improved technical specifications for nuclear power plants are outlined. The objectives of this work are to improve safety, provide a clearer understanding of safety significance, and ease NRC and industry administrative burdens. Line item improvements, bases, and implementation of the specifications are discussed.

  1. Improved Electrophoresis Cell

    Science.gov (United States)

    Rhodes, P. H.; Snyder, R. S.

    1982-01-01

    Several proposed modifications are expected to improve performance of a continous-flow electrophoresis cell. Changes would allow better control of buffer flow and would increase resolution by suppressing thermal gradients. Improved electrophoresis device would have high resolution and be easy to operate. Improvements would allow better flow control and heat dissipation.

  2. Software Process Improvement Defined

    DEFF Research Database (Denmark)

    Aaen, Ivan

    2002-01-01

    This paper argues in favor of the development of explanatory theory on software process improvement. The last one or two decades commitment to prescriptive approaches in software process improvement theory may contribute to the emergence of a gulf dividing theorists and practitioners....... It is proposed that this divide be met by the development of theory evaluating prescriptive approaches and informing practice with a focus on the software process policymaking and process control aspects of improvement efforts...

  3. Software Process Improvement Defined

    DEFF Research Database (Denmark)

    Aaen, Ivan

    2002-01-01

    This paper argues in favor of the development of explanatory theory on software process improvement. The last one or two decades commitment to prescriptive approaches in software process improvement theory may contribute to the emergence of a gulf dividing theorists and practitioners....... It is proposed that this divide be met by the development of theory evaluating prescriptive approaches and informing practice with a focus on the software process policymaking and process control aspects of improvement efforts...

  4. Process Improvement Essentials

    CERN Document Server

    Persse, James R

    2006-01-01

    Process Improvement Essentials combines the foundation needed to understand process improvement theory with the best practices to help individuals implement process improvement initiatives in their organization. The three leading programs: ISO 9001:2000, CMMI, and Six Sigma--amidst the buzz and hype--tend to get lumped together under a common label. This book delivers a combined guide to all three programs, compares their applicability, and then sets the foundation for further exploration.

  5. Improving assisted living care.

    Science.gov (United States)

    Gregory, Nancy; Gesell, Sabina B; Widmer, Tom

    2007-01-01

    In the absence of a national measurement system, private vendors of satisfaction measurement and improvement services have played a crucial role in the quality movement in the assisted living industry. Survey responses from 175 resident-family dyads at 20 facilities were analyzed to identify priorities for service improvement from the customers' perspective. They include improving care provided by aides and management, meal service, and activities. Practical solutions for addressing these issues are presented.

  6. Tree Improvement Glossary

    DEFF Research Database (Denmark)

    Schmidt, Lars Holger

    Forest tree improvement encompasses a number of scientific and technical areas like floral-, reproductive- and micro-biology, genetics breeding methods and strategies, propagation, gene conservation, data analysis and statistics, each area with a comprehensive terminology. The terms selected...... for definition here are those most frequently used in tree improvement literature. Clonal propagation is included in the view of the great expansion of that field as a means of mass multiplication of improved material....

  7. Ergonomic Improvements for Foundries

    Energy Technology Data Exchange (ETDEWEB)

    Frank Peters; Patrick Patterson

    2002-06-18

    The goal of this project was to make improvements to the production systems of the steel casting industry through ergonomic improvements. Because of the wide variety of products, the wide range of product sizes, and the relatively small quantities of any particular product, manual operations remain a vital part of the production systems of the steel casting companies. Ergonomic improvements will assist the operators to more efficiently and consistently produce quality products.

  8. Teaching quality improvement.

    Science.gov (United States)

    Murray, Marry Ellen; Douglas, Stephen; Girdley, Diana; Jarzemsky, Paula

    2010-08-01

    Practicing nurses are required to engage in quality improvement work as a part of their clinical practice, but few undergraduate nursing education programs offer course work and applied experience in this area. This article presents a description of class content and teaching strategies, assignments, and evaluation strategies designed to achieve the Quality and Safety Education in Nursing competencies related to quality improvement and interdisciplinary teams. Students demonstrate their application of the quality improvement process by designing and implementing a small-scale quality improvement project that they report in storyboard format on a virtual conference Web site.

  9. Improving Loop Dependence Analysis

    DEFF Research Database (Denmark)

    Jensen, Nicklas Bo; Karlsson, Sven

    2017-01-01

    Programmers can no longer depend on new processors to have significantly improved single-thread performance. Instead, gains have to come from other sources such as the compiler and its optimization passes. Advanced passes make use of information on the dependencies related to loops. We improve...... the quality of that information by reusing the information given by the programmer for parallelization. We have implemented a prototype based on GCC into which we also add a new optimization pass. Our approach improves the amount of correctly classified dependencies resulting in 46% average improvement...

  10. THE IMPROVED XINANJIANG MODEL

    Institute of Scientific and Technical Information of China (English)

    LI Zhi-jia; YAO Cheng; KONG Xiang-guang

    2005-01-01

    To improve the Xinanjiang model, the runoff generating from infiltration-excess is added to the model.The another 6 parameters are added to Xinanjiang model.In principle, the improved Xinanjiang model can be used to simulate runoff in the humid, semi-humid and also semi-arid regions.The application in Yi River shows the improved Xinanjiang model could forecast discharge with higher accuracy and can satisfy the practical requirements.It also shows that the improved model is reasonable.

  11. Improving Agile Software Practice

    DEFF Research Database (Denmark)

    Tjørnehøj, Gitte

    2006-01-01

    Software process improvement in small and agile organizations is often problematic, but achieving good SPI-assessments can still be necessary to stay in the marked or to meet demands of multinational owners. The traditional norm driven, centralized and control centered improvement approaches has...

  12. Improving palliative care.

    LENUS (Irish Health Repository)

    Moran, Sue

    2009-05-01

    Any service improvement project requires planning, action and evaluation. Using a recognised quality improvement framework can offer a structured approach to implementing and assessing changes to patient care. This article describes how use of the Deming Cycle has helped to identify nurses\\' learning needs.

  13. Automated Student Model Improvement

    Science.gov (United States)

    Koedinger, Kenneth R.; McLaughlin, Elizabeth A.; Stamper, John C.

    2012-01-01

    Student modeling plays a critical role in developing and improving instruction and instructional technologies. We present a technique for automated improvement of student models that leverages the DataShop repository, crowd sourcing, and a version of the Learning Factors Analysis algorithm. We demonstrate this method on eleven educational…

  14. Improving Agile Software Practice

    DEFF Research Database (Denmark)

    Tjørnehøj, Gitte

    2006-01-01

    Software process improvement in small and agile organizations is often problematic, but achieving good SPI-assessments can still be necessary to stay in the marked or to meet demands of multinational owners. The traditional norm driven, centralized and control centered improvement approaches has...

  15. Improved Strategic Planning

    Science.gov (United States)

    1966-04-08

    to analyze the difficulties of providing improved strategic planning needed for more orderly progress in human affairs. This analysis consists of an...identification of important conceptual difficulties which stand in the way of improving strategic planning . This thesis concludes that it is necessary

  16. Teamwork Improves Office Climate.

    Science.gov (United States)

    Winck, Susan K.

    1993-01-01

    The Smeal College of Business Administration at the Pennsylvania State University selected its advising center as the pilot unit for a continuous quality improvement project using Total Quality Management principles. It was found that a quality improvement culture evolves when team practices are carried into the everyday office environment.…

  17. Continuous Personal Improvement.

    Science.gov (United States)

    Emiliani, M. L.

    1998-01-01

    Suggests that continuous improvement tools used in the workplace can be applied to self-improvement. Explains the use of such techniques as one-piece flow, kanban, visual controls, and total productive maintenance. Points out misapplications of these tools and describes the use of fishbone diagrams to diagnose problems. (SK)

  18. Improving College Teaching.

    Science.gov (United States)

    Seldin, Peter; And Others

    This volume contains 20 papers providing practical, ready-to-use, research-based information to foster effective college teaching. Four sections group the papers under the following topics: (1) key influences on teaching quality; (2) programs to improve teaching; (3) strategies for teaching improvement; and (4) approaches to nontraditional…

  19. Improving your oral English

    Institute of Scientific and Technical Information of China (English)

    Kylafree

    2005-01-01

    The most common question my students ask is ""How can I improve my oral English?"" My answer is always the same: practice. There is no quick way to learn another language. You cannot magically learn new words and have perfect pronunciation. The only way to improve is with practice and patience.

  20. Continuous Personal Improvement.

    Science.gov (United States)

    Emiliani, M. L.

    1998-01-01

    Suggests that continuous improvement tools used in the workplace can be applied to self-improvement. Explains the use of such techniques as one-piece flow, kanban, visual controls, and total productive maintenance. Points out misapplications of these tools and describes the use of fishbone diagrams to diagnose problems. (SK)

  1. Improved nonlinear prediction method

    Science.gov (United States)

    Adenan, Nur Hamiza; Md Noorani, Mohd Salmi

    2014-06-01

    The analysis and prediction of time series data have been addressed by researchers. Many techniques have been developed to be applied in various areas, such as weather forecasting, financial markets and hydrological phenomena involving data that are contaminated by noise. Therefore, various techniques to improve the method have been introduced to analyze and predict time series data. In respect of the importance of analysis and the accuracy of the prediction result, a study was undertaken to test the effectiveness of the improved nonlinear prediction method for data that contain noise. The improved nonlinear prediction method involves the formation of composite serial data based on the successive differences of the time series. Then, the phase space reconstruction was performed on the composite data (one-dimensional) to reconstruct a number of space dimensions. Finally the local linear approximation method was employed to make a prediction based on the phase space. This improved method was tested with data series Logistics that contain 0%, 5%, 10%, 20% and 30% of noise. The results show that by using the improved method, the predictions were found to be in close agreement with the observed ones. The correlation coefficient was close to one when the improved method was applied on data with up to 10% noise. Thus, an improvement to analyze data with noise without involving any noise reduction method was introduced to predict the time series data.

  2. Improvement on GM models

    Institute of Scientific and Technical Information of China (English)

    党耀国; 刘思峰; 刘斌

    2004-01-01

    Since grey system theory was established by prof. Deng, GM models and their improvements have all taken the first vector of the original sequence as the initialization, which resulted to deficiency in making use of the latest infor-mation. Based on the principle, which new information should be used fully, we think it is scientific to pay more atten-tion to the new information or endow them a more weigh. So, this paper deals with the GM improvement by taking the n-th vector as the initialization, and gets great improvement in forecasting precision. Last, we validate the practicability and reliability of the moelds with examples.

  3. IMPROVING CONCEPTUAL DESIGN QUALITY

    DEFF Research Database (Denmark)

    Bush, Stuart; Robotham, Antony John

    1999-01-01

    This paper will consider how Quality Function Deployment (QFD) and Design for Manufacture and Assembly (DFMA) processes can be used to improve the design quality of products at the concept stage. We appreciate that both QFD and DFMA are techniques that have been used for some time by mature product...... quality is maintained in design project work. The projects described have been carried out with products manufactured by small to medium sized enterprises (SME's), where we have found significant opportunities for product improvement. The quantitative nature of DFMA analysis results allows the novice...... for continuous improvement of their products. However, we consider that if novice designers are able to successfully utilise design tools like QFD and DFMA and achieve improvements in design quality, then SME’s have no excuses for ignoring the benefits they could bring to their own product development activity....

  4. Improving combustion efficiency

    Energy Technology Data Exchange (ETDEWEB)

    Bulsari, A.; Wemberg, A.; Multas, A. [Nonlinear Solutions Oy (Finland)

    2009-06-15

    The paper describes how nonlinear models are used to improve the efficiency of coal combustion while keeping NOx and other emissions under desired limits in the Naantali 2 boiler of Fortum Power and Heat Oy. 16 refs., 6 figs.

  5. Improved Mass Spectrometer Project

    Data.gov (United States)

    National Aeronautics and Space Administration — The Improved Mass Spectrometer project will develop system requirements and analyze the path to space qualification.   The results of this project...

  6. Improving wetland mapping techniques

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Mapping wetland extent, structure and invasives using radar imagery. Acquiring optical, thermal, LIDAR, and RADAR images and analysis for improved wetland mapping,...

  7. Improved inverted Stepanov apparatus

    Science.gov (United States)

    Berkman, S.; Temple, H. E.

    1979-01-01

    Modifications in inverted Stepanov process improve heat transfer and energy efficiency in growing silicon ribbon crystals. Using system, silicon is directly heated by induction, minimizing heat transfer and contamination problems.

  8. (IITA) Improved Spear Grass

    African Journals Online (AJOL)

    SproDell

    sourced herbicides from open markets, 98.3% perceived that the cost of herbicides ... satisfied with the operation of 6 out of 12 project activities. The study .... need for extension organizations/agents to improve the effectiveness of extension.

  9. Improving Family Communications

    Science.gov (United States)

    ... Spread the Word Shop AAP Find a Pediatrician Family Life Medical Home Family Dynamics Adoption & Foster Care ... Listen Español Text Size Email Print Share Improving Family Communications Page Content Article Body How can I ...

  10. KAIZEN CONTINUOUS IMPROVEMENT

    OpenAIRE

    Yenque D., Julio; Universidad Nacional Mayor de San Marcos; García P., Manuel; Universidad Nacional Mayor de San Marcos; Raez G., Luis; Universidad Nacional Mayor de San Marcos

    2014-01-01

    Many times we ask the question why Japanese companies are competitive?, Surely many of the answers to this mystery have support in the Kaizen. And the Kaizen is not a simple concept, it is a whole way of life that involves both managers and workers in the pursuit of progressive improvement of enterprises. In his book Kaizen, The Key to Japanese Competitive Advantage, Masaaki Imai explains in simple terms what is the essence of this philosophy: Kaizen means improvement means further progressiv...

  11. Improvement of plastic properties

    OpenAIRE

    D. Manas; Manas, M.; Stanek, M.; Daněk, M. (Michal)

    2008-01-01

    Purpose: of this paper is to present the results of research programme on improve polymer materials properties by irradiation. This method can be helpful in improving some of mechanical properties and thermal stability of polymers.Design/methodology/approach: Radiation processing involves the use of natural or man-made sources of high energy radiation on an industrial scale. The principle of the radiation processing is the ability of the high energy radiation to produce reactive cations, anio...

  12. Proposal Improvements That Work

    Science.gov (United States)

    Dunn, F.

    1998-01-01

    Rocketdyne Propulsion and Power, an operating location of Boeing in Canoga Park, California is under contract with NASA's Marshall Space Flight Center (MSFC) in Huntsville, Alabama for design, development, production, and mission support of Space Shuttle Main Engines (SSMEs). The contract was restructured in 1996 to emphasize a mission contracting environment under which Rocketdyne supports the Space Transportation System launch manifest of seven flights a year without the need for a detailed list of contract deliverables such as nozzles, turbopumps, and combustion devices. This contract structure is in line with the overall Space Shuttle program goals established by the NASA to fly safely, meet the flight manifest, and reduce cost. Rocketdyne's Contracts, Pricing, and Estimating team has worked for the past several years with representatives from MSFC, the local Defense Contract Management Command, and the DCAA to improve the quality of cost proposals to MSFC for contract changes on the SSME. The contract changes on the program result primarily from engineering change proposals for product enhancements to improve safety, maintainability, or operability in the space environment. This continuous improvement team effort has been successful in improving proposal quality, reducing cycle time, and reducing cost. Some of the principal lessons learned are highlighted here to show how proposal improvements can be implemented to enhance customer satisfaction and ensure cost proposals can be evaluated easily by external customers.

  13. Improving Healthcare Logistics Processes

    DEFF Research Database (Denmark)

    Feibert, Diana Cordes

    provision whilst providing high quality care. Logistics activities in hospitals provide a significant opportunity for cost containment in healthcare through the implementation of best practices. Literature provides little guidance on how to improve healthcare logistics processes. This study investigates......Healthcare costs are increasing due to an ageing population and more sophisticated technologies and treatments. At the same time, patients expect high quality care at an affordable cost. The healthcare industry has therefore experienced increasing pressures to reduce the cost of healthcare...... logistics processes in hospitals and aims to provide theoretically and empirically based evidence for improving these processes to both expand the knowledge base of healthcare logistics and provide a decision tool for hospital logistics managers to improve their processes. Case studies were conducted...

  14. Improving Precision of Types

    DEFF Research Database (Denmark)

    Winther, Johnni

    Types in programming languages provide a powerful tool for the programmer to document the code so that a large aspect of the intent can not only be presented to fellow programmers but also be checked automatically by compilers. The precision with which types model the behavior of programs...... is crucial to the quality of these automated checks, and in this thesis we present three different improvements to the precision of types in three different aspects of the Java programming language. First we show how to extend the type system in Java with a new type which enables the detection of unintended...... mixing of unrelated types. Secondly, we present an improvement of the type checking algorithm in Java which enables the compiler to detect and ease the use of a common programming idiom called guarded casts. Thirdly, we present an improvement of the precision with which classes generated by a parser...

  15. Imitation improves language comprehension.

    Science.gov (United States)

    Adank, Patti; Hagoort, Peter; Bekkering, Harold

    2010-12-01

    Humans imitate each other during social interaction. This imitative behavior streamlines social interaction and aids in learning to replicate actions. However, the effect of imitation on action comprehension is unclear. This study investigated whether vocal imitation of an unfamiliar accent improved spoken-language comprehension. Following a pretraining accent comprehension test, participants were assigned to one of six groups. The baseline group received no training, but participants in the other five groups listened to accented sentences, listened to and repeated accented sentences in their own accent, listened to and transcribed accented sentences, listened to and imitated accented sentences, or listened to and imitated accented sentences without being able to hear their own vocalizations. Posttraining measures showed that accent comprehension was most improved for participants who imitated the speaker's accent. These results show that imitation may aid in streamlining interaction by improving spoken-language comprehension under adverse listening conditions.

  16. Abuse Tolerance Improvements

    Energy Technology Data Exchange (ETDEWEB)

    Orendorff, Christopher J. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Nagasubramanian, Ganesan [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Fenton, Kyle R. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Allcorn, Eric [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2015-10-01

    As lithium-ion battery technologies mature, the size and energy of these systems continues to increase (> 50 kWh for EVs); making safety and reliability of these high energy systems increasingly important. While most material advances for lithium-ion chemistries are directed toward improving cell performance (capacity, energy, cycle life, etc.), there are a variety of materials advancements that can be made to improve lithium-ion battery safety. Issues including energetic thermal runaway, electrolyte decomposition and flammability, anode SEI stability, and cell-level abuse tolerance continue to be critical safety concerns. This report highlights work with our collaborators to develop advanced materials to improve lithium-ion battery safety and abuse tolerance and to perform cell-level characterization of new materials.

  17. GPS Control Segment Improvements

    Science.gov (United States)

    2015-04-29

    Systems Center GPS Control Segment Improvements Mr. Tim McIntyre GPS Product Support Manager GPS Ops Support and Sustainment Division Peterson...DATE 29 APR 2015 2. REPORT TYPE 3. DATES COVERED 00-00-2015 to 00-00-2015 4. TITLE AND SUBTITLE GPS Control Segment Improvements 5a. CONTRACT...ORGANIZATION NAME(S) AND ADDRESS(ES) Air Force Space Command,Space and Missile Systems Center, GPS Ops Support and Sustainment Division,Peterson AFB,CO,80916 8

  18. An improved variational method

    Institute of Scientific and Technical Information of China (English)

    ZENG Zhuo-Quan; SHEN Peng-Nian; DING Yi-Bing

    2009-01-01

    In order to improve the unitarity of the S-matrix, an improved variational formulism is derived by proposing new generating functionals and adopting proper asymptotic boundary conditions for trial relative wave functions. The formulas with the weighted line-column balance for the single-channel and multi-channel scatterings, where the non-central interaction is implicitly considered, are presented. A numerical check is performed with a soluble model in a four coupled channel scattering problem. The result shows that the high accuracy and the unitarity of the S-matrix are reached.

  19. Improving designer productivity

    Science.gov (United States)

    Hill, Gary C.

    1992-01-01

    Designer and design team productivity improves with skill, experience, and the tools available. The design process involves numerous trials and errors, analyses, refinements, and addition of details. Computerized tools have greatly speeded the analysis, and now new theories and methods, emerging under the label Artificial Intelligence (AI), are being used to automate skill and experience. These tools improve designer productivity by capturing experience, emulating recognized skillful designers, and making the essence of complex programs easier to grasp. This paper outlines the aircraft design process in today's technology and business climate, presenting some of the challenges ahead and some of the promising AI methods for meeting those challenges.

  20. Improve your communication skills

    CERN Document Server

    Barker, Alan

    2016-01-01

    Excellent communication skills are vital in today's workplace. Whether keeping the interest of a large audience, impressing a potential employer or simply winning the argument at an important meeting, sounding the part is key. This fourth edition of Improve Your Communication Skills is full of practical advice on all aspects of verbal and non-verbal communication. It gives vital tips on improving conversations and building rapport with colleagues, learning the skills of persuasion, and writing effective emails, letters and reports. This editionincludes new information focusing on communicating across borders and virtual teams and a new chapter on managing difficult conversations."

  1. Nuclear energy efficiency improvements

    Energy Technology Data Exchange (ETDEWEB)

    Lauritzen, B.; Nonboel, E. [Technical Univ. of Denmark. DTU Nutech, Roskilde (Denmark); Kyrki-Rajamaeki, R. [Lappeenranta Univ. of Technology (Finland)

    2012-11-15

    Nuclear energy already today plays an important role in decarbonisation of the electricity sector while providing energy security and being economically competitive. Nuclear energy is characterized by its very high energy density and is well suited for large-scale, baseload electricity supply. Similar to renewable energy sources such as wind, solar or biomass, nuclear power is characterized by an abundant supply of its primary energy source, uranium, but is not limited to the same extent as these renewable energy sources from being an intermittent energy supply or imposing severe restrictions on land-use. Improving energy efficiency of nuclear power plants has contributed to a better utilization of the uranium resources and has helped improving the economic performance of nuclear power plants. This is to a large degree accomplished through optimisation of nuclear fuel assemblies as well as renewing turbines and generators. More importantly however, the overall economy of nuclear power has improved though better plant management leading to higher capacity factors and by extending the lifetimes of existing nuclear power plants. Provided that improved safety, economics and successful waste management can be demonstrated nuclear power is likely to grow in the future. Non-electricity applications may further boost the growth of nuclear energy, especially with the development of new reactor systems allowing for cogeneration of electricity and hydrogen or biofuels for transport. (Author)

  2. Software Process Improvement

    DEFF Research Database (Denmark)

    Kuhrmann, Marco; Diebold, Philipp; Münch, Jürgen

    2016-01-01

    Software process improvement (SPI) is around for decades: frameworks are proposed, success factors are studied, and experiences have been reported. However, the sheer mass of concepts, approaches, and standards published over the years overwhelms practitioners as well as researchers. What is out...

  3. Improving Software Developer's Competence

    DEFF Research Database (Denmark)

    Abrahamsson, Pekka; Kautz, Karlheinz; Sieppi, Heikki

    2002-01-01

    Emerging agile software development methods are people oriented development approaches to be used by the software industry. The personal software process (PSP) is an accepted method for improving the capabilities of a single software engineer. Five original hypotheses regarding the impact...

  4. Improve Your BIM Effectiveness

    OpenAIRE

    Boeykens, Stefan

    2013-01-01

    Do you want to improve your firm’s use of BIM during the early design phases? Here are ten tips, applicable in most BIM applications, based on experience gathered from teaching, researching, and using BIM software. Share these with your project teams!

  5. Keeping Improvement in Mind

    Science.gov (United States)

    Mielke, Paul; Frontier, Tony

    2012-01-01

    Like high-stakes student assessment, high-stakes teacher evaluation threatens to be an occasional event that is disconnected from day-to-day teaching and learning, producing results that do not help teachers improve their performance and placing teachers in a passive role as recipients of external judgment. For several years, the authors have…

  6. Improving Teachers' Verbal Skills.

    Science.gov (United States)

    Albrecht, Kay

    1992-01-01

    Suggests strategies center directors can use to improve teachers' verbal interactions with children. Directors can help teachers (1) understand child growth and development; (2) understand that what they say matters; (3) hear themselves talking to children; and (4) develop their observation skills. Directors can also share good models with…

  7. Imitation improves language comprehension

    NARCIS (Netherlands)

    Adank, P.M.; Hagoort, P.; Bekkering, H.

    2010-01-01

    Humans imitate each other during social interaction. This imitative behavior streamlines social interaction and aids in learning to replicate actions. However, the effect of imitation on action comprehension is unclear. This study investigated whether vocal imitation of an unfamiliar accent improved

  8. Software Process Improvement

    DEFF Research Database (Denmark)

    Kuhrmann, Marco; Konopka, Claudia; Nellemann, Peter

    2016-01-01

    Software process improvement (SPI) is around for decades: frameworks are proposed, success factors are studied, and experiences have been reported. However, the sheer mass of concepts, approaches, and standards published over the years overwhelms practitioners as well as researchers. What is out...

  9. Improving Software Developer's Competence

    DEFF Research Database (Denmark)

    Abrahamsson, Pekka; Kautz, Karlheinz; Sieppi, Heikki

    2002-01-01

    Emerging agile software development methods are people oriented development approaches to be used by the software industry. The personal software process (PSP) is an accepted method for improving the capabilities of a single software engineer. Five original hypotheses regarding the impact...

  10. Cave Dwellers’ Lives Improved

    Institute of Scientific and Technical Information of China (English)

    1994-01-01

    IN the Loess Plateau of northern Shaanxi. there are many gullies but little rain, which has deeply affected the growth of crops there. People have been living under hard conditions for generations until very recently. The State government has encouraged rural economic policies which has enabled the people of this area to develop a diversified economy that has greatly improved life.

  11. Improving Communication in Design

    DEFF Research Database (Denmark)

    Maier, Anja; Doenmez, Denniz; Hepperle, Clemens

    2011-01-01

    Communication permeates every aspect of an engineer’s work – from clarifying product specifications to shaping social ties. This paper offers an overview of recommendations from literature to improve communication within and among engineering teams. We assume communication problems are often...

  12. MCNP Progress & Performance Improvements

    Energy Technology Data Exchange (ETDEWEB)

    Brown, Forrest B. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Bull, Jeffrey S. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Rising, Michael Evan [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2015-04-14

    Twenty-eight slides give information about the work of the US DOE/NNSA Nuclear Criticality Safety Program on MCNP6 under the following headings: MCNP6.1.1 Release, with ENDF/B-VII.1; Verification/Validation; User Support & Training; Performance Improvements; and Work in Progress. Whisper methodology will be incorporated into the code, and run speed should be increased.

  13. Sulfur recovery further improved

    Energy Technology Data Exchange (ETDEWEB)

    Borsboom, J.; Grinsven, M. van; Warners, A. van [Jacobs Nederland B.V., (Netherlands); Nisselrooy, P. van [Gastec N.V., (Netherlands)

    2002-04-01

    The original 100-year-old Claus process for producing sulfur from hydrogen sulfide in acid gas is described together with improvements which have been made over the years. The most recent modification, EUROCLAUS, achieves sulfur recoveries of 99-99.9 per cent. Five commercial units are being designed.

  14. Globalisation, Effectiveness and Improvement.

    Science.gov (United States)

    Mortimore, Peter

    This paper reports principally on two studies, prompted by research on school effectiveness in the United States and England, which indicate globalization is beginning to affect school improvement. The first study cites case studies of two schools--from working-class, multi-ethnic, poorly educated areas of Singapore and London--to determine if…

  15. Improving Attitudes Toward Reading.

    Science.gov (United States)

    Dean, Stephanie J.; Trent, Jane A.

    This report describes a program for improving students' attitudes toward reading. The targeted population consisted of second and third grade students in a growing middle class community. The problem of the lack of interest in reading and the poor quality of classroom work were evident in parent and student surveys, and teacher observations.…

  16. Improvements in agricultural sciences

    Science.gov (United States)

    This editorial provides insight on investigations regarding advancements in agri-food quality and testing of eco-friendly organic farming methodologies. The discussion elaborates on the advantages of recent farming techniques and their impact on improved crop yield, crop quality, and minimization of...

  17. Improving Educational Administrative Decisions.

    Science.gov (United States)

    Wolfe, A. E.

    This paper discusses the financial crisis facing public education in the United States today and argues that the most effective response to this crisis is to improve the decision-making skills of educational administrators. Based on a review of the literature on administrative decision-making and organizational change, the author examines several…

  18. Room for Improvement

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    With an 8-percent growth rate all but secured, China needs to focus more on improving the quality of its economic growth China experienced a successful economic rebound in 2009, thanks to the government’s mobilization of resources to support the growth.

  19. Improved reservoir exploitation

    Energy Technology Data Exchange (ETDEWEB)

    Thomassen, P.R. [IKU Petroleumsforskning A/S, Trondheim (Norway)

    1996-12-31

    This paper deals with reservoir exploitation and it highlights some ideas on how to improve exploitive skills to optimise the recovery of a field. The author looks closer at what needs to be done to optimise the reservoir data and the exploitation tools, and what are the needs of the reservoir production management. 2 refs., 3 figs.

  20. Improving machinery reliability

    CERN Document Server

    Bloch, Heinz P

    1998-01-01

    This totally revised, updated and expanded edition provides proven techniques and procedures that extend machinery life, reduce maintenance costs, and achieve optimum machinery reliability. This essential text clearly describes the reliability improvement and failure avoidance steps practiced by best-of-class process plants in the U.S. and Europe.

  1. Driving collaborative improvement processes

    NARCIS (Netherlands)

    Middel, Rick; Gieskes, José; Fisscher, Olaf

    2002-01-01

    Continuous Improvement is a consolidated concept in theory and practice, mainly in the context of stand-alone companies. However, the battlefield of competition is increasingly moving from the level of individual firms to that of organisational settings based on loose company boundaries and collabor

  2. Driving collaborative improvement processes

    NARCIS (Netherlands)

    Middel, R.; Gieskes, J.; Fisscher, O.

    2005-01-01

    Continuous improvement is a consolidated concept in theory and practice, mainly in the context of stand-alone companies. However, the battlefield of competition is increasingly moving from the level of individual firms to that of organizational settings based on loose company boundaries and collabor

  3. Process Improvement: Customer Service.

    Science.gov (United States)

    Cull, Donald

    2015-01-01

    Utilizing the comment section of patient satisfaction surveys, Clark Memorial Hospital in Jeffersonville, IN went through a thoughtful process to arrive at an experience that patients said they wanted. Two Lean Six Sigma tools were used--the Voice of the Customer (VoC) and the Affinity Diagram. Even when using these tools, a facility will not be able to accomplish everything the patient may want. Guidelines were set and rules were established for the Process Improvement Team in order to lessen frustration, increase focus, and ultimately be successful. The project's success is driven by the team members carrying its message back to their areas. It's about ensuring that everyone is striving to improve the patients' experience by listening to what they say is being done right and what they say can be done better. And then acting on it.

  4. IMPROVING PATIENT SAFETY:

    DEFF Research Database (Denmark)

    Bagger, Bettan; Taylor Kelly, Hélène; Hørdam, Britta

    2013-01-01

    Every year millions of patients worldwide suffer injury or death due to unsafe care, thus improving patient safety is both a national and international priority. A developmental project involving University College Zealand and clinical partners in the region focused upon the improvement of patient...... safety by optimizing the theory-practice connection with respect to the development of students’ competencies and the reporting of clinical errors. Population: 2nd year nursing students at University College Zealand (N: 56). Informed consent and full anonymity. Aims: - To increase patient safety...... errors. An interesting finding though is that despite the legal requirements concerning the mandatory reporting of all clinical errors, 37% of the students participating in this study report that they perhaps would be reluctant to report an eventual clinical error. Further initiatives are thus necessary...

  5. Improving Communication in Design

    DEFF Research Database (Denmark)

    Maier, Anja; Doenmez, Denniz; Hepperle, Clemens

    2011-01-01

    the outcome of underlying factors and that it is fruitful to study and improve these influences. Having been empirically elicited in prior research, 24 factors considered in this paper include, e.g., availability of information about product specifications, roles and responsibilities, and overview of sequence...... of tasks. To improve these factors in order to enable effective communication, this paper collates more than hundred recommendations from journal articles and textbooks published in the fields of engineering design, management science, sociology, and psychology. Recommendations include, for example......, identify priorities through risk and bottleneck analysis, give clear descriptions and role expectations, and employ effective process modeling tools. Contributions of this paper are a list of recommendations for industry practitioners and an effort-benefit evaluation of individual recommendations....

  6. IMPROVING PATIENT SAFETY:

    DEFF Research Database (Denmark)

    Bagger, Bettan; Taylor Kelly, Hélène; Hørdam, Britta

    2013-01-01

    , social and cultural factors have resulted in a greater emphasis upon digital technology. Attempts to improve patient safety by optimizing students’ competencies in relation to the reporting of clinical errors, has resulted in the development of an interdisciplinary e-learning concept. The program makes......Improving patient safety is both a national and international priority as millions of patients Worldwide suffer injury or death every year due to unsafe care. University College Zealand employs innovative pedagogical approaches in educational design. Regional challenges related to geographic...... it possible for the students to train and test their knowledge and understanding independent of time and place. Data accumulated from the e-learning program will be used to further develop digital learning initiatives....

  7. Diversification improves interpolation

    CERN Document Server

    Giesbrecht, Mark

    2011-01-01

    We consider the problem of interpolating an unknown multivariate polynomial with coefficients taken from a finite field or as numerical approximations of complex numbers. Building on the recent work of Garg and Schost, we improve on the best-known algorithm for interpolation over large finite fields by presenting a Las Vegas randomized algorithm that uses fewer black box evaluations. Using related techniques, we also address numerical interpolation of sparse complex polynomials, and provide the first provably stable algorithm (in the sense of relative error) for this problem, at the cost of modestly more interpolation points. A key new technique is a randomization which makes all coefficients of the unknown polynomial distinguishable, producing what we call a diverse polynomial. Another departure of our algorithms from most previous approaches is that they do not rely on root finding as a subroutine. We show how these improvements affect the practical performance with trial implementations.

  8. Measuring to improve.

    Science.gov (United States)

    Klein, R; Bobbitt, M

    1995-01-01

    Rush Prudential Health Plans, a managed care company located in Chicago, Illinois, is implementing a service quality improvement process across the three products it markets in the Chicago area: The Anchor Plan (a primarily staff model HMO), The Affiliates Plan (a network model HMO), and The Plus Plan (a point of service plan). In 1994, the company instituted an annual member satisfaction research study, conducted across the three plans, and began building a link between external customer requirements and internal operations. The research process consisted of three stages: determining external customer requirements, translating these customer-defined "symptoms" into underlying root causes, and developing a service quality improvement action plan. Rush Prudential determined that traditional "report card" surveys would not meet their goals for the information measurement process. A detailed diagnostic telephone survey was used to provide a picture of the entire clinical encounter, from scheduling an appointment through the time a member left the physician's office.

  9. IMPROVING ENGLISH TEACHER TALK

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Research shows teachers’speaking less so involvesstudents more.So English teacher talk determines tosome extent whether the teaching is successful or not.After giving a brief introduction to teacher talk inEnglish class,this paper analyzes the possible factorsthat affect teacher talk.It then suggests some im-provements of teacher talk in order to better our teach-ing methodology.

  10. Improve your reading

    CERN Document Server

    Fry, Ron

    2012-01-01

    Help your students discover the practical solution to their reading frustrations, with Improve Your Reading. Written by bestselling author and education advocate Ron Fry, this book avoids gimmicks and tricks in favor of proven strategies that will help your students better retain and comprehend what they've read in any textbook, in any course, at any academic level. Endlessly adaptable to each student's individual learning needs, the text focuses on fundamental skills students can carry beyond the classroom.

  11. Improved Adaptive Fingerprint Binarization

    OpenAIRE

    Bartunek, Josef Ström; Nilsson, Mikael; Nordberg, Jörgen; Claesson, Ingvar

    2008-01-01

    In this paper improvements to a previous work are presented. Removing the redundant artifacts in the fingerprint mask is introduced enhancing the final result. The proposed method is entirely adaptive process adjusting to each fingerprint without any further supervision of the user. Hence, the algorithm is insensitive to the characteristics of the fingerprint sensor and the various physical appearances of the fingerprints. Further, a detailed description of fingerprint mask generation not ful...

  12. Improving Carbon Fixation Pathways

    OpenAIRE

    Ducat, Daniel C.; Silver, Pamela A

    2012-01-01

    A recent resurgence in basic and applied research on photosynthesis has been driven in part by recognition that fulfilling future food and energy requirements will necessitate improvements in crop carbon-fixation efficiencies. Photosynthesis in traditional terrestrial crops is being reexamined in light of molecular strategies employed by photosynthetic microbes to enhance the activity of the Calvin cycle. Synthetic biology is well-situated to provide original approaches for compartmentalizing...

  13. MEMORY IMPROVING FOODS

    Directory of Open Access Journals (Sweden)

    Akula Annapurna

    2013-09-01

    Full Text Available Learning is a lifelong process of transforming information and experience into knowledge, skills, behaviorand attitudes. Memory is the ability of the brain to store, retain and subsequently to recall information received fromthe world. Cognition can be defined as organization of information. It includes acquiring information (perception,selecting (attention, representing (understanding and retaining (memory information and using it to guidebehavior (reasoning and coordination of motor outputs.There are so many conditions associated with memory and cognitive impairment which include Aging,Alzheimer’s disease, Stroke, Stress, Head injuries, Seizures, Benzodiazepines, Brain tumors, Depression, Temporallobe defects and Schizophrenia etc.Choline rich foods can enhance memory and learning and may be useful in improving cognitive abilities. Theseinclude sea foods, liver, egg yolk, soysbeans, broccoli, ash gourd. Coloured fruits and vegetables are good source ofantioxidants which improve concentration. It is advised to decrease the consumption of foods rich in transfats likehydrogenated oils, fried foods, beef, pork, mutton and ice creams and pastries. Such foods increase the deposition offats in the neurons and impair cognition. Tea, cocoa and turmeric are reported to have good nootropic activity i.e.improving memory and learning. Apart from the foods, one should keep the brain active to maintain its cognitivefunction well.

  14. Improved Marine Waters Monitoring

    Science.gov (United States)

    Palazov, Atanas; Yakushev, Evgeniy; Milkova, Tanya; Slabakova, Violeta; Hristova, Ognyana

    2017-04-01

    IMAMO - Improved Marine Waters Monitoring is a project under the Programme BG02: Improved monitoring of marine waters, managed by Bulgarian Ministry of environment and waters and co-financed by the Financial Mechanism of the European Economic Area (EEA FM) 2009 - 2014. Project Beneficiary is the Institute of oceanology - Bulgarian Academy of Sciences with two partners: Norwegian Institute for Water Research and Bulgarian Black Sea Basin Directorate. The Project aims to improve the monitoring capacity and expertise of the organizations responsible for marine waters monitoring in Bulgaria to meet the requirements of EU and national legislation. The main outcomes are to fill the gaps in information from the Initial assessment of the marine environment and to collect data to assess the current ecological status of marine waters including information as a base for revision of ecological targets established by the monitoring programme prepared in 2014 under Art. 11 of MSFD. Project activities are targeted to ensure data for Descriptors 5, 8 and 9. IMAMO aims to increase the institutional capacity of the Bulgarian partners related to the monitoring and assessment of the Black Sea environment. The main outputs are: establishment of real time monitoring and set up of accredited laboratory facilities for marine waters and sediments chemical analysis to ensure the ability of Bulgarian partners to monitor progress of subsequent measures undertaken.

  15. MDSplus quality improvement project

    Energy Technology Data Exchange (ETDEWEB)

    Fredian, Thomas W., E-mail: twf@psfc.mit.edu [Massachusetts Institute of Technology, 175 Albany Street, Cambridge, MA 02139 (United States); Stillerman, Joshua [Massachusetts Institute of Technology, 175 Albany Street, Cambridge, MA 02139 (United States); Manduchi, Gabriele; Rigoni, Andrea [Consorzio RFX, Euratom-ENEA Association, Corso Stati Uniti 4, Padova 35127 (Italy); Erickson, Keith [Princeton Plasma Physics Laboratory, Princeton, NJ 08543 (United States)

    2016-11-15

    Highlights: • Project to improve the quality of the MDSplus software package. • Use of modern software technology, compiler options, automake. • Refactoring of older code. • Use of testing tools. - Abstract: MDSplus is a data acquisition and analysis system used worldwide predominantly in the fusion research community. Development began 29 years ago on the OpenVMS operating system. Since that time there have been many new features added and the code has been ported to many different operating systems. There have been contributions to the MDSplus development from the fusion community in the way of feature suggestions, feature implementations, documentation and porting to different operating systems. The bulk of the development and support of MDSplus, however, has been provided by a relatively small core developer group of three or four members. Given the size of the development team and the large number of users much more effort was focused on providing new features for the community than on keeping the underlying code and documentation up to date with the evolving software development standards. To ensure that MDSplus will continue to provide the needs of the community in the future, the MDSplus development team along with other members of the MDSplus user community has commenced on a major quality improvement project. The planned improvements include changes to software build scripts to better use GNU Autoconf and Automake tools, refactoring many of the source code modules using new language features available in modern compilers, using GNU MinGW-w64 to create MS Windows distributions, migrating to a more modern source code management system, improvement of source documentation as well as improvements to the (www.mdsplus.org) web site documentation and layout, and the addition of more comprehensive test suites to apply to MDSplus code builds prior to releasing installation kits to the community. This work should lead to a much more robust product and

  16. Improved flywheel materials :

    Energy Technology Data Exchange (ETDEWEB)

    Boyle, Timothy J.; Bell, Nelson S; Ehlen, Mark Andrew; Anderson, Benjamin John; Miller, William Kenneth

    2013-09-01

    As alternative energy generating devices (i.e., solar, wind, etc) are added onto the electrical energy grid (AC grid), irregularities in the available electricity due to natural occurrences (i.e., clouds reducing solar input or wind burst increasing wind powered turbines) will be dramatically increased. Due to their almost instantaneous response, modern flywheel-based energy storage devices can act a mechanical mechanism to regulate the AC grid; however, improved spin speeds will be required to meet the necessary energy levels to balance these green energy variances. Focusing on composite flywheels, we have investigated methods for improving the spin speeds based on materials needs. The so-called composite flywheels are composed of carbon fiber (C-fiber), glass fiber, and a glue (resin) to hold them together. For this effort, we have focused on the addition of fillers to the resin in order to improve its properties. Based on the high loads required for standard meso-sized fillers, this project investigated the utility of ceramic nanofillers since they can be added at very low load levels due to their high surface area. The impact that TiO2 nanowires had on the final strength of the flywheel material was determined by a three-point-bend test. The results of the introduction of nanomaterials demonstrated an increase in strength of the flywheels C-fiber-resin moiety, with an upper limit of a 30% increase being reported. An analysis of the economic impact concerning the utilization of the nanowires was undertaken and after accounting for new-technology and additional production costs, return on improved-nanocomposite investment was approximated at 4-6% per year over the 20-year expected service life. Further, it was determined based on the 30% improvement in strength, this change may enable a 20-30% reduction in flywheel energy storage cost ($/kW-h).

  17. Improving ATLAS reprocessing software

    CERN Document Server

    Novak, Tadej

    2014-01-01

    For my CERN Summer Student programme I have been working with ATLAS reprocessing group. Data taken at ATLAS experiment is not only processed after being taken, but is also reprocessed multiple times afterwards. This allows applying new alignments, calibration of detector and using improved or faster algorithms. Reprocessing is usually done in campaigns for different periods of data or for different interest groups. The idea of my project was to simplify the definition of tasks and monitoring of their progress. I created a LIST configuration files generator script in Python and a monitoring webpage for tracking current reprocessing tasks.

  18. Software Process Improvement

    DEFF Research Database (Denmark)

    Kuhrmann, Marco; Konopka, Claudia; Nellemann, Peter

    2016-01-01

    Software process improvement (SPI) is around for decades: frameworks are proposed, success factors are studied, and experiences have been reported. However, the sheer mass of concepts, approaches, and standards published over the years overwhelms practitioners as well as researchers. What is out...... directions. An analysis of 635 publications draws a big picture of SPI-related research of the past 25 years. Our study shows a high number of solution proposals, experience reports, and secondary studies, but only few theories. In particular, standard SPI models are analyzed and evaluated for applicability...

  19. Improved Rhenium Thrust Chambers

    Science.gov (United States)

    O'Dell, John Scott

    2015-01-01

    Radiation-cooled bipropellant thrust chambers are being considered for ascent/ descent engines and reaction control systems on various NASA missions and spacecraft, such as the Mars Sample Return and Orion Multi-Purpose Crew Vehicle (MPCV). Currently, iridium (Ir)-lined rhenium (Re) combustion chambers are the state of the art for in-space engines. NASA's Advanced Materials Bipropellant Rocket (AMBR) engine, a 150-lbf Ir-Re chamber produced by Plasma Processes and Aerojet Rocketdyne, recently set a hydrazine specific impulse record of 333.5 seconds. To withstand the high loads during terrestrial launch, Re chambers with improved mechanical properties are needed. Recent electrochemical forming (EL-Form"TM") results have shown considerable promise for improving Re's mechanical properties by producing a multilayered deposit composed of a tailored microstructure (i.e., Engineered Re). The Engineered Re processing techniques were optimized, and detailed characterization and mechanical properties tests were performed. The most promising techniques were selected and used to produce an Engineered Re AMBR-sized combustion chamber for testing at Aerojet Rocketdyne.

  20. Software Engineering Improvement Plan

    Science.gov (United States)

    2006-01-01

    In performance of this task order, bd Systems personnel provided support to the Flight Software Branch and the Software Working Group through multiple tasks related to software engineering improvement and to activities of the independent Technical Authority (iTA) Discipline Technical Warrant Holder (DTWH) for software engineering. To ensure that the products, comments, and recommendations complied with customer requirements and the statement of work, bd Systems personnel maintained close coordination with the customer. These personnel performed work in areas such as update of agency requirements and directives database, software effort estimation, software problem reports, a web-based process asset library, miscellaneous documentation review, software system requirements, issue tracking software survey, systems engineering NPR, and project-related reviews. This report contains a summary of the work performed and the accomplishments in each of these areas.

  1. Improved NAIBEA and IFEL

    Science.gov (United States)

    Parsa, Zohreh

    1997-04-01

    The Nonlinear Amplification of Inverse-Bremsstrahlung Electron Acceleration (NAIBEA) and Inverse Free Electron Laser (IFEL), can be enhanced in schemes where the applied fields are changed from the (conventional) sinusoidal patterns to a (new) square wave (with respect to the laser field phase). The effect on IFEL performance using a wiggler that creates a nearly square-wave periodic field pattern results in a gain in energy by as much as two times (equivalent to four times the laser power)(Z. Parsa, New IFEL Experiment Proposal for BNL-ATF Report, 96; Z. Parsa, M. Pato, to be published 97;) when compared with the conventional IFEL with a sinusoidal wiggler. Our result shows similar improvement in the energy gain and particle trajectory for the NAIBEA. The percentage gain in energy is increasd as the field is changed from sinusoidal toward (and to a) square wave pattern. (Z. Parsa, ITP 96; Z. Parsa, T. Marshall, PAC97, to be published 97.)

  2. Improving University Research Value

    Directory of Open Access Journals (Sweden)

    Kelley O’Reilly

    2012-07-01

    Full Text Available This article investigates the current data management practices of university researchers at an Intermountain West land-grant research university in the United States. Key findings suggest that researchers are primarily focused on the collection and housing of research data. However, additional research value exists within the other life cycle stages for research data—specifically in the stages of delivery and maintenance. These stages are where most new demands and requirements exist for data management plans and policies that are conditional for external grant funding; therefore, these findings expose a “gap” in current research practice. These findings should be of interest to academics and practitioners alike as findings highlight key management gaps in the life cycle of research data. This study also suggests a course of action for academic institutions to coalesce campus-wide assets to assist researchers in improving research value.

  3. Room for improvement

    DEFF Research Database (Denmark)

    Storvang, Pia; Dalby, Mette Strømgaard

    2015-01-01

    This paper develops the notion of a project war room as an innovation practice in companies. We argue that the consistent use of a project war room, in which customer and user research serves as a background for design work, improve the quality of product innovation. We describe our experiences...... from a project with four Danish medium-sized manufacturing companies aiming to become more competitive in the European export market. In the project, one challenge was how to convey results from customer interviews and user studies from the researcher team (which in all instances included a company...... manager) to the development team in each company. We chose to collaboratively build a ‘war room’ in each of the companies to make sense of research materials and establish design principles for products that would better align with customer needs....

  4. Improved Lattice Radial Quantization

    CERN Document Server

    Brower, Richard C; Fleming, George T

    2014-01-01

    Lattice radial quantization was proposed in a recent paper by Brower, Fleming and Neuberger[1] as a nonperturbative method especially suited to numerically solve Euclidean conformal field theories. The lessons learned from the lattice radial quantization of the 3D Ising model on a longitudinal cylinder with 2D Icosahedral cross-section suggested the need for an improved discretization. We consider here the use of the Finite Element Methods(FEM) to descretize the universally-equivalent $\\phi^4$ Lagrangian on $\\mathbb R \\times \\mathbb S^2$. It is argued that this lattice regularization will approach the exact conformal theory at the Wilson-Fisher fixed point in the continuum. Numerical tests are underway to support this conjecture.

  5. Wind energy efficiency improvements

    Energy Technology Data Exchange (ETDEWEB)

    Hauge Madsen, P.; Badger, J.; Rasmussen, Flemming; Soerensen, Poul

    2012-11-15

    As we have shown above, wind energy can help to secure energy efficiency in power generation, and research results and tools are being developed that will increase the role of wind energy in the global energy supply. An important instrument is the development of wind turbine technology to reduce capital and operational costs. This has not been the emphasis in this chapter, though; instead we have focused on equally important instruments, namely making best use of the wind resource and available sites, adapting wind farm layout and technology to the increased exploitation of wind, and improving the interaction between wind farms and the power system. With these developments we expect that wind energy can become the backbone of the power system globally and play a major role in creating an efficient and sustainable power system. (Author)

  6. Deceleration Orbit Improvements

    Energy Technology Data Exchange (ETDEWEB)

    Church, M.

    1991-04-26

    During the accelerator studies period of 12/90-1/91 much study time was dedicated to improving the E760 deceleration ramps. 4 general goals were in mind: (1) Reduce the relative orbit deviations from the nominal reference orbit as much as possible. This reduces the potential error in the orbit length calculation - which is the primary source of error in the beam energy calculation. (2) Maximize the transverse apertures. This minimizes beam loss during deceleration and during accidental beam blow-ups. (3) Measure and correct lattice parameters. Knowledge of {gamma}{sub T}, {eta}, Q{sub h}, Q{sub v}, and the dispersion in the straight sections allows for a more accurate energy calculation and reliable SYNCH calculations. (4) Minimize the coupling. This allows one to discern between horizontal and vertical tunes.

  7. Improving Power Converter Reliability

    DEFF Research Database (Denmark)

    Ghimire, Pramod; de Vega, Angel Ruiz; Beczkowski, Szymon

    2014-01-01

    The real-time junction temperature monitoring of a high-power insulated-gate bipolar transistor (IGBT) module is important to increase the overall reliability of power converters for industrial applications. This article proposes a new method to measure the on-state collector?emitter voltage...... of a high-power IGBT module during converter operation, which may play a vital role in improving the reliability of the power converters. The measured voltage is used to estimate the module average junction temperature of the high and low-voltage side of a half-bridge IGBT separately in every fundamental...... is measured in a wind power converter at a low fundamental frequency. To illustrate more, the test method as well as the performance of the measurement circuit are also presented. This measurement is also useful to indicate failure mechanisms such as bond wire lift-off and solder layer degradation...

  8. Improving Pathologists' Communication Skills.

    Science.gov (United States)

    Dintzis, Suzanne

    2016-08-01

    The 2015 Institute of Medicine report on diagnostic error has placed a national spotlight on the importance of improving communication among clinicians and between clinicians and patients [1]. The report emphasizes the critical role that communication plays in patient safety and outlines ways that pathologists can support this process. Despite recognition of communication as an essential element in patient care, pathologists currently undergo limited (if any) formal training in communication skills. To address this gap, we at the University of Washington Medical Center developed communication training with the goal of establishing best practice procedures for effective pathology communication. The course includes lectures, role playing, and simulated clinician-pathologist interactions for training and evaluation of pathology communication performance. Providing communication training can help create reliable communication pathways that anticipate and address potential barriers and errors before they happen.

  9. Improving Metal Casting Process

    Science.gov (United States)

    1998-01-01

    Don Sirois, an Auburn University research associate, and Bruce Strom, a mechanical engineering Co-Op Student, are evaluating the dimensional characteristics of an aluminum automobile engine casting. More accurate metal casting processes may reduce the weight of some cast metal products used in automobiles, such as engines. Research in low gravity has taken an important first step toward making metal products used in homes, automobiles, and aircraft less expensive, safer, and more durable. Auburn University and industry are partnering with NASA to develop one of the first accurate computer model predictions of molten metals and molding materials used in a manufacturing process called casting. Ford Motor Company's casting plant in Cleveland, Ohio is using NASA-sponsored computer modeling information to improve the casting process of automobile and light-truck engine blocks.

  10. Continuous Improvement and Collaborative Improvement: Similarities and Differences

    DEFF Research Database (Denmark)

    Middel, Rick; Boer, Harry; Fisscher, Olaf

    2006-01-01

    A substantial body of theoretical and practical knowledge has been developed on continuous improvement. However, there is still a considerable lack of impirically grounded contributions and theories on collaborative improvement, that is, continuous improvement in an interorganizational setting....... The CO-IMPROVE project investigated whether and how the concept of continuous improvement can be extended and transferred to such settings. The objective of this article is ti evaluate the CO-IMPROVE research findings in view of existing theories on continuous innovation. The article investigates...

  11. Regulatory Streamlining and Improvement

    Energy Technology Data Exchange (ETDEWEB)

    Mark A. Carl

    2006-07-11

    The Interstate Oil and Gas Compact Commission (IOGCC) engaged in numerous projects outlined under the scope of work discussed in the United States Department of Energy (DOE) grant number DE-FC26-04NT15456 awarded to the IOGCC. Numerous projects were completed that were extremely valuable to state oil and gas agencies as a result of work performed utilizing resources provided by the grant. There are numerous areas in which state agencies still need assistance. This additional assistance will need to be addressed under future scopes of work submitted annually to DOE's Project Officer for this grant. This report discusses the progress of the projects outlined under the grant scope of work for the 2005-2006 areas of interest, which are as follows: Area of Interest No. 1--Regulatory Streamlining and Improvement: This area of interest continues to support IOGCC's regulatory streamlining efforts that include the identification and elimination of unnecessary duplications of efforts between and among state and federal programs dealing with exploration and production on public lands. Area of Interest No. 2--Technology: This area of interest seeks to improve efficiency in states through the identification of technologies that can reduce costs. Area of Interest No. 3--Training and Education: This area of interest is vital to upgrading the skills of regulators and industry alike. Within the National Energy Policy, there are many appropriate training and education opportunities. Education was strongly endorsed by the President's National Energy Policy Development group. Acting through the governors offices, states are very effective conduits for the dissemination of energy education information. While the IOGCC favors the development of a comprehensive, long-term energy education plan, states are also supportive of immediate action on important concerns, such as energy prices, availability and conservation. Area of Interest No. 4--Resource Assessment and

  12. Refines Efficiency Improvement

    Energy Technology Data Exchange (ETDEWEB)

    WRI

    2002-05-15

    Refinery processes that convert heavy oils to lighter distillate fuels require heating for distillation, hydrogen addition or carbon rejection (coking). Efficiency is limited by the formation of insoluble carbon-rich coke deposits. Heat exchangers and other refinery units must be shut down for mechanical coke removal, resulting in a significant loss of output and revenue. When a residuum is heated above the temperature at which pyrolysis occurs (340 C, 650 F), there is typically an induction period before coke formation begins (Magaril and Aksenova 1968, Wiehe 1993). To avoid fouling, refiners often stop heating a residuum before coke formation begins, using arbitrary criteria. In many cases, this heating is stopped sooner than need be, resulting in less than maximum product yield. Western Research Institute (WRI) has developed innovative Coking Index concepts (patent pending) which can be used for process control by refiners to heat residua to the threshold, but not beyond the point at which coke formation begins when petroleum residua materials are heated at pyrolysis temperatures (Schabron et al. 2001). The development of this universal predictor solves a long standing problem in petroleum refining. These Coking Indexes have great potential value in improving the efficiency of distillation processes. The Coking Indexes were found to apply to residua in a universal manner, and the theoretical basis for the indexes has been established (Schabron et al. 2001a, 2001b, 2001c). For the first time, a few simple measurements indicates how close undesired coke formation is on the coke formation induction time line. The Coking Indexes can lead to new process controls that can improve refinery distillation efficiency by several percentage points. Petroleum residua consist of an ordered continuum of solvated polar materials usually referred to as asphaltenes dispersed in a lower polarity solvent phase held together by intermediate polarity materials usually referred to as

  13. Efficiency improvements in transport

    Energy Technology Data Exchange (ETDEWEB)

    Schramm, J. [Technical Univ. of Denmark. DTU Mechanical Engineering, Kgs. Lyngby (Denmark); Christensen, Linda; Jensen, Thomas C. [Technical Univ. of Denmark. DTU Transport, Kgs. Lyngby (Denmark)

    2012-11-15

    Transport of people, personal belongings and goods in private cars is fundamental to our modern welfare society and economic growth, and has grown steadily over many decades. Motor fuels have been based almost entirely on crude oil for the last century. During the last couple of decades engines built for traditional fuels have become more advanced and efficient; this has reduced fuel consumption by around 40% and emissions by more than 90%. Only in the same time span have we begun to look at alternatives to fossil fuels. Biofuels such as biodiesel, bioethanol, biomethanol and biogas can replace petrol and diesel, and in recent years algae have shown a new potential for diesel fuel. Natural gas is also becoming an interesting fuel due to its large resources worldwide. GTL, CTL and BTL are liquid fuels produced from solid or gaseous sources. GTL and CTL are expensive to produce and not very CO{sub 2}-friendly, but they are easily introduced and need little investment in infrastructure and vehicles. DME is an excellent fuel for diesel engines. Methanol and DME produced from biomass are among the most CO{sub 2}-reducing fuels and at the same time the most energy-efficient renewable fuels. Fuel cell vehicles (FCVs) are currently fuelled by hydrogen, but other fuels are also possible. There are, however, several barriers to the implementation of fuel cell vehicles. In particular, a hydrogen infrastructure needs to be developed. Electric vehicles (EVs) have the advantage that energy conversion is centralised at the power plant where it can be done at optimum efficiency and emissions. EVs have to be charged at home, and also away from home when travelling longer distances. With an acceptable fast charging infrastructure at least 85% of the one-car families in Denmark could be potential EV customers. Range improvements resulting from better batteries are expected to create a large increase in the number of EVs in Denmark between 2020 and 2030. The hybrid electric vehicle

  14. Improved Search Techniques

    Science.gov (United States)

    Albornoz, Caleb Ronald

    2012-01-01

    Thousands of millions of documents are stored and updated daily in the World Wide Web. Most of the information is not efficiently organized to build knowledge from the stored data. Nowadays, search engines are mainly used by users who rely on their skills to look for the information needed. This paper presents different techniques search engine users can apply in Google Search to improve the relevancy of search results. According to the Pew Research Center, the average person spends eight hours a month searching for the right information. For instance, a company that employs 1000 employees wastes $2.5 million dollars on looking for nonexistent and/or not found information. The cost is very high because decisions are made based on the information that is readily available to use. Whenever the information necessary to formulate an argument is not available or found, poor decisions may be made and mistakes will be more likely to occur. Also, the survey indicates that only 56% of Google users feel confident with their current search skills. Moreover, just 76% of the information that is available on the Internet is accurate.

  15. PESTICIDE APPLICATION TECHNICS IMPROVEMENT

    Directory of Open Access Journals (Sweden)

    Đuro Banaj

    2011-06-01

    Full Text Available The academic textbook Pesticide application tehnics improvement is the result of several-year recording theoretical models, numerous practical tests, and data collection relating to technical systems in plant protection and its environment in the narrowest sense. In this first edition, the authors cover the area they have dealt with for many years. The authors aimed to present complete and clear methods how to solve specific problems in the agricultural practice management, plant protection, and direct practice application – ‘‘Know- How'', with as many as possible useful data. References used, along with local ones, are mostly American and from Western Europe. This textbook is intended for those who already use the agricultural technique in plant protection and those who are just acquiring the basics of technical systems proper application in daily practice, regardless the size of the agricultural farm. The authors covered in details and explained some bases of physics logic, analysis, and synthesis of specific laws while using pesticides due to extremely importance in understanding the problem area.

  16. Improving Project Manufacturing Coordination

    Directory of Open Access Journals (Sweden)

    Korpivaara Ville

    2014-09-01

    Full Text Available The objective of this research is to develop firms’ project manufacturing coordination. The development will be made by centralizing the manufacturing information flows in one system. To be able to centralize information, a deep user need assessment is required. After user needs have been identified, the existing system will be developed to match these needs. The theoretical background is achieved through exploring the literature of project manufacturing, development project success factors and different frameworks and tools for development project execution. The focus of this research is rather in customer need assessment than in system’s technical expertise. To ensure the deep understanding of customer needs this study is executed by action research method. As a result of this research the information system for project manufacturing coordination was developed to respond revealed needs of the stakeholders. The new system improves the quality of the manufacturing information, eliminates waste in manufacturing coordination processes and offers a better visibility to the project manufacturing. Hence it provides a solid base for the further development of project manufacturing.

  17. Continuous Improvement and Collaborative Improvement: Similarities and Differences

    NARCIS (Netherlands)

    Middel, Rick; Boer, Harry; Fisscher, Olaf

    2006-01-01

    A substantial body of theoretical and practical knowledge has been developed on continuous improvement. However, there is still a considerable lack of empirically grounded contributions and theories on collaborative improvement, that is, continuous improvement in an inter-organizational setting. The

  18. CONFORMANCE IMPROVEMENT USING GELS

    Energy Technology Data Exchange (ETDEWEB)

    Randall S. Seright

    2004-09-30

    This report describes work performed during the third and final year of the project, ''Conformance Improvement Using Gels.'' Corefloods revealed throughput dependencies of permeability reduction by polymers and gels that were much more prolonged during oil flow than water flow. This behavior was explained using simple mobility ratio arguments. A model was developed that quantitatively fits the results and predicts ''clean up'' times for oil productivity when production wells are returned to service after application of a polymer or gel treatment. X-ray computed microtomography studies of gels in strongly water-wet Berea sandstone and strongly oil-wet porous polyethylene suggested that oil penetration through gel-filled pores occurs by a gel-dehydration mechanism, rather than gel-ripping or gel-displacement mechanisms. In contrast, analysis of data from the University of Kansas suggests that the gel-ripping or displacement mechanisms are more important in more permeable, strongly water-wet sandpacks. These findings help to explain why aqueous gels can reduce permeability to water more than to oil under different conditions. Since cement is the most commonly used material for water shutoff, we considered when gels are preferred over cements. Our analysis and experimental results indicated that cement cannot be expected to completely fill (top to bottom) a vertical fracture of any width, except near the wellbore. For vertical fractures with apertures less than 4 mm, the cement slurry will simply not penetrate very far into the fracture. For vertical fractures with apertures greater than 4 mm, the slurry may penetrate a substantial distance into the bottom part of the fracture. However, except near the wellbore, the upper part of the fracture will remain open due to gravity segregation. We compared various approaches to plugging fractures using gels, including (1) varying polymer content, (2) varying placement (extrusion) rate

  19. CONFORMANCE IMPROVEMENT USING GELS

    Energy Technology Data Exchange (ETDEWEB)

    Randall S. Seright

    2003-09-01

    This report describes work performed during the second year of the project, ''Conformance Improvement Using Gels.'' The project has two objectives. The first objective is to identify gel compositions and conditions that substantially reduce flow through fractures that allow direct channeling between wells, while leaving secondary fractures open so that high fluid injection and production rates can be maintained. The second objective is to optimize treatments in fractured production wells, where the gel must reduce permeability to water much more than that to oil. Pore-level images from X-ray computed microtomography were re-examined for Berea sandstone and porous polyethylene. This analysis suggests that oil penetration through gel-filled pores occurs by a gel-dehydration mechanism, rather than a gel-ripping mechanism. This finding helps to explain why aqueous gels can reduce permeability to water more than to oil. We analyzed a Cr(III)-acetate-HPAM gel treatment in a production well in the Arbuckle formation. The availability of accurate pressure data before, during, and after the treatment was critical for the analysis. After the gel treatment, water productivity was fairly constant at about 20% of the pre-treatment value. However, oil productivity was stimulated by a factor of 18 immediately after the treatment. During the six months after the treatment, oil productivity gradually decreased to approach the pre-treatment value. To explain this behavior, we proposed that the fracture area open to oil flow was increased substantially by the gel treatment, followed by a gradual closing of the fractures during subsequent production. For a conventional Cr(III)-acetate-HPAM gel, the delay between gelant preparation and injection into a fracture impacts the placement, leakoff, and permeability reduction behavior. Formulations placed as partially formed gels showed relatively low pressure gradients during placement, and yet substantially reduced the

  20. YOGA IMPROVES CARDIOVASCULAR PARAMETERS

    Directory of Open Access Journals (Sweden)

    Pramod P. Kadu

    2016-06-01

    Full Text Available ABSTRACT Yoga in ancient technique practices by sage for a desirable and healthy life. Yogic exercise and Pranayam may modulate cardiovascular function. To assess the cardiovascular parameter in control and study group. We selected 90 healthy volunteers between age group 35 – 50 years and divided into two groups. i Study group – 45 ii Control group – 45. Control group was not doing any type of exercise or yoga during 1 yr of period whereas yoga group did yogic exercise for 1 yr under supervision of yoga expert. In both the group heart rate SBP and DBP evaluate at 0, 6 and 12 month period. In control group heart rate, SBP, and DBP showed no significant change at 0, 6, and 12 month reading, whereas study group (yoga 81.96±5.65 showed significant decreased heart rate From 81.96 ±5.65 to 75.60 ± 3.44 at 6 month and 73.75 ± 11.36 at 12 month (p<0.001 SBP decreased from 128 ± 7.66 to 120.97 ± 4.21 at 6 month and 120.48± 3.86 at 12 months (p<0.001. DBP showed significant decreased from 88.44 ± 5.25 to 80.53 ± 3.44 at 6 months and 80.53 ± 2.53 at 12months (p<0.001. Yogic exercise and Pranayam done regularly at long term improve cardiovascular efficiency.

  1. Improving clinical cognitive testing

    Science.gov (United States)

    Gale, Seth A.; Barrett, A.M.; Boeve, Bradley F.; Chatterjee, Anjan; Coslett, H. Branch; D'Esposito, Mark; Finney, Glen R.; Gitelman, Darren R.; Hart, John J.; Lerner, Alan J.; Meador, Kimford J.; Pietras, Alison C.; Voeller, Kytja S.; Kaufer, Daniel I.

    2015-01-01

    Objective: To evaluate the evidence basis of single-domain cognitive tests frequently used by behavioral neurologists in an effort to improve the quality of clinical cognitive assessment. Methods: Behavioral Neurology Section members of the American Academy of Neurology were surveyed about how they conduct clinical cognitive testing, with a particular focus on the Neurobehavioral Status Exam (NBSE). In contrast to general screening cognitive tests, an NBSE consists of tests of individual cognitive domains (e.g., memory or language) that provide a more comprehensive diagnostic assessment. Workgroups for each of 5 cognitive domains (attention, executive function, memory, language, and spatial cognition) conducted evidence-based reviews of frequently used tests. Reviews focused on suitability for office-based clinical practice, including test administration time, accessibility of normative data, disease populations studied, and availability in the public domain. Results: Demographic and clinical practice data were obtained from 200 respondents who reported using a wide range of cognitive tests. Based on survey data and ancillary information, between 5 and 15 tests in each cognitive domain were reviewed. Within each domain, several tests are highlighted as being well-suited for an NBSE. Conclusions: We identified frequently used single-domain cognitive tests that are suitable for an NBSE to help make informed choices about clinical cognitive assessment. Some frequently used tests have limited normative data or have not been well-studied in common neurologic disorders. Utilizing standardized cognitive tests, particularly those with normative data based on the individual's age and educational level, can enhance the rigor and utility of clinical cognitive assessment. PMID:26163433

  2. Improved automobile gas turbine engine

    Science.gov (United States)

    Kofskey, M. G.; Katsanis, T.; Roelke, R. J.; Mclallin, K. L.; Wong, R. Y.; Schumann, L. F.; Galvas, M. R.

    1976-01-01

    Upgraded engine delivers 100 hp in 3500 lb vehicle. Improved fuel economy is due to combined effects of reduced weight, reduced power-to-weight ratio, increased turbine inlet pressure, and improved component efficiencies at part power.

  3. Improved design for frontal protection

    NARCIS (Netherlands)

    Sharpe, N.; Vendrig, R.; Houtzager, K.

    2001-01-01

    The requirements of frontal impact legislation and the comparative evaluations of consumer organizations have improved occupant crash protection. Passenger vehicle bodies have crumple zones developed through rigid flat barrier testing and improved passenger cell stability has resulted from considera

  4. Quality Improvement of Concrete Articles

    Directory of Open Access Journals (Sweden)

    Svatovskaya Larisa

    2016-01-01

    Full Text Available In the paper it is shown that quality of concrete articles and structures may be significantly improved by silica sol solution absorption. Improvements include increase of compressive strength, resistance to low temperatures, coefficient of constructive quality, decrease of water sorption, contraction. The reason of improvement is discussed.

  5. NCCDS configuration management process improvement

    Science.gov (United States)

    Shay, Kathy

    1993-01-01

    By concentrating on defining and improving specific Configuration Management (CM) functions, processes, procedures, personnel selection/development, and tools, internal and external customers received improved CM services. Job performance within the section increased in both satisfaction and output. Participation in achieving major improvements has led to the delivery of consistent quality CM products as well as significant decreases in every measured CM metrics category.

  6. Interstate Electrification Improvement Project

    Energy Technology Data Exchange (ETDEWEB)

    Puckette, Margaret [Shorepower Technologies, Hillsboro, OR (United States); Kim, Jeff [Shorepower Technologies, Hillsboro, OR (United States)

    2015-07-01

    The Interstate Electrification Improvement Project, publicly known as the Shorepower Truck Electrification Project (STEP), started in May 2011 and ended in March 2015. The project grant was awarded by the Department of Energy’s Vehicles Technology Office in the amount of $22.2 million. It had three overarching missions: 1. Reduce the idling of Class 8 tractors when parked at truck stops, to reduce diesel fuel consumption and thus U.S. dependence on foreign petroleum; 2. Stimulate job creation and economic activity as part of the American Reinvestment and Recovery Act of 2009; 3. Reduce greenhouse gas emissions (GHG) from diesel combustion and the carbon footprint of the truck transportation industry. The project design was straightforward. First, build fifty Truck Stop Electrification (TSE) facilities in truck stop parking lots across the country so trucks could plug-in to 110V, 220V, or 480VAC, and shut down the engine instead of idling. These facilities were strategically located at fifty truck stops along major U.S. Interstates with heavy truck traffic. Approximately 1,350 connection points were installed, including 150 high-voltage electric standby Transport Refrigeration Unit (eTRU) plugs--eTRUs are capable of plugging in to shore power1 to cool the refrigerated trailer for loads such as produce, meats and ice cream. Second, the project provided financial incentives on idle reduction equipment to 5,000 trucks in the form of rebates, to install equipment compatible with shore power. This equipment enables drivers to shut down the main engine when parked, to heat or cool their cab, charge batteries, or use other household appliances without idling—a common practice that uses approximately 1 gallon of diesel per hour. The rebate recipients were intended to be the first fleets to plug into Shorepower to save diesel fuel and ensure there is significant population of shore power capable trucks. This two part project was designed to complement each other by

  7. Georgia - Improving General Education Quality, Improved Learning Environment Infrastructure

    Data.gov (United States)

    Millenium Challenge Corporation — The school rehabilitation activity seeks to decrease student and teacher absenteeism, increase students’ time on task, and, ultimately, improve learning and labor...

  8. Overcoming challenges in improvement work.

    Science.gov (United States)

    Crisp, Helen

    2013-09-01

    The Health Foundation is an independent charity working to improve healthcare in the UK, so that we have a system of the highest possible quality-safe, effective, person-centred, timely, efficient and equitable. We believe that in order to achieve this, health services need to continually improve the way they work. The Foundation conducts research and evaluation, puts ideas into practice through improvement programmes, develops leaders and shares evidence to drive wider change. The work is a focused around two priority areas: patient safety and person-centred care. The Foundation has supported work to improve services for patients with kidney disease and, in common with other quality improvement projects, there have been challenges to overcome. Awareness of these common challenges can help others to be more prepared when planning service improvements. © 2013 European Dialysis and Transplant Nurses Association/European Renal Care Association.

  9. Framework for Patient Flow Improvement

    Directory of Open Access Journals (Sweden)

    S.V. Medina-León

    2014-07-01

    Full Text Available There has been much research where the flow of patients was improved, but most of this study is case-specific and only a few papers offer guidelines for patient flow analysis and improvement. In this study a general framework for the analysis and improvement of patient flow is presented, based on a literature review and on experience from a case study in a hospital in Mexico dealing with identifying improvement opportunities that reduced waiting times in the obstetrics/gynecology area of the emergency department. The framework involves an initial analysis using basic tools followed by the selection of a strategy based on system complexity; financial investment required and team participation. The alternative strategies considered were use of advanced analysis tools; use of kaizen events; or direct recommendations. The aim of the framework is to serve as guideline in patient flow improvement projects by helping select the most appropriate improvement path, resulting in project success.

  10. Improved Polyurethane Storage Tank Performance

    Science.gov (United States)

    2014-06-30

    Figure 5.2.4 – Teen / Twenty Berm Bays from Tank 11 Corner Improved Polyurethane Storage Tank Performance Page 63 of 197 FY2009 Final Technical...5.3.9 Pump Discharge Pressure Measurement Improved Polyurethane Storage Tank Performance Page 76 of 197 FY2009 Final Technical Report...chamber pressure Improved Polyurethane Storage Tank Performance Page 173 of 197 FY2009 Final Technical Report Seaman Corporation could not be

  11. Performance improvement in multinational corporations

    OpenAIRE

    Liu, Yang

    2015-01-01

    The aim of this thesis work is to develop a performance improvement model template which supports multinational corporations in their daily operations. This has been achieved through literature review and four case studies. With analysis and synthesis, a complete performance improvement model template is carried out based on balanced score card which can be considered as an instruction or reference for improvement work in multinational corporations. After experienced the transformation from i...

  12. Georgia - Improved Learning Environment Infrastructure

    Data.gov (United States)

    Millennium Challenge Corporation — The school rehabilitation activity seeks to decrease student and teacher absenteeism, increase students’ time on task, and, ultimately, improve learning and labor...

  13. Improved hyperspectral imaging technologies Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Improved hyperspectral imaging technologies could enable lower-cost analysis for planetary science including atmospheric studies, mineralogical investigations, and...

  14. ¿ENFERMEDAD DE GAUCHER: UNA CAUSA INFRECUENTE DE SÍNDROME DE FANCONI ?

    OpenAIRE

    Musso CG; Reynaldi J; Navarro M; Vilas M; Jáuregui R; Imperiali N; Algranati L.

    2007-01-01

    La enfermedad de Gaucher es un trastorno genético autosómico recesivo generador de un déficit de la enzima lisosomal glucosilceramida-beta-glucosidasa ácida. Dicha enzima degrada la glucosilceramida, sustancia a partir de la cual se sintetizan muchos esfingo y glucolípidos. La falta de su degradación conduce a su almacenamiento en los macrófagos tisulares con las consiguientes complicaciones mecánicas y funcionales. El compromiso renal es infrecuente en esta enfermedad, pero cuando se present...

  15. Thinking of VACTERL-H? Rule out Fanconi Anemia according to PHENOS.

    Science.gov (United States)

    Alter, Blanche P; Giri, Neelam

    2016-06-01

    VACTERL-H association includes three of eight features: vertebral anomalies, anal atresia, congenital heart disease, tracheo-esophageal fistula, esophageal atresia, renal, limb anomalies, and hydrocephalus. The VACTERL-H phenotype among cases with FA is considered to be about 5%; the frequency of FA among patients with VACTERL-H is unknown. We examined 54 patients with FA in the National Cancer Institute Inherited Bone Marrow Failure Syndrome Cohort for features of VACTERL-H, including imaging studies (radiology and ultrasound). Eighteen of the fifty-four patients had three or more VACTERL-H features. The presence of VACTERL-H association in 33% of those with FA is much higher than the previous estimate of 5% (P H; these findings were more frequent in the patients with FA who had VACTERL-H. Identification of any components of the VACTERL-H association should lead to imaging studies, and to consideration of the diagnosis of FA, particularly if the patient has radial ray and renal anomalies, as well as many features of PHENOS. There was no association of the presence or absence of VACTERL-H with development of cancer, stem cell transplant, or survival. Early diagnosis will lead to genetic counseling and early surveillance and management of complications of FA. © 2016 Wiley Periodicals, Inc.

  16. Oxidative Stress ‑a Phenotypic Hallmark of Fanconi Anemia and ...

    African Journals Online (AJOL)

    chromosomal aberrations[1] and cancer proneness are hallmark ... Results: Children with FA and DS had elevated levels of oxidative stress and more DNA damage ... Cytogenetic study: ..... of congenital heart defects and persistent pulmonary.

  17. Sequential renal and bone marrow transplants in a child with Fanconi anemia.

    Science.gov (United States)

    Vincent, Carol L; Primack, William A; Hipps, John; Kasow, Kimberly A

    2016-02-01

    FA is an autosomal recessive disorder characterized by small stature and renal abnormalities. FA can lead to progressive bone marrow failure, myelodysplastic syndrome, or acute leukemia. Using a multidisciplinary team approach, we managed a 3-yr-old boy with FA who simultaneously developed renal and hematopoietic failure. Because renal function was insufficient to support the conditioning regimen for HCT, we performed a deceased donor renal transplant in December 2012 prior to HCT with the known risk of graft-versus-graft rejection of the donor kidney. Seven months later he underwent allogeneic HCT. He obtained myeloid engraftment on day +11 and peripheral blood chimerism demonstrated all donor by day +21. He developed asymptomatic CMV reactivation and despite antirejection medications, mild skin graft-versus-host disease. He has maintained excellent renal function and remains transfusion independent with full hematopoietic recovery. He has not experienced any renal rejection episodes nor developed donor-specific antibodies toward his renal donor. Peripheral blood chimerism remains completely HCT donor. He is clinically well, now greater than two and a half yr after renal transplant and two yr after HCT. The continuing close collaboration between the Pediatric Nephrology and Bone Marrow Transplant teams is a major factor in this successful outcome.

  18. Gene editing in hematopoietic stem cells: A potential therapeutic approach for Fanconi anemia

    OpenAIRE

    2015-01-01

    Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología. Fecha de lectura: 14-12-2015 La terapia génica constituye hoy en día una alternativa segura y eficaz para el tratamiento de determinadas enfermedades monogénicas que afectan al sistema hematopoyético. Sin embargo, puesto que el riesgo de mutagénesis insercional debido al uso de vectores integrativos no se puede descartar completamente, la terapia génica de edición se ...

  19. The Role of Fanconi/BRCA DNA Repair Pathway in Epithelial Ovarian Carcinogenesis

    Science.gov (United States)

    2015-01-01

    Mutagen 35:206-221. Wu JH, Jones NJ (2012): Assessment of DNA interstrand crosslinks using the modified alkaline comet assay. Methods Mol Biol 817...transferred to nitrocellulose membranes, which were probed for FANCD2 (1:100) or nucleoporin (1:200) (Santa Cruz Biotechnology; Santa Cruz, CA), as an...10 µg of total protein from each fraction •Protein separation by SDS/PAGE and transferred to nitrocellulose •Probe for FANCD2 •Loading controls

  20. Fanconi anaemia proteins are associated with sister chromatid bridging in mitosis

    DEFF Research Database (Denmark)

    Ying, Songmin; Hickson, Ian D

    2011-01-01

    that specifically occur during chromosome segregation in mitosis. The BS protein, BLM, was shown recently to define a novel class of anaphase DNA bridge structures that, in some cases, also contain FA proteins. We will discuss the possible source of these bridges and the role that FA proteins and BLM might play...

  1. Disease-corrected haematopoietic progenitors from Fanconi anemia induced pluripotent stem cells

    OpenAIRE

    Raya, Ángel; Rodríguez-Pizà, Ignasi; Guenechea, Guillermo; Vassena, Rita; Navarro, Susana; Barrero, María José; Consiglio, Antonella; Castellà, Maria; Río, Paula; Sleep, Eduard; González, Federico; Tiscornia, Gustavo; Garreta, Elena; Aasen, Trond; Veiga, Anna

    2009-01-01

    Premi a l'excel·lència investigadora. Àmbit de les Ciències de la Salut. 2010 The generation of induced pluripotent stem (iPS) cells by ectopic expression of a defined set of factors1-5 has enabled the derivation of patient-specific pluripotent cells and provided valuable experimental platforms to model human disease6-8. Patientspecific iPS cells are also thought to hold great therapeutic potential, although direct evidence for this is still lacking. Here we show that somatic cells from Fa...

  2. ¿ENFERMEDAD DE GAUCHER: UNA CAUSA INFRECUENTE DE SÍNDROME DE FANCONI ?

    OpenAIRE

    Musso CG; Reynaldi J; Navarro M; Vilas M; Jáuregui R; Imperiali N; Algranati L

    2007-01-01

    La enfermedad de Gaucher es un trastorno genético autosómico recesivo generador de un déficit de la enzima lisosomal glucosilceramida-beta-glucosidasa ácida. Dicha enzima degrada la glucosilceramida, sustancia a partir de la cual se sintetizan muchos esfingo y glucolípidos. La falta de su degradación conduce a su almacenamiento en los macrófagos tisulares con las consiguientes complicaciones mecánicas y funcionales. El compromiso renal es infrecuente en esta enfermedad, pero cuando se present...

  3. Improving Outcomes in Hypertrophic Cardiomyopathy

    NARCIS (Netherlands)

    P.A. Vriesendorp (Pieter)

    2016-01-01

    markdownabstractImproving outcomes in hypertrophic cardiomyopathy (HCM) is focused on the improvement of the therapeutic strategies for patients with HCM. First it demonstrates that individual patient selection in patients with obstructive and symptomatic HCM can lead to near normal life-expectancy;

  4. Improved PLL For FM Demodulator

    Science.gov (United States)

    Kirkham, Harold; Jackson, Shannon P.

    1992-01-01

    Phase-locked loop (PLL) for frequency demodulator contains improved frequency-to-voltage converter producing less ripple than conventional phase detector. In improved PLL, phase detector replaced by state estimator, implemented by ramp/sample-and-hold circuit. Intended to reduce noise in receiver of frequency-modulated (FM) telemetry link without sacrificing bandwidth. Also applicable to processing received FM signals.

  5. An Improved Moving Mesh Algorithm

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    we consider an iterative algorithm of mesh optimization for finite element solution, and give an improved moving mesh strategy that reduces rapidly the complexity and cost of solving variational problems.A numerical result is presented for a 2-dimensional problem by the improved algorithm.

  6. Substantial Improvements of Fuel Economy

    DEFF Research Database (Denmark)

    Jørgensen, Kaj; Nielsen, Lars H.

    1996-01-01

    The paper evaluates the scope for improving the energy and environmental impacts of road transport by means of electrical and hybrid propulsion. These technologies promise considerable improvements of the fuel economy compared to equivalent vehicles mas well as beneficial effects for the energy...

  7. Substantial Improvements of Fuel Economy

    DEFF Research Database (Denmark)

    Jørgensen, Kaj; Nielsen, Lars H.

    1996-01-01

    The paper evaluates the scope for improving the energy and environmental impacts of road transport by means of electrical and hybrid propulsion. These technologies promise considerable improvements of the fuel economy compared to equivalent vehicles mas well as beneficial effects for the energy...... and traffic systems. A case study concerning passenger cars is analysed by means of computer simulation....

  8. Improvement Of The Helmholtz Absorber

    Science.gov (United States)

    Morrow, Duane L.

    1992-01-01

    Helmholtz-resonator system improved to enable it to absorb sound at more than one frequency without appreciable loss of effectiveness at primary frequency. Addition of annular cavities enables absorption of sound at harmonic frequencies in addition to primary frequency. Improved absorber designed for use on structures of high transmission loss. Applied to such machines as fixed-speed engines and fans.

  9. Healthcare quality improvement programme improves monitoring of people with diabetes

    NARCIS (Netherlands)

    Denig, Petra

    2004-01-01

    Question. Does a healthcare quality improvement programme, incorporating education and claims-based feedback about practice-specific models of monitoring diabetes care, increase the regularity with which primary care physicians assess people with diabetes mellitus receiving Medicare benefits? Study

  10. Improving self-esteem by improving physical attractiveness.

    Science.gov (United States)

    Patzer, G L

    1997-01-01

    Many characteristics comprise a person's personality: achievement orientation, interest to be sociable, aggressiveness, need for order, disposition, and so on. One of the most important personality characteristics in every person's life is self-esteem, which can be defined in terms of cognitive generalizations derived from past experiences. Since people are not isolated from their environment, a person's experiences impact his or her self-esteem. Since a person's physical attractiveness is known to be a major factor in his or her experiences, it is logical (as well as empirically documented) to be a substantial influence on self-esteem. The research shows that improving a physical trait improves attitude, personality, and self-esteem. Likewise, improving physical attractiveness improves interpersonal interactions. These more positive interactions are internalized intrapersonally (within a person), with direct, corresponding impact on the person's self-esteem.

  11. Lessons Learned on Stage: How Improv Can Improve Science Communication

    Science.gov (United States)

    Wong, G. J.; Kohn, C.; McPeek, M. A.; Serrell, N.

    2014-12-01

    A challenge facing STEM graduate students is the daunting task of communicating their research to a non-specialist audience. Strategies that work well in lab group meetings, such as using acronyms and jargon, do not work in the real world. Ideally, scientists should directly connect with any audience, responding spontaneously and actively, distilling their messages into conversational morsels that resonate with that audience. Scientists should listen. This presentation highlights a 10-week, interdisciplinary graduate course at Dartmouth College that teaches methods for communicating science with clarity, vividness, and emotion. The course was developed in partnership with Stony Brook University's Alan Alda Center for Communicating Science, and emphasizes story-telling, two-way communication, active listening, and so much more. Effective message development and communication skills - spontaneity, authenticity, and connectivity - are honed through improvisational theater exercises. One might ask, "why improv?" As a co-developer/co-instructor of this graduate course and a Ph.D. candidate in Earth Sciences, my response is, "why not improv?" Improv is acting without a script. It is also underground rap battles, baking from scratch, and playing jazz flute. Improv is Macguyver. Improv is not any one particular thing so much as it is a process through which we do things. Improv can teach us a lot: how to play, how to feel comfortable and present even while flailing, and how to truly listen.

  12. From continuous improvement to collaborative improvement: scope, scale, skill and social networking in collaborative improvement

    NARCIS (Netherlands)

    Middel, H.G.A.; Groen, Arend J.; Fisscher, O.A.M.

    2004-01-01

    More than ever, companies are challenged to improve their performance and respond quickly and accurately to changes within the market. As competitive battlefield is moving towards the level of networks of organisations, the individual firm is an inadequate entity for identifying improvements.

  13. Improving a Dental School's Clinic Operations Using Lean Process Improvement.

    Science.gov (United States)

    Robinson, Fonda G; Cunningham, Larry L; Turner, Sharon P; Lindroth, John; Ray, Deborah; Khan, Talib; Yates, Audrey

    2016-10-01

    The term "lean production," also known as "Lean," describes a process of operations management pioneered at the Toyota Motor Company that contributed significantly to the success of the company. Although developed by Toyota, the Lean process has been implemented at many other organizations, including those in health care, and should be considered by dental schools in evaluating their clinical operations. Lean combines engineering principles with operations management and improvement tools to optimize business and operating processes. One of the core concepts is relentless elimination of waste (non-value-added components of a process). Another key concept is utilization of individuals closest to the actual work to analyze and improve the process. When the medical center of the University of Kentucky adopted the Lean process for improving clinical operations, members of the College of Dentistry trained in the process applied the techniques to improve inefficient operations at the Walk-In Dental Clinic. The purpose of this project was to reduce patients' average in-the-door-to-out-the-door time from over four hours to three hours within 90 days. Achievement of this goal was realized by streamlining patient flow and strategically relocating key phases of the process. This initiative resulted in patient benefits such as shortening average in-the-door-to-out-the-door time by over an hour, improving satisfaction by 21%, and reducing negative comments by 24%, as well as providing opportunity to implement the electronic health record, improving teamwork, and enhancing educational experiences for students. These benefits were achieved while maintaining high-quality patient care with zero adverse outcomes during and two years following the process improvement project.

  14. Progress Report: Experimental Saltmarsh Improvement

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — A series of recommendations for the improvement of the Parker River National Wildlife refuge salt marshes including mound constructions as well as plantings and...

  15. Process improvement in transfusion medicine.

    Science.gov (United States)

    Kopko, P M; Holland, P V

    1999-07-01

    Ongoing efforts to decrease costs in the clinical laboratory make continuous process improvement especially important in difficult economic times. Process improvement can result in decreased workload, cost savings, and increased customer satisfaction but is an abstract concept in and of itself. To illustrate the steps of process improvement, we applied them to our blood component retrieval policy. By identifying the problems with the current system, proposing and implementing solutions, and measuring the effects before and after revamping the process, we have been able to show impressive reductions in the number of component retrievals initiated, the number acted on, wasted components, and customer complaints, all of which translate into cost savings. Once the cycle is completed, it begins anew. There must always be continuous process improvement.

  16. Windows with improved energy performances

    DEFF Research Database (Denmark)

    Laustsen, Jacob Birck; Svendsen, Svend

    2003-01-01

    Heat loss through windows represents a considerable part of the total heat loss from houses. However, apart from providing daylight access and view, windows offer a unique potential for solar gain to be exploited during the heating season. Until now valuation of the energy performance of windows...... has primary focused on the heat loss coefficient, U-value. However, as the U-value, especially for the glazing part, has improved considerably during the last years, the total solar energy transmittance, g-value, has become equally important to the total energy performance of windows. Improved energy...... performance of windows can be reached by development of each element of the window, but to gain a considerable improvement in the overall energy performance all elements of the windows need to be examined together and the construction optimised. This paper describes potential improvements of window elements...

  17. How to maintain improved cultivars

    NARCIS (Netherlands)

    Parlevliet, J.E.

    2007-01-01

    Improved cultivars loose their identity and healthiness unless maintained properly. Contaminating and degrading forces, such as outcrossing, volunteer plants, mixing, natural selection, mutation and seed-borne diseases, are at the root of this. Maintenance selection can prevent this deterioration.

  18. Improved Casting Furnace Conceptual Design

    Energy Technology Data Exchange (ETDEWEB)

    Fielding, Randall Sidney [Idaho National Lab. (INL), Idaho Falls, ID (United States); Tolman, David Donald [Idaho National Lab. (INL), Idaho Falls, ID (United States)

    2017-02-01

    In an attempt to ensure more consistent casting results and remove some schedule variance associated with casting, an improved casting furnace concept has been developed. The improved furnace uses the existing arc melter hardware and glovebox utilities. The furnace concept was designed around physical and operational requirements such as; a charge sized of less than 30 grams, high heating rates and minimal additional footprint. The conceptual model is shown in the report as well as a summary of how the requirements were met.

  19. Possibilities of Logistics Policy Improvement

    OpenAIRE

    Petr Průša; David Tilkeridis

    2009-01-01

    The paper presents the strategic logistics management with emphasis on clear, accurate and effective material flow from the suppliers and internally, as well as an outline of the logistics policy for continuous improvement. The implementation of a complete Supplier Logistics Performance System is essential to support internal processes efficiency and establish a continuous improvement system according to the main logistics policy. Every company should consider such a system in order to win in...

  20. Improved Vacuum-Tight Connector

    Science.gov (United States)

    Rudin, Frank

    1989-01-01

    Simple reinforcing tube increases service life and improves seal. Short stainless-steel tube inserted in copper tube to reinforce against compression, preventing leaks due to thermal distortion or to collapse under squeeze of ferrule in compressure fitting. Several test specimens of improved connector constructed, tested, and evaluated. Fittings not only operated successfully at required operating conditions of vacuum and temperature but also consistently demonstrated high reliability after loosened and tightened many times.

  1. Improving public disclosure in banking

    OpenAIRE

    anonymous

    2000-01-01

    The use of market discipline as a complement to bank supervision and regulation has gained greater acceptance in the United States and abroad. It is also widely recognized that effective market discipline depends on market participants' having information about the risks and financial condition of banking organizations. Therefore, attention is being focused increasingly on ways to improve transparency in banking. Staff of the Federal Reserve System undertook a staff study, Improving Public Di...

  2. Improving efficiency in meat production.

    Science.gov (United States)

    Brameld, John M; Parr, Tim

    2016-08-01

    Selective breeding and improved nutritional management over the past 20-30 years has resulted in dramatic improvements in growth efficiency for pigs and poultry, particularly lean tissue growth. However, this has been achieved using high-quality feed ingredients, such as wheat and soya that are also used for human consumption and more recently biofuels production. Ruminants on the other hand are less efficient, but are normally fed poorer quality ingredients that cannot be digested by human subjects, such as grass or silage. The challenges therefore are to: (i) maintain the current efficiency of growth of pigs and poultry, but using more ingredients not needed to feed the increasing human population or for the production of biofuels; (ii) improve the efficiency of growth in ruminants; (iii) at the same time produce animal products (meat, milk and eggs) of equal or improved quality. This review will describe the use of: (a) enzyme additives for animal feeds, to improve feed digestibility; (b) known growth promoting agents, such as growth hormone, β-agonists and anabolic steroids, currently banned in the European Union but used in other parts of the world; (c) recent transcriptomic studies into molecular mechanisms for improved growth efficiency via low residual feed intake. In doing so, the use of genetic manipulation in animals will also be discussed.

  3. Historical Improvement in Speed Skating Economy.

    Science.gov (United States)

    Noordhof, Dionne A; van Tok, Elmy; Joosten, Florentine S J G M; Hettinga, Florentina J; Hoozemans, Marco J M; Foster, Carl; de Koning, Jos J

    2017-02-01

    Half the improvement in 1500-m speed-skating world records can be explained by technological innovations and the other half by athletic improvement. It is hypothesized that improved skating economy is accountable for much of the athletic improvement.

  4. Adaptation improves face trustworthiness discrimination

    Science.gov (United States)

    Keefe, B. D.; Dzhelyova, M.; Perrett, D. I.; Barraclough, N. E.

    2013-01-01

    Adaptation to facial characteristics, such as gender and viewpoint, has been shown to both bias our perception of faces and improve facial discrimination. In this study, we examined whether adapting to two levels of face trustworthiness improved sensitivity around the adapted level. Facial trustworthiness was manipulated by morphing between trustworthy and untrustworthy prototypes, each generated by morphing eight trustworthy and eight untrustworthy faces, respectively. In the first experiment, just-noticeable differences (JNDs) were calculated for an untrustworthy face after participants adapted to an untrustworthy face, a trustworthy face, or did not adapt. In the second experiment, the three conditions were identical, except that JNDs were calculated for a trustworthy face. In the third experiment we examined whether adapting to an untrustworthy male face improved discrimination to an untrustworthy female face. In all experiments, participants completed a two-interval forced-choice (2-IFC) adaptive staircase procedure, in which they judged which face was more untrustworthy. JNDs were derived from a psychometric function fitted to the data. Adaptation improved sensitivity to faces conveying the same level of trustworthiness when compared to no adaptation. When adapting to and discriminating around a different level of face trustworthiness there was no improvement in sensitivity and JNDs were equivalent to those in the no adaptation condition. The improvement in sensitivity was found to occur even when adapting to a face with different gender and identity. These results suggest that adaptation to facial trustworthiness can selectively enhance mechanisms underlying the coding of facial trustworthiness to improve perceptual sensitivity. These findings have implications for the role of our visual experience in the decisions we make about the trustworthiness of other individuals. PMID:23801979

  5. Adaptation improves face trustworthiness discrimination.

    Science.gov (United States)

    Keefe, B D; Dzhelyova, M; Perrett, D I; Barraclough, N E

    2013-01-01

    Adaptation to facial characteristics, such as gender and viewpoint, has been shown to both bias our perception of faces and improve facial discrimination. In this study, we examined whether adapting to two levels of face trustworthiness improved sensitivity around the adapted level. Facial trustworthiness was manipulated by morphing between trustworthy and untrustworthy prototypes, each generated by morphing eight trustworthy and eight untrustworthy faces, respectively. In the first experiment, just-noticeable differences (JNDs) were calculated for an untrustworthy face after participants adapted to an untrustworthy face, a trustworthy face, or did not adapt. In the second experiment, the three conditions were identical, except that JNDs were calculated for a trustworthy face. In the third experiment we examined whether adapting to an untrustworthy male face improved discrimination to an untrustworthy female face. In all experiments, participants completed a two-interval forced-choice (2-IFC) adaptive staircase procedure, in which they judged which face was more untrustworthy. JNDs were derived from a psychometric function fitted to the data. Adaptation improved sensitivity to faces conveying the same level of trustworthiness when compared to no adaptation. When adapting to and discriminating around a different level of face trustworthiness there was no improvement in sensitivity and JNDs were equivalent to those in the no adaptation condition. The improvement in sensitivity was found to occur even when adapting to a face with different gender and identity. These results suggest that adaptation to facial trustworthiness can selectively enhance mechanisms underlying the coding of facial trustworthiness to improve perceptual sensitivity. These findings have implications for the role of our visual experience in the decisions we make about the trustworthiness of other individuals.

  6. Adaptation improves face trustworthiness discrimination

    Directory of Open Access Journals (Sweden)

    Bruce D Keefe

    2013-06-01

    Full Text Available Adaptation to facial characteristics, such as gender and viewpoint, has been shown to both bias our perception of faces and improve facial discrimination. In this study, we examined whether adapting to two levels of face trustworthiness improved sensitivity around the adapted level. Facial trustworthiness was manipulated by morphing between trustworthy and untrustworthy prototypes, each generated by morphing eight trustworthy and eight untrustworthy faces respectively. In the first experiment, just-noticeable differences (JNDs were calculated for an untrustworthy face after participants adapted to an untrustworthy face, a trustworthy face, or did not adapt. In the second experiment, the three conditions were identical, except that JNDs were calculated for a trustworthy face. In the third experiment we examined whether adapting to an untrustworthy male face improved discrimination to an untrustworthy female face. In all experiments, participants completed a two-interval forced-choice adaptive staircase procedure, in which they judged which face was more untrustworthy. JNDs were derived from a psychometric function fitted to the data. Adaptation improved sensitivity to faces conveying the same level of trustworthiness when compared to no adaptation. When adapting to and discriminating around a different level of face trustworthiness there was no improvement in sensitivity and JNDs were equivalent to those in the no adaptation condition. The improvement in sensitivity was found to occur even when adapting to a face with different gender and identity. These results suggest that adaptation to facial trustworthiness can selectively enhance mechanisms underlying the coding of facial trustworthiness to improve perceptual sensitivity. These findings have implications for the role of our visual experience in the decisions we make about the trustworthiness of other individuals.

  7. Improvability of assembly systems II: Improvability indicators and case study

    Directory of Open Access Journals (Sweden)

    S.-Y. Chiang

    2000-01-01

    Full Text Available Based on the performance analysis technique developed in Part I, this paper presents improvability indicators for assembly lines with unreliable machines. In particular, it shows that assembly lines are unimprovable with respect to workforce re-distribution if each buffer is, on the average, close to being half full. These lines are unimprovable with respect to buffer capacity re-distribution if each machine is starved and blocked with almost equal frequency. In addition, the paper provides indicators for identification of bottleneck machines and bottleneck buffers. Finally, the paper reports on an application of these improvability indicators in a case study at an automotive components plant.

  8. CADASTRAL DATABASE POSITIONAL ACCURACY IMPROVEMENT

    Directory of Open Access Journals (Sweden)

    N. M. Hashim

    2017-10-01

    Full Text Available Positional Accuracy Improvement (PAI is the refining process of the geometry feature in a geospatial dataset to improve its actual position. This actual position relates to the absolute position in specific coordinate system and the relation to the neighborhood features. With the growth of spatial based technology especially Geographical Information System (GIS and Global Navigation Satellite System (GNSS, the PAI campaign is inevitable especially to the legacy cadastral database. Integration of legacy dataset and higher accuracy dataset like GNSS observation is a potential solution for improving the legacy dataset. However, by merely integrating both datasets will lead to a distortion of the relative geometry. The improved dataset should be further treated to minimize inherent errors and fitting to the new accurate dataset. The main focus of this study is to describe a method of angular based Least Square Adjustment (LSA for PAI process of legacy dataset. The existing high accuracy dataset known as National Digital Cadastral Database (NDCDB is then used as bench mark to validate the results. It was found that the propose technique is highly possible for positional accuracy improvement of legacy spatial datasets.

  9. Improving Case Discussion with an Improv Mind-Set

    Science.gov (United States)

    Aylesworth, Andy

    2008-01-01

    Improvisational comedy emphasizes collaboration over competition. This leads to creative ideas and solutions to problems. By establishing this "improv mind-set" in the business classroom, an instructor may be able to overcome some of the problems associated with the case method (e.g., shy students, dominating students). By doing so, the learning…

  10. Improving Case Discussion with an Improv Mind-Set

    Science.gov (United States)

    Aylesworth, Andy

    2008-01-01

    Improvisational comedy emphasizes collaboration over competition. This leads to creative ideas and solutions to problems. By establishing this "improv mind-set" in the business classroom, an instructor may be able to overcome some of the problems associated with the case method (e.g., shy students, dominating students). By doing so, the learning…

  11. Improving the Identification of Schools for Chapter 1 Program Improvement.

    Science.gov (United States)

    D'Agostino, Jerome

    Technical problems with norm-referenced achievement testing that can lead to the erroneous evaluation of schools for Chapter 1 Program improvement is discussed, and an alternative testing model is presented. The history of Chapter 1 testing and evaluation policies is briefly reviewed, and problems with the norm-referenced model are explored. Data…

  12. Improving Software Citation and Credit

    CERN Document Server

    Allen, Alice; DuPrie, Kimberly; Mink, Jessica; Nemiroff, Robert; Robitaille, Thomas; Shamir, Lior; Shortridge, Keith; Taylor, Mark; Teuben, Peter; Wallin, John

    2015-01-01

    The past year has seen movement on several fronts for improving software citation, including the Center for Open Science's Transparency and Openness Promotion (TOP) Guidelines, the Software Publishing Special Interest Group that was started at January's AAS meeting in Seattle at the request of that organization's Working Group on Astronomical Software, a Sloan-sponsored meeting at GitHub in San Francisco to begin work on a cohesive research software citation-enabling platform, the work of Force11 to "transform and improve" research communication, and WSSSPE's ongoing efforts that include software publication, citation, credit, and sustainability. Brief reports on these efforts were shared at the BoF, after which participants discussed ideas for improving software citation, generating a list of recommendations to the community of software authors, journal publishers, ADS, and research authors. The discussion, recommendations, and feedback will help form recommendations for software citation to those publishers...

  13. Improved Heat-Stress Algorithm

    Science.gov (United States)

    Teets, Edward H., Jr.; Fehn, Steven

    2007-01-01

    NASA Dryden presents an improved and automated site-specific algorithm for heat-stress approximation using standard atmospheric measurements routinely obtained from the Edwards Air Force Base weather detachment. Heat stress, which is the net heat load a worker may be exposed to, is officially measured using a thermal-environment monitoring system to calculate the wet-bulb globe temperature (WBGT). This instrument uses three independent thermometers to measure wet-bulb, dry-bulb, and the black-globe temperatures. By using these improvements, a more realistic WBGT estimation value can now be produced. This is extremely useful for researchers and other employees who are working on outdoor projects that are distant from the areas that the Web system monitors. Most importantly, the improved WBGT estimations will make outdoor work sites safer by reducing the likelihood of heat stress.

  14. Improved BLAST for wireless communications

    Institute of Scientific and Technical Information of China (English)

    Li Yongzhao; Liao Guisheng; Wang Feng

    2006-01-01

    Bell layered space-time architecture (BLAST) is a multi-antenna communication structure with high spectrum efficiency, and it has found wide applications in LANs and WLANs. However, its performance is much poorer than those of other space-time coding approaches. In order to improve its performance, an improved BLAST based on RAKE receiving is investigated. The new system introduces orthogonal spreading sequences (OSS) into the transmitter while retains the basic structure of BLAST. The proposed receiver suppresses interferences from other antennas by the orthogonality contained in the received signals, and extracts information from each receiving antenna by using RAKE receiving principle to construct efficient statistic decision. Simulation results show that the improved system performs well over both frequency-flat and frequency-selective fading channels.

  15. Motor activity improves temporal expectancy.

    Directory of Open Access Journals (Sweden)

    Lilian Fautrelle

    Full Text Available Certain brain areas involved in interval timing are also important in motor activity. This raises the possibility that motor activity might influence interval timing. To test this hypothesis, we assessed interval timing in healthy adults following different types of training. The pre- and post-training tasks consisted of a button press in response to the presentation of a rhythmic visual stimulus. Alterations in temporal expectancy were evaluated by measuring response times. Training consisted of responding to the visual presentation of regularly appearing stimuli by either: (1 pointing with a whole-body movement, (2 pointing only with the arm, (3 imagining pointing with a whole-body movement, (4 simply watching the stimulus presentation, (5 pointing with a whole-body movement in response to a target that appeared at irregular intervals (6 reading a newspaper. Participants performing a motor activity in response to the regular target showed significant improvements in judgment times compared to individuals with no associated motor activity. Individuals who only imagined pointing with a whole-body movement also showed significant improvements. No improvements were observed in the group that trained with a motor response to an irregular stimulus, hence eliminating the explanation that the improved temporal expectations of the other motor training groups was purely due to an improved motor capacity to press the response button. All groups performed a secondary task equally well, hence indicating that our results could not simply be attributed to differences in attention between the groups. Our results show that motor activity, even when it does not play a causal or corrective role, can lead to improved interval timing judgments.

  16. Engaged Research in Process Improvement

    DEFF Research Database (Denmark)

    Pries-Heje, Jan

    2010-01-01

    This keynote initiates from an example of engaged research; a Danish software house that made it from maturity level 1 to 5 in eight years. The organizational change implied at each step is discussed and a design theory of process improvement and change derived.......This keynote initiates from an example of engaged research; a Danish software house that made it from maturity level 1 to 5 in eight years. The organizational change implied at each step is discussed and a design theory of process improvement and change derived....

  17. Improving Precision of Generated ASTs

    DEFF Research Database (Denmark)

    Winther, Johnni

    The parser-generator is an essential tool in grammarware and its output, the parse tree in form of the concrete or abstract syntax tree, often forms the basis for the whole structure of the grammarware application. Several tools for Java encode the parse tree in a class hierarchy generated to mod...... the parsed documents closely within the Java type system. We present two algorithms used in the generation of such classes which improve the precision with which the parsed input is modeled and show that these improvements greatly ease the use of the generated classes....

  18. Improving outcomes in peripartum cardiomyopathy.

    Science.gov (United States)

    Dalzell, Jonathan R; Cannon, Jane A; Simpson, Joanne; Gardner, Roy S; Petrie, Mark C

    2015-06-01

    Peripartum cardiomyopathy (PPCM) is a rare condition with a diverse spectrum of potential outcomes, ranging from frequent complete recovery to fulminant heart failure and death. The pathogenesis of PPCM is not well understood, and relatively little is known about its incidence and prevalence. PPCM is often under-recognised in the clinical setting. Early investigation and diagnosis with subsequent expert management may improve outcomes. The development of registries will allow this condition to be better characterised and may help answer crucial questions regarding its optimal medical and surgical management. This paper reviews the potential approaches to improve outcomes in patients with PPCM.

  19. Improving designer productivity. [artificial intelligence

    Science.gov (United States)

    Hill, Gary C.

    1992-01-01

    Designer and design team productivity improves with skill, experience, and the tools available. The design process involves numerous trials and errors, analyses, refinements, and addition of details. Computerized tools have greatly speeded the analysis, and now new theories and methods, emerging under the label Artificial Intelligence (AI), are being used to automate skill and experience. These tools improve designer productivity by capturing experience, emulating recognized skillful designers, and making the essence of complex programs easier to grasp. This paper outlines the aircraft design process in today's technology and business climate, presenting some of the challenges ahead and some of the promising AI methods for meeting these challenges.

  20. Improving designer productivity. [artificial intelligence

    Science.gov (United States)

    Hill, Gary C.

    1992-01-01

    Designer and design team productivity improves with skill, experience, and the tools available. The design process involves numerous trials and errors, analyses, refinements, and addition of details. Computerized tools have greatly speeded the analysis, and now new theories and methods, emerging under the label Artificial Intelligence (AI), are being used to automate skill and experience. These tools improve designer productivity by capturing experience, emulating recognized skillful designers, and making the essence of complex programs easier to grasp. This paper outlines the aircraft design process in today's technology and business climate, presenting some of the challenges ahead and some of the promising AI methods for meeting these challenges.

  1. Improved Ternary Subdivision Interpolation Scheme

    Institute of Scientific and Technical Information of China (English)

    WANG Huawei; QIN Kaihuai

    2005-01-01

    An improved ternary subdivision interpolation scheme was developed for computer graphics applications that can manipulate open control polygons unlike the previous ternary scheme, with the resulting curve proved to be still C2-continuous. Parameterizations of the limit curve near the two endpoints are given with expressions for the boundary derivatives. The split joint problem is handled with the interpolating ternary subdivision scheme. The improved scheme can be used for modeling interpolation curves in computer aided geometric design systems, and provides a method for joining two limit curves of interpolating ternary subdivisions.

  2. Using Simulation to Improve Systems.

    Science.gov (United States)

    Kearney, James A; Deutsch, Ellen S

    2017-10-01

    Attempts to understand and improve health care delivery often focus on the characteristics of the patient and the characteristics of the health care providers, but larger systems surround and integrate with patients and providers. Components of health care delivery systems can support or interfere with efforts to provide optimal health care. Simulation in situ, involving real teams participating in simulations in real care settings, can be used to identify latent safety threats and improve the work environment while simultaneously supporting participant learning. Thoughtful planning and skilled debriefing are essential. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Performance improvement CME: managing schizophrenia.

    Science.gov (United States)

    Kane, John M; Correll, Christoph U

    2011-10-01

    Schizophrenia is a highly disabling disorder characterized by positive and negative symptoms and poor functioning in almost every area of life. Multiple antipsychotics have demonstrated varying levels of efficacy in reducing symptoms in schizophrenia, but adverse effects are common, adherence to medication is low, and relapse rates are high. Psychosocial interventions used in conjunction with antipsychotic pharmacotherapy may help improve treatment outcomes. This Performance Improvement CME activity focuses on individualizing treatment for schizophrenia, assessing treatment adherence, minimizing medication-induced adverse events, and preventing relapse, for children, adolescents, and adults with schizophrenia.

  4. Genomic Databases for Crop Improvement

    Directory of Open Access Journals (Sweden)

    David Edwards

    2012-03-01

    Full Text Available Genomics is playing an increasing role in plant breeding and this is accelerating with the rapid advances in genome technology. Translating the vast abundance of data being produced by genome technologies requires the development of custom bioinformatics tools and advanced databases. These range from large generic databases which hold specific data types for a broad range of species, to carefully integrated and curated databases which act as a resource for the improvement of specific crops. In this review, we outline some of the features of plant genome databases, identify specific resources for the improvement of individual crops and comment on the potential future direction of crop genome databases.

  5. Ways to Improve Oral English

    Institute of Scientific and Technical Information of China (English)

    张婧婧

    2015-01-01

    Speaking has been the bottom of the list in college English teaching since last few decades. This dissertation focus on this topic and it is mainly divided into following parts:Firstly, it analyses why college students make no significant progress in oral English. Secondly, it argues how to reform college English teaching to change this situation. It is concluded that teachers should em⁃phasize the importance of oral English in commercial lives and incent students to make great effort to improve speaking. Finally, ways to improve students' English speaking skill both in and outside the classroom are suggested.

  6. Acute exercise improves motor memory

    DEFF Research Database (Denmark)

    Skriver, Kasper Christen; Roig, Marc; Lundbye-Jensen, Jesper

    2014-01-01

    We have recently shown that a single bout of acute cardiovascular exercise improves motor skill learning through an optimization of long-term motor memory. Here we expand this previous finding, to explore potential exercise-related biomarkers and their association with measures of motor memory...... practice whereas lactate correlated with better retention 1 hour as well as 24 hours and 7 days after practice. Thus, improvements in motor skill acquisition and retention induced by acute cardiovascular exercise are associated with increased concentrations of biomarkers involved in memory and learning...... processes. More mechanistic studies are required to elucidate the specific role of each biomarker in the formation of motor memory....

  7. Improving hip surgery patients’ outcomes:

    DEFF Research Database (Denmark)

    Bagger, Bettan; Poulsen, Dorthe Varning; Taylor Kelly, Hélène

    2013-01-01

    This presentation focuses upon the improvement of hip surgery patients’ outcomes with respect to health promotion and rehabilitation. The overall aims of the EU financed orthopedic nursing project will be introduced. Speakers highlight the project’s contribution to: -the development of nurse...

  8. Application Process Improvement Yields Results.

    Science.gov (United States)

    Holesovsky, Jan Paul

    1995-01-01

    After a continuing effort to improve its grant application process, the department of medical microbiology and immunology at the University of Wisconsin-Madison is submitting many more applications and realizing increased funding. The methods and strategy used to make the process more efficient and effective are outlined. (Author/MSE)

  9. Improving Career Exploration. Implementation Manual.

    Science.gov (United States)

    Southwest Iowa Learning Resources Center, Red Oak.

    This junior high/middle school career exploration implementation manual is designed to assist in implementing a comprehensive career exploration program using four career exploration components developed in the Improving Career Exploration project. The first of six sections addresses career exploration and career/vocational development. Basic…

  10. Piloting improved cookstoves in India.

    Science.gov (United States)

    Lewis, Jessica J; Bhojvaid, Vasundhara; Brooks, Nina; Das, Ipsita; Jeuland, Marc A; Patange, Omkar; Pattanayak, Subhrendu K

    2015-01-01

    Despite the potential of improved cookstoves to reduce the adverse environmental and health impacts of solid fuel use, their adoption and use remains low. Social marketing-with its focus on the marketing mix of promotion, product, price, and place-offers a useful way to understand household behaviors and design campaigns to change biomass fuel use. We report on a series of pilots across 3 Indian states that use different combinations of the marketing mix. We find sales varying from 0% to 60%. Behavior change promotion that combined door-to-door personalized demonstrations with information pamphlets was effective. When given a choice amongst products, households strongly preferred an electric stove over improved biomass-burning options. Among different stove attributes, reduced cooking time was considered most valuable by those adopting a new stove. Households clearly identified price as a significant barrier to adoption, while provision of discounts (e.g., rebates given if households used the stove) or payments in installments were related to higher purchase. Place-based factors such as remoteness and nongovernmental organization operations significantly affected the ability to supply and convince households to buy and use improved cookstoves. Collectively, these pilots point to the importance of continued and extensive testing of messages, pricing models, and different stove types before scale-up. Thus, we caution that a one-size-fits-all approach will not boost improved cookstove adoption.

  11. Grouting for Pile Foundation Improvement

    NARCIS (Netherlands)

    Van der Stoel, A.E.C.

    2001-01-01

    The aim of this research was to examine the use of grouting methods for pile foundation improvement, a generic term that is used here to define both foundation renovation (increasing the bearing capacity of a pile foundation that has insufficient bearing capacity) and foundation protection (safeguar

  12. [Improving adhesion to antiretroviral treatment].

    Science.gov (United States)

    2008-01-01

    To facilitate unified criteria for health professionals to improve adhesion to antiretroviral therapy. The recommendations were drawn up and agreed upon by an expert panel from the SPNS, GESIDA and SEFH, after an exhaustive review of the latest relevant epidemiological and clinical studies that have been published in the medical literature and/or presented at congresses and scientific forums. The factors related to adhesion with antiretroviral therapy came from individuals, health care professionals and treatment variables. Current available methods for measuring adhesion are diverse and classified as direct and indirect. The ideal method is shown to be one which is highly sensitive and specific, enables quantitative and continuous measurement and is reliable, reproducible, economical and quick. The doctor, nurse and pharmacist play a key role in the strategies for adhesion improvement. Specific programmes based on exhaustive knowledge of individualized variables from patients and their antiretroviral therapy should be developed. The use of combined methods which are adapted to healthcare facility characteristics for adhesion improvement is recommended. The structured support to interpersonal adhesion developed by trained healthcare professionals and individualized strategies has been demonstrated as being the most effective intervention strategy to improve adhesion with antiretroviral treatment.

  13. Improving Students' English Reading Skills

    Institute of Scientific and Technical Information of China (English)

    段士爱

    2009-01-01

    This paper aims to help students who study English as a second language improve reading skills.Based on the reading theoretical foundation.some problems which often encountered during the process of reading will be discussed.Finally,a conclusion as to how to solve these problems will be made.

  14. Improving Speaking Accuracy through Awareness

    Science.gov (United States)

    Dormer, Jan Edwards

    2013-01-01

    Increased English learner accuracy can be achieved by leading students through six stages of awareness. The first three awareness stages build up students' motivation to improve, and the second three provide learners with crucial input for change. The final result is "sustained language awareness," resulting in ongoing…

  15. Improving moral judgments: philosophical considerations

    NARCIS (Netherlands)

    Kalis, A.|info:eu-repo/dai/nl/304823244

    2010-01-01

    In contemporary moral psychology, an often-heard claim is that knowing how we make moral judgments can help us make better moral judgments. Discussions about moral development and improvement are often framed in terms of the question of which mental processes have a better chance of leading to good

  16. Improving Junior High Classroom Management.

    Science.gov (United States)

    Emmer, Edmund T.; And Others

    A field experiment was conducted to determine whether descriptive-correlational results from classroom management research could be implemented by junior high school teachers, and whether such implementation would result in improved classroom management. An experimental group (18 teachers) received management manuals developed by researchers, and…

  17. How to Improve Reading Speed

    Institute of Scientific and Technical Information of China (English)

    王仲亮

    2008-01-01

    @@ It is well known that reading plays an important role not only in our daily life but also in learning a foreign language.And,of course,reading depends on reading speed to some degree.So it is natural that it is important to improve reading speed.

  18. Transgene Stacking in Cotton Improvement

    Institute of Scientific and Technical Information of China (English)

    YANG Ye-hua; WANG Xue-kui; YAO Ming-jing; FAN Yu-peng; GAO Da-yu

    2008-01-01

    @@ To date,more and more transgenic varieties of upland cotton (Gossypium hirsuturn L.) generated with transgenes,which derived from varies of alien species,are playing important role in agricultural production.Stacking of multi-transgenes has a potential for combining all the merits of distinct transgenic lines in a cultivar and possibly makes a significant contribution to cultivar improvement.

  19. The Health Improvement Network (THIN)

    Science.gov (United States)

    The Health Improvement Network is a collaboration between Cegedim Strategic Data EPIC, an expert in the provision of UK primary care patient data that is used for medical research, and In Practice Systems (InPS), who continue to develop and supply the widely-used Vision general practice computer system.

  20. Improved corn protein based articles

    Science.gov (United States)

    Developing higher value uses for zein (corn protein), a potential major co-product of the bio-ethanol industry, will improve the economics of this business. Historically, zein was predominantly used in the textile fiber industry. Unfortunately the techniques used at that time to modify the zein cann...

  1. How to improve English skills?

    Institute of Scientific and Technical Information of China (English)

    袁芳; 赵仰博

    2010-01-01

    The purpose of middle school English teaching is to improve the students'four skills of listening,speaking,reading and writing,with the base of necessary phonetics,large vocabulary and good grammar,but this is not the final purpose.The final purpose is to let students be able to use the language.

  2. Farm cooperation to improve sustainability.

    Science.gov (United States)

    Andersson, Hans; Larsén, Karin; Lagerkvist, Carl-Johan; Andersson, Chrisitian; Blad, Fredrik; Samuelsson, Johan; Skargren, Per

    2005-06-01

    In this paper, it is demonstrated that partnership arrangements between farmers might be a way to secure the economic viability of their farms as well as to increase profitability. The article discusses empirical analyses of three different forms of collaboration, with an emphasis on the environmental improvements associated with collaboration. Collaboration between a dairy farm and a crop farm is analyzed in the first case. The results show that potential gains from improved diversification and crop rotation are substantial, and even larger when the collaboration also involves machinery. The second analysis considers external integration between farrowing and finishing-pig operations. Gains from collaboration originate from biological and technical factors, such as improved growth rate of the pigs and better utilization of buildings. Finally, an evaluation of a group of collaborating crop farmers is performed. In this case, the benefits that arise are mainly due to reduced machinery costs and/or gains due to other factors, such as improved crop rotation and managerial/marketing strategies.

  3. Rational design of improved pharmabiotics.

    LENUS (Irish Health Repository)

    Sleator, Roy D

    2009-01-01

    Herein we review the most recent advances in probiotic research and applications with particular emphasis on the novel concept of patho-biotechnology: the application of pathogen-derived (ex vivo and in vivo) stress survival strategies for the design of more technologically robust and effective probiotic cultures with improved biotechnological and clinical applications.

  4. Phytases for improved iron absorption

    DEFF Research Database (Denmark)

    Nielsen, Anne Veller Friis; Meyer, Anne S.

    2016-01-01

    Phytase enzymes present an alternative to iron supplements, because they have been shown to improve iron absorption by means of catalysing the degradation of a potent iron absorption inhibitor: phytic acid. Phytic acid is a hexaphosphate of inositol and is particularly prevalent in cereal grains...

  5. Improved Ion-Channel Biosensors

    Science.gov (United States)

    Nadeau, Jay; White, Victor; Dougherty, Dennis; Maurer, Joshua

    2004-01-01

    An effort is underway to develop improved biosensors of a type based on ion channels in biomimetic membranes. These sensors are microfabricated from silicon and other materials compatible with silicon. As described, these sensors offer a number of advantages over prior sensors of this type.

  6. Working together to improve usability

    DEFF Research Database (Denmark)

    Nørgaard, Mie; Hornbæk, Kasper

    2010-01-01

    In theory, usability work is an important and well-integrated activity in developing software. In practice, collaboration on improving usability is ridden with challenges relating to conflicting professional goals, tight project schedules, and unclear usability findings. The authors study those...

  7. Improving Technology and Engineering Education

    Science.gov (United States)

    Tech Directions, 2013

    2013-01-01

    Improving Technology and Engineering Education for All Students: A Plan of Action is the theme of this year's International Technology and Engineering Educators Association (ITEEA) annual conference, which meets March 7-9 in Columbus, OH. The theme is aligned with ITEEA's 2012-15 Strategic Plan: Investing in People as Educational Change Agents.…

  8. Training in practical ergonomics improvements.

    Science.gov (United States)

    Kogi, K

    1989-06-01

    Recent ILO experiences show that concrete ergonomics improvements can result from learning-by-doing training in real settings. Particularly important is to build on local practice focusing on good examples already available. Checklist exercise, demonstrating low-cost solutions and group work are effective training tools. Opportunities can be widely created by such enabling training.

  9. New Ideas for School Improvement.

    Science.gov (United States)

    Dunlap, Diane

    1985-01-01

    This report is comprised of brief summaries of various research-based and theoretical concepts and techniques--taken mostly from business management--that might improve educational administration. The topics discussed include (1) a list of successful business practices identified by the book, "In Search of Excellence"; (2) Theories X, Y, and Z,…

  10. Improved immunocytochemical detection of daunomycin

    DEFF Research Database (Denmark)

    Ohara, Koji; Shin, Masashi; Larsson, Lars-Inge

    2007-01-01

    Improved immunocytochemical (ICC) detection of the anthracycline anticancer antibiotic daunomycin (DM) has been achieved by used of hydrogen peroxide oxidation prior to ICC staining for DM. The new method greatly enhanced the localization of DM accumulation in cardiac, smooth and skeletal muscle...

  11. Rational Design of Improved Pharmabiotics

    Directory of Open Access Journals (Sweden)

    Roy D. Sleator

    2009-01-01

    Full Text Available Herein we review the most recent advances in probiotic research and applications with particular emphasis on the novel concept of patho-biotechnology: the application of pathogen-derived (ex vivo and in vivo stress survival strategies for the design of more technologically robust and effective probiotic cultures with improved biotechnological and clinical applications.

  12. Improved switch-resistor packaging

    Science.gov (United States)

    Redmerski, R. E.

    1980-01-01

    Packaging approach makes resistors more accessible and easily identified with specific switches. Failures are repaired more quickly because of improved accessibility. Typical board includes one resistor that acts as circuit breaker, and others are positioned so that their values can be easily measured when switch is operated. Approach saves weight by using less wire and saves valuable panel space.

  13. Zymomonas with improved xylose utilization

    Science.gov (United States)

    Viitanen, Paul V [West Chester, PA; Tao, Luan [Havertown, PA; Zhang, Yuying [New Hope, PA; Caimi, Perry G [Kennett Square, PA; McCutchen, Carol M [Wilmington, DE; McCole, Laura [East Fallowfield, PA; Zhang, Min [Lakewood, CO; Chou, Yat-Chen [Lakewood, CO; Franden, Mary Ann [Centennial, CO

    2011-08-16

    Strains of Zymomonas were engineered by introducing a chimeric xylose isomerase gene that contains a mutant promoter of the Z. mobilis glyceraldehyde-3-phosphate dehydrogenase gene. The promoter directs increased expression of xylose isomerase, and when the strain is in addition engineered for expression of xylulokinase, transaldolase and transketolase, improved utilization of xylose is obtained.

  14. Improved serological diagnosis of rubella.

    OpenAIRE

    1983-01-01

    The use of an enzyme immunoassay-immunoglobulin G antibody test instead of the hemagglutination inhibition test as a primary test for the serological diagnosis of current infection, with complement fixation as an alternate test for use when enzyme immunoassay results are high and stationary, improved the serological diagnosis of rubella.

  15. Performance improvement. The American way.

    Science.gov (United States)

    Walker, Karen

    2007-02-15

    The role of a US-style 'improvement adviser' is to ensure chages are successfully implemented. They use coaching and facilitation to support project teams and are trained to overcome common obstacles. The advisers have advantages over traditional consultants, as they work with full inside knowledge of the organization and are there for the long-term.

  16. Improvement of 3D Scanner

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    The disadvantage remaining in 3D scanning system and its reasons are discussed. A new host-and-slave structure with high speed image acquisition and processing system is proposed to quicken the image processing and improve the performance of 3D scanning system.

  17. Viscosity Index Improvers and Thickeners

    Science.gov (United States)

    Stambaugh, R. L.; Kinker, B. G.

    The viscosity index of an oil or an oil formulation is an important physical parameter. Viscosity index improvers, VIIs, are comprised of five main classes of polymers: polymethylmethacrylates (PMAs), olefin copolymers (OCPs), hydrogenated poly(styrene-co-butadiene or isoprene) (HSD/SIP/HRIs), esterified polystyrene-co-maleic anhydride (SPEs) and a combination of PMA/OCP systems. The chemistry, manufacture, dispersancy and utility of each class are described. The comparative functions, properties, thickening ability, dispersancy and degradation of VIIs are discussed. Permanent and temporary shear thinning of VII-thickened formulations are described and compared. The end-use performance and choice of VI improvers is discussed in terms of low- and high-temperature viscosities, journal bearing oil film thickness, fuel economy, oil consumption, high-temperature pumping efficiency and deposit control. Discussion of future developments concludes that VI improvers will evolve to meet new challenges of increased thermal-oxidative degradation from increased engine operating temperatures, different base stocks of either synthetic base oils or vegetable oil-based, together with alcohol- or vegetable oil-based fuels. VI improvers must also evolve to deal with higher levels of fuel dilution and new types of sludge and also enhanced low-temperature requirements.

  18. A strategy for company improvement.

    Science.gov (United States)

    Howley, L

    2000-03-01

    Strategies based on the kaizen methodology are designed to continuously improve company performance without the need for large capital investments. This article looks at how one company used simple kaizen principles to its advantage, achieving 67% increase in productivity and 10% reduction in the standard cost of product.

  19. Improving efficiency in pig production

    African Journals Online (AJOL)

    important. The production of lean meat is shown to be improved significantly by adopting ... is interested in the biology of pig production, then biological efficiency and its .... scientific basis, I have calculated the economic effects of a number of ...

  20. Improving Reading Performance through Hypnosis.

    Science.gov (United States)

    Fillmer, H. Thompson; And Others

    1981-01-01

    Describes a study investigating the effects of group hypnosis on the reading performance of university students in a reading and writing center. Discusses study procedures and presents data on pretest scores and gains in vocabulary and comprehension scores. Concludes that regular use of self-hypnosis significantly improved performance. (DMM)

  1. Improving Reading Performances through Hypnosis.

    Science.gov (United States)

    Fillmer, H. Thompson; And Others

    A study was undertaken to investigate the effects of one hypnotic session on the reading improvement of high-risk college students with low aptitude scores and histories of failure in academic situations. The 27 students in the experimental group participated in a one-hour hypnosis session in which they were given a procedure to follow for…

  2. Blended Learning Improves Science Education.

    Science.gov (United States)

    Stockwell, Brent R; Stockwell, Melissa S; Cennamo, Michael; Jiang, Elise

    2015-08-27

    Blended learning is an emerging paradigm for science education but has not been rigorously assessed. We performed a randomized controlled trial of blended learning. We found that in-class problem solving improved exam performance, and video assignments increased attendance and satisfaction. This validates a new model for science communication and education.

  3. Two Improved Digital Signature Schemes

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    In this paper, two improved digital signature schemes are presented based on the design of directed signaturescheme [3]. The peculiarity of the system is that only if the scheme is specific recipient, the signature is authenticated.Since the scheme adds the screen of some information parameters, the difficulty of deciphered keys and the security ofdigital signature system are increased.

  4. Improvement of Drivers’ Training Methods

    Directory of Open Access Journals (Sweden)

    Аltay А. Makenov

    2013-01-01

    Full Text Available This article presents the results of the evaluation of the activity of driving schools of Ust-Kamenogorsk city, the study of risk drivers and polling of driving schools students, which can be used for the improvement of drivers’ training methods

  5. Supporting colleagues to improve care: educating for quality improvement.

    Science.gov (United States)

    Runnacles, Jane; Roueché, Alice

    2015-08-01

    Clinicians at the front line of healthcare delivery are very well positioned to identify and improve the system in which they work. Training curricula, however, have not always equipped them with the skills or knowledge to implement change. This article looks at educational approaches to support clinicians to be actively involved with quality improvement (QI). It looks at the role of doctors in postgraduate training (DrPGT) and their educational supervisors and builds on the topics discussed throughout the 'EQUIPPED' article series. Factors for success of a QI education programme and practical ideas for overcoming barriers to supporting clinicians in QI are discussed. We present examples of educational initiatives and a framework for evaluating such programmes, and we examine the role of faculty development to help inspire and support colleagues to improve care. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  6. Improving Culture, One Quality Improvement Project at a Time.

    Science.gov (United States)

    Vander Schaaf, Emily B; Cornett, Amanda C; Randolph, Greg D

    2017-04-04

    A culture of quality improvement (QI) values collaboration, transparency, and staff empowerment. Organizations exhibiting a culture of QI are more likely to engage in QI. We examined whether local health departments' (LHDs') participation in a longitudinal, experiential QI training program changes QI culture. Prior to and following participation in a QI training program, all employees of participating LHDs were asked to complete an 8-item survey assessing components of QI culture on a 5-point scale. From 2010 to 2015, multidisciplinary teams from North Carolina LHDs participated in sequential cohorts of a 6-month QI training program, during which the teams completed a QI project. We dichotomized culture survey responses, with 4 or 5 being "Supportive." We compared adjusted proportions, using linear regression, clustering at LHD, and controlling for cohort. Data from 42 LHDs were included. At baseline, 7.8% responded that their LHD had a supportive culture for all 8 components, compared with 12% at follow-up (P cultures increased for all components of culture including communication by 4.1% (95% CI: 2.0%-6.2%), problem solving by 2.9% (95% CI: 1.6%-5.5%), team work by 5.2% (95% CI: 2.5%-7.8%), vision by 4.3% (95% CI: 1.1%-7.5%), performance measures by 5.6% (95% CI: 1.6%-9.6%), recognition by 4.7% (95% CI: 1.4%-8.0%), for conflict by 5.5% (95% CI: 1.7%-9.4%), and alignment by 5.8% (95% CI: 2.3%-9.2%). Engagement with structured QI training programs-and perhaps simply completing QI projects-can cause small, but important changes in organizations' cultures, thus increasing engagement in future QI and improving overall care and services. The article demonstrates that when LHDs participate in a longitudinal, experiential QI training program, their cultures of QI improve. Local health departments participating in similar training programs might experience similar improvements in culture, increasing subsequent participation in QI projects and improving related health

  7. ISO 14001: time for improvements?

    DEFF Research Database (Denmark)

    Jørgensen, Tine Herreborg

    2007-01-01

    The aim of this paper is to discuss a number of issues related to ISO 14001:2004, the international standard for Environmental Management Systems (EMS) with the purpose of improving the next edition in order to recognise and reflect new recognitions in approaches to pollution prevention. A case s...... improvements and to include a demand for publication of an environmental report to promote a constructive dialogue with relevant stakeholders....... study is presented and shows lack of life cycle thinking in product development. This paper suggests changes of ISO 14001:2004 in order to include a more product-oriented approach and a stronger focus on stakeholders. It also suggests to formulate clearer demands for targets and environmental...

  8. Improved Windows for Cold Climates

    DEFF Research Database (Denmark)

    Laustsen, Jacob Birck; Svendsen, Svend

    2005-01-01

    of the heating demand in typical single-family houses in Denmark and Greenland. The examined windows are typical new windows from Nordic countries and new proposals of improved windows with low thermal transmittance and high total solar energy transmittance. The results show that net energy gain can be increased...... considerably by reducing the frame width, which results in a larger transparent area causing a larger solar gain but still main-taining a low thermal transmittance. Using three layers of glass with large gaps, using very slim frame profiles, and omitting the edge constructions that normally causes thermal...... bridges achieve this. Applying shutters or low emissivity coated roller blinds incorporated in the glazing that are activated during night time can improve the energy performance of windows. The results from this work show that it is possible to develop windows with a positive net energy in a fairly...

  9. Improved power performance assessment methods

    Energy Technology Data Exchange (ETDEWEB)

    Frandsen, S.; Antoniou, I.; Dahlberg, J.A. [and others

    1999-03-01

    The uncertainty of presently-used methods for retrospective assessment of the productive capacity of wind farms is unacceptably large. The possibilities of improving the accuracy have been investigated and are reported. A method is presented that includes an extended power curve and site calibration. In addition, blockage effects with respect to reference wind speed measurements are analysed. It is found that significant accuracy improvements are possible by the introduction of more input variables such as turbulence and wind shear, in addition to mean wind speed and air density. Also, the testing of several or all machines in the wind farm - instead of only one or two - may provide a better estimate of the average performance. (au)

  10. Improved Windows for Cold Climates

    DEFF Research Database (Denmark)

    Laustsen, Jacob Birck; Svendsen, Svend

    2005-01-01

    A large part of the energy consumption in countries in Nordic and Arctic climates is used for space heating in buildings. In typical buildings the windows are responsible for a considerable part of the heat losses. Therefore there is a large potential for energy savings by developing and using...... windows with improved energy performance. Traditionally evaluation of the energy performance of windows has focussed on the thermal transmittance, but as windows differ from the rest of the building envelope by allowing solar energy to enter the building, the total solar energy transmittance is equally...... of the heating demand in typical single-family houses in Denmark and Greenland. The examined windows are typical new windows from Nordic countries and new proposals of improved windows with low thermal transmittance and high total solar energy transmittance. The results show that net energy gain can be increased...

  11. Fuel Efficiencies Through Airframe Improvements

    Science.gov (United States)

    Bezos-O'Connor, Gaudy M.; Mangelsdorf, Mark F.; Maliska, Heather A.; Washburn, Anthony E.; Wahls, Richard A.

    2011-01-01

    The factors of continuing strong growth in air traffic volume, the vital role of the air transport system on the economy, and concerns about the environmental impact of aviation have added focus to the National Aeronautics Research Policy. To address these concerns in the context of the National Policy, NASA has set aggressive goals in noise reduction, emissions, and energy consumption. With respect to the goal of reducing energy consumption in the fleet, the development of promising airframe technologies is required to realize the significant improvements that are desired. Furthermore, the combination of advances in materials and structures with aerodynamic technologies may lead to a paradigm shift in terms of potential configurations for the future. Some of these promising airframe technologies targeted at improved efficiency are highlighted.

  12. Group discussion improves lie detection.

    Science.gov (United States)

    Klein, Nadav; Epley, Nicholas

    2015-06-16

    Groups of individuals can sometimes make more accurate judgments than the average individual could make alone. We tested whether this group advantage extends to lie detection, an exceptionally challenging judgment with accuracy rates rarely exceeding chance. In four experiments, we find that groups are consistently more accurate than individuals in distinguishing truths from lies, an effect that comes primarily from an increased ability to correctly identify when a person is lying. These experiments demonstrate that the group advantage in lie detection comes through the process of group discussion, and is not a product of aggregating individual opinions (a "wisdom-of-crowds" effect) or of altering response biases (such as reducing the "truth bias"). Interventions to improve lie detection typically focus on improving individual judgment, a costly and generally ineffective endeavor. Our findings suggest a cheap and simple synergistic approach of enabling group discussion before rendering a judgment.

  13. Windows with improved energy performance

    DEFF Research Database (Denmark)

    Noyé, Peter Anders; Laustsen, Jacob Birck; Svendsen, Svend

    2002-01-01

    the paper describes how the net energy gain from a complete typical window can be increased in a fairly simple way by reducing the frame width and using glass with low iron content. The changes primary increase the g-value. All improvements are based on existing technology and manufacturing methods...... performances. During the last 20 years the U-value of the glazing part of windows has been improved considerably, but the frame part has not followed the same development with respect to energy performance. Therefore an increasingly large part of the total heat loss through windows is relating to the frame...... part, for which reason, as far as energy efficiency and total economy are concerned, it has become more interesting to further develop frame structures. Traditionally, the energy performance of windows has primarily been characterised by the heat loss coefficient, U-value. However as the heat loss has...

  14. An Improved Multicast Routing Algorithm

    Institute of Scientific and Technical Information of China (English)

    蒋廷耀; 李庆华

    2004-01-01

    Multicasting is a communication service that allows an application to efficiently transmit copies of data packets to a set of destination nodes. The problem of finding a minimum cost multicast tree can be formulated as a minimum Steiner tree problem in networks, which is NP-completeness. MPH (minimum path cost heuristic) algorithm is a famous solution to this problem. In this paper,we present a novel solution TPMPH (two phase minimum path cost heuristic) to improve the MPH by generating the nodes and the edges of multicast tree separately. The cost of multicast tree generated by the proposed algorithm with the same time as MPH is no more than that of MPH in the worst case. Extensive simulation results show that TPMPH can effectively improve the performance on MPH, and performs better in large-scale networks and wireless networks.

  15. Biological improvement of radiation resistance

    Energy Technology Data Exchange (ETDEWEB)

    Chun, K. J.; Lee, Y. K.; Kim, J. S.; Kim, J. K.; Lee, S. J

    2000-08-01

    To investigate the mechanisms of gene action related to the radiation resistance in microorganisms could be essentially helpful for the development of radiation protectants and hormeric effects of low dose radiation. This book described isolation of radiation-resistant microorganisms, induction of radiation-resistant and functionally improved mutants by gamma-ray radiation, cloning and analysis of the radiation resistance related genes and analysis of the expressed proteins of the radiation resistant related genes.

  16. Developing a Continuous Improvement System

    Science.gov (United States)

    2016-09-16

    to ensure that its employees enhance their knowledge, skills and experiences. These improved competencies help them achieve personal and career ...Army’s Career Acquisition Personnel and Position Management In- formation System. This system allows the employee to plan, coordinate, and manage their...The initial chal- lenge was to adapt the prototype equipment to the facilities at CAAA, which received the primary pieces of equipment such as the

  17. An improvement of Papadakis' theorem

    Institute of Scientific and Technical Information of China (English)

    ZHANG Zhihua; MU Lehua; ZHANG Peixuan

    2004-01-01

    There exist many orthonormal wavelets which cannot be derived by multiresolution analysis (MRA) with a single scaling function.In 2000,Papadakis announced that any orthonormal wavelet is derived by a generalized MRA with countable scaling functions at most.We improve Papadakis' theorem and find that for any othonormal wavelet,the least number of the corresponding scaling functions is just the essential supremum of the dimension function of the orthonormal wavelet.Moreover,we construct directly the fewest scaling functions.

  18. Design Review Improvements Product Overview

    Science.gov (United States)

    2015-05-07

    Boeing Anne Ramsey, Harris Corporation Ronald H. Mandel, Lockheed Martin Mark King, Micropac Industries Melanie Berg , NASA Cindy Kohlmiller...Improvements Topic • Design escapes continue to impact program cost, schedule and mission performance • Our design review and development test programs...for and conduct design reviews – Surveyed team member companies – 49 test cases – Reviewed Aerospace on-orbit anomaly data (Classified) – 121 test cases

  19. Cassegrain-Antenna Gain Improvement

    Science.gov (United States)

    Galindo, V.; Cha, A. G.; Mittra, R.

    1986-01-01

    Modified antenna feed with dual-shaped subreflectors yields 10-to20-percent improvement in efficiency of existing large-aperture paraboloidal or Cassegrainian antennas. Such offset dual-shaped subreflector (DSS) feed brings gain of existing paraboloid or Cassegrain antennas up to that of reflector antennas of more recent design at cost considerably lower than for reshaping existing reflecting surfaces. Mathematical procedures developed for synthesizing nearly optimum shapes for DSS elements of new feeds.

  20. How To Improve English Reading

    Institute of Scientific and Technical Information of China (English)

    李薇

    2010-01-01

    @@ 1.INTRODUCTION The necessity of reading improving Reading is a pleasure of your mind,which means that it is like a sport: your eagerness and knowledge and quickness make you a good reader.Reading is fun,not because the writer is telling you something,but because it makes your mind work.Your own imagination works along with the author's or even goes beyond his.

  1. Improving Peptide Applications Using Nanotechnology.

    Science.gov (United States)

    Narayanaswamy, Radhika; Wang, Tao; Torchilin, Vladimir P

    2016-01-01

    Peptides are being successfully used in various fields including therapy and drug delivery. With advancement in nanotechnology and targeted delivery carrier systems, suitable modification of peptides has enabled achievement of many desirable goals over-riding some of the major disadvantages associated with the delivery of peptides in vivo. Conjugation or physical encapsulation of peptides to various nanocarriers, such as liposomes, micelles and solid-lipid nanoparticles, has improved their in vivo performance multi-fold. The amenability of peptides to modification in chemistry and functionalization with suitable nanocarriers are very relevant aspects in their use and have led to the use of 'smart' nanoparticles with suitable linker chemistries that favor peptide targeting or release at the desired sites, minimizing off-target effects. This review focuses on how nanotechnology has been used to improve the number of peptide applications. The paper also focuses on the chemistry behind peptide conjugation to nanocarriers, the commonly employed linker chemistries and the several improvements that have already been achieved in the areas of peptide use with the help of nanotechnology.

  2. Improving immunization approaches to cholera.

    Science.gov (United States)

    Saha, Amit; Rosewell, Alexander; Hayen, Andrew; MacIntyre, C Raina; Qadri, Firdausi

    2017-03-01

    Cholera's impact is greatest in resource-limited countries. In the last decade several large epidemics have led to a global push to improve and implement the tools for cholera prevention and control. Areas covered: PubMed, Google Scholar and the WHO website were searched to review the literature and summarize the current status of cholera vaccines to make recommendations on improving immunization approaches to cholera. Oral cholera vaccines (OCVs) have demonstrated their effectiveness in endemic, outbreak response and emergency settings, highlighting their potential for wider adoption. While two doses of the currently available OCVs are recommended by manufacturers, a single dose would be easier to implement. Encouragingly, recent studies have shown that cold chain requirements may no longer be essential. The establishment of the global OCV stockpile in 2013 has been a major advance in cholera preparedness. New killed and live-attenuated vaccines are being actively explored as candidate vaccines for endemic settings and/or as a traveller's vaccine. The recent advances in cholera vaccination approaches should be considered in the global cholera control strategy. Expert commentary: The development of affordable cholera vaccines is a major success to improve cholera control. New vaccines and country specific interventions will further reduce the burden of this disease globally.

  3. Improving emergency department patient flow.

    Science.gov (United States)

    Jarvis, Paul Richard Edwin

    2016-06-01

    Emergency departments (ED) face significant challenges in delivering high quality and timely patient care on an ever-present background of increasing patient numbers and limited hospital resources. A mismatch between patient demand and the ED's capacity to deliver care often leads to poor patient flow and departmental crowding. These are associated with reduction in the quality of the care delivered and poor patient outcomes. A literature review was performed to identify evidence-based strategies to reduce the amount of time patients spend in the ED in order to improve patient flow and reduce crowding in the ED. The use of doctor triage, rapid assessment, streaming and the co-location of a primary care clinician in the ED have all been shown to improve patient flow. In addition, when used effectively point of care testing has been shown to reduce patient time in the ED. Patient flow and departmental crowding can be improved by implementing new patterns of working and introducing new technologies such as point of care testing in the ED.

  4. Improved Digital Image Correlation method

    Science.gov (United States)

    Mudassar, Asloob Ahmad; Butt, Saira

    2016-12-01

    Digital Image Correlation (DIC) is a powerful technique which is used to correlate two image segments to determine the similarity between them. A correlation image is formed which gives a peak known as correlation peak. If the two image segments are identical the peak is known as auto-correlation peak otherwise it is known as cross correlation peak. The location of the peak in a correlation image gives the relative displacement between the two image segments. Use of DIC for in-plane displacement and deformation measurements in Electronic Speckle Photography (ESP) is well known. In ESP two speckle images are correlated using DIC and relative displacement is measured. We are presenting background review of ESP and disclosing a technique based on DIC for improved relative measurements which we regard as the improved DIC method. Simulation and experimental results reveal that the proposed improved-DIC method is superior to the conventional DIC method in two aspects, in resolution and in the availability of reference position in displacement measurements.

  5. Improving mental health outcomes: achieving equity through quality improvement

    Science.gov (United States)

    Poots, Alan J.; Green, Stuart A.; Honeybourne, Emmi; Green, John; Woodcock, Thomas; Barnes, Ruth; Bell, Derek

    2014-01-01

    Objective To investigate equity of patient outcomes in a psychological therapy service, following increased access achieved by a quality improvement (QI) initiative. Design Retrospective service evaluation of health outcomes; data analysed by ANOVA, chi-squared and Statistical Process Control. Setting A psychological therapy service in Westminster, London, UK. Participants People living in the Borough of Westminster, London, attending the service (from either healthcare professional or self-referral) between February 2009 and May 2012. Intervention(s) Social marketing interventions were used to increase referrals, including the promotion of the service through local media and through existing social networks. Main Outcome Measure(s) (i) Severity of depression on entry using Patient Health Questionnaire-9 (PHQ9). (ii) Changes to severity of depression following treatment (ΔPHQ9). (iii) Changes in attainment of a meaningful improvement in condition assessed by a key performance indicator. Results Patients from areas of high deprivation entered the service with more severe depression (M = 15.47, SD = 6.75), compared with patients from areas of low (M = 13.20, SD = 6.75) and medium (M = 14.44, SD = 6.64) deprivation. Patients in low, medium and high deprivation areas attained similar changes in depression score (ΔPHQ9: M = −6.60, SD = 6.41). Similar proportions of patients achieved the key performance indicator across initiative phase and deprivation categories. Conclusions QI methods improved access to mental health services; this paper finds no evidence for differences in clinical outcomes in patients, regardless of level of deprivation, interpreted as no evidence of inequity in the service with respect to this outcome. PMID:24521701

  6. Improved Biomass Cooking Stoves and Improved Stove Emission Equipment

    Energy Technology Data Exchange (ETDEWEB)

    HATFIELD, MICHAEL; Still, Dean

    2013-04-15

    In developing countries, there is an urgent need for access to safe, efficient, and more affordable cooking technologies. Nearly 2.5 billion people currently use an open fire or traditional cookstove to prepare their meals, and recent models predict that use of biomass for cooking will continue to be the dominant energy use in rural, resource-poor households through 2030. For these families, cooking poses serious risks to health, safety, and income. An alarming 4 million people, primarily women and children, die prematurely each year from indoor and outdoor exposure to the harmful emissions released by solid fuel combustion. Use of traditional stoves can also have a significant impact on deforestation and climate change. This dire situation creates a critical need for cookstoves that significantly and verifiably reduce fuel use and emissions in order to reach protective levels for human health and the environment. Additionally, advances in the scientific equipment needed to measure and monitor stove fuel use and emissions have not kept pace with the significant need within the industry. While several testing centers in the developed world may have hundred thousand-dollar emissions testing systems, organizations in the field have had little more than a thermometer, a scale, and subjective observations to quantify the performance of stove designs. There is an urgent need for easy-to-use, inexpensive, accurate, and robust stove testing equipment for use by laboratory and field researchers around the world. ASAT and their research partner, Aprovecho Research Center (ARC), have over thirty years of experience addressing these two needs, improved cookstoves and emissions monitoring equipment, with expertise spanning the full spectrum of development from conceptual design to product manufacturing and dissemination. This includes: 1) research, design, and verification of clean biomass cookstove technology and emissions monitoring equipment; 2) mass production of quality

  7. Shipbuilding pipeline production quality improvement

    Directory of Open Access Journals (Sweden)

    T. Buksa

    2010-06-01

    Full Text Available Purpose: The pipeline production is one of major processes in shipbuilding industry. Quality improvement and risk assessment in this process can yield significant savings, both in terms of internal quality costs as well as in terms of customer satisfactions.Design/methodology/approach: Shipbuilding pipeline production quality improvement has been carried out by application of FMEA (Failure Mode and Effect Analysis method. For the successful implementation of FMEA method it is necessary to identify process failure modes or possibility of the appearance of non-compliance, as well as their possible causes. For qualitative analysis of key input variables of the process, in the paper is used Ishikawa diagram and p-chart.Findings: It is shown that proposed approach to risk assessment in shipbuilding pipeline production is applicable to real casa scenario. The analysis has identified the points in the process with the highest probability of occurrence of nonconformities, or the highest risk for error.Research limitations/implications: As the experimenting has been conducted in shipyard, within production process, research schedule must have been set in accordance with production pace. Also, due to character of production process the data collecting was adopted to the production plan in that particular moment.Practical implications: Dealing with causes of potential nonconformities in the process can significantly contribute to the reliability and robustness of the process. Corrective actions that have been taken based on results of analysis significantly contributed to the level of quality in the pipeline production process.Originality/value: The pepper is dealing with a well known method applied in different production environment that are mostly conservative in production approach. It was shown that successful application of proposed approach can yield benefits especially in improved quality of produced pipelines within shipbuilding industry.

  8. Orthogeriatric care: improving patient outcomes

    Directory of Open Access Journals (Sweden)

    Tarazona-Santabalbina FJ

    2016-06-01

    Full Text Available Francisco José Tarazona-Santabalbina,1,2 Ángel Belenguer-Varea,1,2 Eduardo Rovira,1,2 David Cuesta-Peredó1,21Geriatric Medicine Unit, Internal Medicine Department, Hospital Universitario de la Ribera, 2Medical School, Universidad Católica de Valencia San vicente Mártir, Valencia, SpainAbstract: Hip fractures are a very serious socio-economic problem in western countries. Since the 1950s, orthogeriatric units have introduced improvements in the care of geriatric patients admitted to hospital because of hip fractures. During this period, these units have reduced mean hospital stays, number of complications, and both in-hospital mortality and mortality over the middle term after hospital discharge, along with improvements in the quality of care and a reduction in costs. Likewise, a recent clinical trial has reported greater functional gains among the affected patients. Studies in this field have identified the prognostic factors present upon admission or manifesting themselves during admission and that increase the risk of patient mortality or disability. In addition, improved care afforded by orthogeriatric units has proved to reduce costs. Nevertheless, a number of management issues remain to be clarified, such as the optimum anesthetic, analgesic, and thromboprophylactic protocols; the type of diagnostic and therapeutic approach best suited to patients with cognitive problems; or the efficiency of the programs used in convalescence units or in home rehabilitation care. Randomized clinical trials are needed to consolidate the evidence in this regard. Keywords: hip fractures, geriatric assessment, orthogeriatric care, recovery of function, mortality

  9. How to Improve Spoken English

    Institute of Scientific and Technical Information of China (English)

    郑瑜

    2015-01-01

    Undoubtedly,English has become more and more important in our daily lives,and how to communicate with others in English fluently has aroused general concern.Picking up a second language is always not that easy.Ironically,the truth is that many Chinese realize it is a big problem to speak English fluently although they can easily get a high score in some English written exams.Spoken English is so important that I mainly introduce some effective methods to practice and improve it in this essay.

  10. How to Improve Spoken English

    Institute of Scientific and Technical Information of China (English)

    郑瑜

    2015-01-01

    Undoubtedly,English has become more and more important in our daily lives,and how to communicate with others in English fluently has aroused general concern.Picking up a second language is always not that easy.Ironically,the truth is that many Chinese realize it is a big problem to speak English fluently although they can easily get a high score in some English written exams.Spoken English is so important that I mainly introduce some effective methods to practice and improve it in this essay .

  11. Improvement of Hartman's linearization theorem

    Institute of Scientific and Technical Information of China (English)

    SHI; Jinlin(史金麟)

    2003-01-01

    Hartman's linearization theorem tells us that if matrix A has no zero real part and f(x) isbounded and satisfies Lipchitz condition with small Lipchitzian constant, then there exists a homeomorphismof Rn sending the solutions of nonlinear system x' = Ax + f(x) onto the solutions of linear system x' = Ax.In this paper, some components of the nonlinear item f(x) are permitted to be unbounded and we provethe result of global topological linearization without any special limitation and adding any condition. Thus,Hartman's linearization theorem is improved essentially.

  12. Distributed Wind Competitiveness Improvement Project

    Energy Technology Data Exchange (ETDEWEB)

    2016-05-01

    The Competitiveness Improvement Project (CIP) is a periodic solicitation through the U.S. Department of Energy and its National Renewable Energy Laboratory. Manufacturers of small and medium wind turbines are awarded cost-shared grants via a competitive process to optimize their designs, develop advanced manufacturing processes, and perform turbine testing. The goals of the CIP are to make wind energy cost competitive with other distributed generation technology and increase the number of wind turbine designs certified to national testing standards. This fact sheet describes the CIP and funding awarded as part of the project.

  13. ISO 14001: time for improvements?

    DEFF Research Database (Denmark)

    Jørgensen, Tine Herreborg

    2007-01-01

    The aim of this paper is to discuss a number of issues related to ISO 14001:2004, the international standard for Environmental Management Systems (EMS) with the purpose of improving the next edition in order to recognise and reflect new recognitions in approaches to pollution prevention. A case...... study is presented and shows lack of life cycle thinking in product development. This paper suggests changes of ISO 14001:2004 in order to include a more product-oriented approach and a stronger focus on stakeholders. It also suggests to formulate clearer demands for targets and environmental...

  14. Phytases for Improved Iron Absorption

    DEFF Research Database (Denmark)

    Nielsen, Anne Veller Friis; Nyffenegger, Christian; Meyer, Anne S.

    2014-01-01

    Microbial phytases (EC 3.1.3.8) catalyse dephosphorylation of phytic acid, which is the primary storage compound for phosphorous in cereal kernels. The negatively charged phosphates in phytic acid chelate iron (Fe3+) and thus retards iron bioavailability in humans 1. Supplementation of microbial...... phytase can improve iron absorption from cereal-based diets 2. In order for phytase to catalyse iron release in vivo the phytase must be robust to low pH and proteolysis in the gastric ventricle. Our work has compared the robustness of five different microbial phytases, evaluating thermal stability...

  15. How to improve skin notation

    DEFF Research Database (Denmark)

    Sartorelli, Pietro; Ahlers, Heinz W.; Alanko, Kristiina

    2007-01-01

    The ICOH Scientific Committee on Occupational and Environmental Dermatoses organized an International Workshop on “Dermal risk assessment at workplace” with the aim of focussing on the different ways of approaching the concept of skin notation (S) for chemicals. The Workshop participants presented...... their ideas on several aspects of S such as the problems related to the absorption through the compromised skin, the different approaches to S and models that can be used as alternatives to S. Participants agreed to produce a position paper with the goal of exploring the actions needed to improve the S system...

  16. Windows with improved energy performances

    DEFF Research Database (Denmark)

    Laustsen, Jacob Birck; Svendsen, Svend

    2003-01-01

    Heat loss through windows represents a considerable part of the total heat loss from houses. However, apart from providing daylight access and view, windows offer a unique potential for solar gain to be exploited during the heating season. Until now valuation of the energy performance of windows...... resulted in a window with a positive net energy gain (in short the Net Gain Window), which means that it contributes to the space heating of the building. All improvements are based on existing technology and manufacturing methods. The results from this work show that the energy performances of windows can...

  17. Improving healthcare using Lean processes.

    Science.gov (United States)

    Baker, G Ross

    2014-01-01

    For more than a decade, healthcare organizations across Canada have been using Lean management tools to improve care processes, reduce preventable adverse events, increase patient satisfaction and create better work environments. The largest system-wide effort in Canada, and perhaps anywhere, is currently under way in Saskatchewan. The jury is still out on whether Lean efforts in that province, or elsewhere in Canada, are robust enough to transform current delivery systems and sustain new levels of performance. This issue of Healthcare Quarterly features several articles that provide a perspective on Lean methods in healthcare.

  18. IMPROVING QUALITY MANAGEMENT IN PANIFICATION

    Directory of Open Access Journals (Sweden)

    Cornelia Petroman

    2010-12-01

    Full Text Available Consumers of panification products (as well as consumers of any other type of product or service are concerned about the quality of the products they purchase. Implementing the quality management system in the food industry is not compulsory, but it can bring about numerous, palpable benefits, particularly in reducing the amount of acryl amide. It is a modern system allowing the management analysis aiming at checking and reaching the goals to define new objectives, and the continuous improvement of the quality of processes and products.

  19. Adaptive Crowdsourcing and Improved Innovation

    DEFF Research Database (Denmark)

    Edgeman, Rick; Engell, Toke; Jensen, Nik Grewy

    Crowdsourcing is central to enterprise open innovation efforts, providing a source of labor, funding, and ideas. Though use of crowdsourcing in selected environments is well understood, application in business-to-business (B2B) market environments has been limited. Selected reasons for this, incl...... improvements are extracted are science parks, innovation clusters, innovation contests, free zones, smart cities, government-to-citizen interaction, and citizen science.......Crowdsourcing is central to enterprise open innovation efforts, providing a source of labor, funding, and ideas. Though use of crowdsourcing in selected environments is well understood, application in business-to-business (B2B) market environments has been limited. Selected reasons for this...

  20. Improving physics education in radiology.

    Science.gov (United States)

    Hendee, William R

    2007-08-01

    Concern is growing that the physics education of radiologists is flawed and that without knowledge of physics principles and applications, mastery of the technology of medical imaging is impaired. Furthermore, it is proposed that a mastery of imaging technology is necessary to perfect the clinical acumen of radiologists and to preserve the quality, safety, and cost-effectiveness of imaging procedures. These issues were the focus of a multiorganizational educational summit on physics education of radiologists held in January 2006 in Atlanta. Recommendations for improving the physics education and knowledge of radiologists that evolved from this summit are presented here, together with progress made to date on their fulfillment.

  1. An Improved Implementation of Grain

    CERN Document Server

    Mansouri, Shohreh Sharif

    2009-01-01

    A common approach to protect confidential information is to use a stream cipher which combines plain text bits with a pseudo-random bit sequence. Among the existing stream ciphers, Non-Linear Feedback Shift Register (NLFSR)-based ones provide the best trade-off between cryptographic security and hardware efficiency. In this paper, we show how to further improve the hardware efficiency of Grain stream cipher. By transforming the NLFSR of Grain from its original Fibonacci configuration to the Galois configuration and by introducing a clock division block, we double the throughput of the 80 and 128-bit key 1bit/cycle architectures of Grain with no area penalty.

  2. Windows with improved energy performance

    DEFF Research Database (Denmark)

    Noyé, Peter Anders; Laustsen, Jacob Birck; Svendsen, Svend

    2002-01-01

    the paper describes how the net energy gain from a complete typical window can be increased in a fairly simple way by reducing the frame width and using glass with low iron content. The changes primary increase the g-value. All improvements are based on existing technology and manufacturing methods...... part, for which reason, as far as energy efficiency and total economy are concerned, it has become more interesting to further develop frame structures. Traditionally, the energy performance of windows has primarily been characterised by the heat loss coefficient, U-value. However as the heat loss has...

  3. Cellular and Molecular Actions of Methylene Blue in the Nervous System

    Science.gov (United States)

    Oz, Murat; Lorke, Dietrich E.; Hasan, Mohammed; Petroianu, George A.

    2010-01-01

    Methylene Blue (MB), following its introduction to biology in the 19th century by Ehrlich, has found uses in various areas of medicine and biology. At present, MB is the first line of treatment in methemoglobinemias, is used frequently in the treatment of ifosfamide-induced encephalopathy, and is routinely employed as a diagnostic tool in surgical procedures. Furthermore, recent studies suggest that MB has beneficial effects in Alzheimer's disease and memory improvement. Although the modulation of the cGMP pathway is considered the most significant effect of MB, mediating its pharmacological actions, recent studies indicate that it has multiple cellular and molecular targets. In the majority of cases, biological effects and clinical applications of MB are dictated by its unique physicochemical properties including its planar structure, redox chemistry, ionic charges, and light spectrum characteristics. In this review article, these physicochemical features and the actions of MB on multiple cellular and molecular targets are discussed with regard to their relevance to the nervous system. PMID:19760660

  4. Improving cosmic string network simulations

    Science.gov (United States)

    Hindmarsh, Mark; Rummukainen, Kari; Tenkanen, Tuomas V. I.; Weir, David J.

    2014-08-01

    In real-time lattice simulations of cosmic strings in the Abelian Higgs model, the broken translational invariance introduces lattice artifacts; relativistic strings therefore decelerate and radiate. We introduce two different methods to construct a moving string on the lattice, and study in detail the lattice effects on moving strings. We find that there are two types of lattice artifact: there is an effective maximum speed with which a moving string can be placed on the lattice, and a moving string also slows down, with the deceleration approximately proportional to the exponential of the velocity. To mitigate this, we introduce and study an improved discretization, based on the tree-level Lüscher-Weisz action, which is found to reduce the deceleration by an order of magnitude, and to increase the string speed limit by an amount equivalent to halving the lattice spacing. The improved algorithm is expected to be very useful for 3D simulations of cosmic strings in the early Universe, where one wishes to simulate as large a volume as possible.

  5. Improving cosmic string network simulations

    CERN Document Server

    Hindmarsh, Mark; Tenkanen, Tuomas V I; Weir, David J

    2014-01-01

    In real-time lattice simulations of cosmic strings in the Abelian Higgs model, the broken translational invariance introduces lattice artefacts; relativistic strings therefore decelerate and radiate. We introduce two different methods to construct a moving string on the lattice, and study in detail the lattice effects on moving strings. We find that there are two types of lattice artefact: there is an effective maximum speed with which a moving string can be placed on the lattice, and a moving string also slows down, with the deceleration approximately proportional to the exponential of the velocity. To mitigate this, we introduce and study an improved discretisation, based on the tree-level L\\"{u}scher-Weisz action, which is found to reduce the deceleration by an order of magnitude, and to increase the string speed limit by an amount equivalent to halving the lattice spacing. The improved algorithm is expected to be very useful for 3D simulations of cosmic strings in the early universe, where one wishes to s...

  6. Improvements of evaporation drag model

    Institute of Scientific and Technical Information of China (English)

    LI Xiao-Yan; XU Ji-Jun

    2004-01-01

    A special visible experiment facility has been designed and built, and an observable experiment is performed by pouring one or several high-temperature particles into a water pool in the facility. The experiment result has verified Yang's evaporation drag model, which holds that the non-symmetric profile of the local evaporation rate and the local density of vapor would bring about a resultant force on the hot particle so as to resist its motion. However, in Yang's evaporation drag model, radiation heat transfer is taken as the only way to transfer heat from hot particle to the vapor-liquid interface, and all of the radiation energy is deposited on the vapor-liquid interface and contributed to the vaporization rate and mass balance of the vapor film. In improved model heat conduction and heat convection are taken into account. This paper presents calculations of the improved model, putting emphasis on the effect of hot particle's temperature on the radiation absorption behavior of water.

  7. Technology improves upper extremity rehabilitation.

    Science.gov (United States)

    Kowalczewski, Jan; Prochazka, Arthur

    2011-01-01

    Stroke survivors with hemiparesis and spinal cord injury (SCI) survivors with tetraplegia find it difficult or impossible to perform many activities of daily life. There is growing evidence that intensive exercise therapy, especially when supplemented with functional electrical stimulation (FES), can improve upper extremity function, but delivering the treatment can be costly, particularly after recipients leave rehabilitation facilities. Recently, there has been a growing level of interest among researchers and healthcare policymakers to deliver upper extremity treatments to people in their homes using in-home teletherapy (IHT). The few studies that have been carried out so far have encountered a variety of logistical and technical problems, not least the difficulty of conducting properly controlled and blinded protocols that satisfy the requirements of high-level evidence-based research. In most cases, the equipment and communications technology were not designed for individuals with upper extremity disability. It is clear that exercise therapy combined with interventions such as FES, supervised over the Internet, will soon be adopted worldwide in one form or another. Therefore it is timely that researchers, clinicians, and healthcare planners interested in assessing IHT be aware of the pros and cons of the new technology and the factors involved in designing appropriate studies of it. It is crucial to understand the technical barriers, the role of telesupervisors, the motor improvements that participants can reasonably expect and the process of optimizing IHT-exercise therapy protocols to maximize the benefits of the emerging technology.

  8. Improving federal response to drought

    Energy Technology Data Exchange (ETDEWEB)

    Wilhite, D.A.; Rosenberg, N.J.; Glantz, M.H.

    1986-03-01

    Severe and widespread drought occurred over a large portion of the US between 1974 and 1977. Impacts on agriculture and other industries, as well as local water supplies, were substantial. The federal government responded with forty assistance programs administered by sixteen federal agencies. Assistance was provided primarily in the form of loans and grants to people, businesses and governments experiencing hardship caused by drought. The total cost of the program is estimated at $7-8 billion. Federal response to the mid-1970s drought was largely untimely, ineffective and poorly coordinated. Four recommendations are offered that, if implemented, would improve future drought assessment and response efforts: 1) reliable and timely informational products and dissemination plans; 2) improved impact assessment techniques, especially in the agricultural sector, for use by government to identify periods of enhanced risk and to trigger assistance measures; 3) administratively centralized drought declaration procedures that are well publicized and consistently applied; and 4) standby assistance measures that encourage appropriate levels of risk management by producers and that are equitable, consistent and predictable. The development of a national drought plan that incorporates these four items is recommended. Atmospheric scientists have an important role to play in the collection and interpretation of near-real time weather data for use by government decision makers.

  9. Performance improvement CME: managing chronic pain.

    Science.gov (United States)

    Fishman, Scott M

    2010-12-01

    Performance Improvement CME (PI CME) is an educational activity in which clinicians retrospectively assess their current clinical practice, choose areas for improvement and implement interventions based on treatment guidelines and health care standards, and then re-evaluate their clinical practice to assess the improvements made. This PI CME activity focuses on improving the safety and efficacy of treating chronic pain with opioid medications.

  10. OLED with improved light outcoupling

    Energy Technology Data Exchange (ETDEWEB)

    Forrest, Stephen; Sun, Yiru

    2016-11-29

    An OLED may include regions of a material having a refractive index less than that of the substrate, or of the organic region, allowing for emitted light in a waveguide mode to be extracted into air. These regions can be placed adjacent to the emissive regions of an OLED in a direction parallel to the electrodes. The substrate may also be given a nonstandard shape to further improve the conversion of waveguide mode and/or glass mode light to air mode. The outcoupling efficiency of such a device may be up to two to three times the efficiency of a standard OLED. Methods for fabricating such a transparent or top-emitting OLED is also provided.

  11. Hadronic Screening in Improved Taste

    CERN Document Server

    Gupta, Sourendu

    2013-01-01

    We present our results on meson and nucleon screening masses in finite temperature two flavour QCD using smeared staggered valence quarks and staggered thin-link sea quarks with different lattice spacings and quark masses. We investigate optimization of smearing by observing its effects on the infrared (IR) and ultraviolet (UV) components of gluon and quark fields. The application of smearing to screening at finite temperature also provides a transparent window into the mechanism of the interplay of smearing and chiral symmetry. The improved hadronic operators show that above the finite temperature cross over, T_c, screening masses are consistent with weak-coupling predictions. There is also evidence for a rapid opening up of a spectral gap of the Dirac operator immediately above T_c.

  12. Power Quality Improvement Using UPQC

    Directory of Open Access Journals (Sweden)

    K. Kalaipriya

    2014-05-01

    Full Text Available This paper presents the power quality improvement using UPQC. UPQC consists of series inverter, shunt inverter and capacitance. Every inverter connected with pulse generator for switching on. UPQC is especially obtained to resolve different kind of power quality drawback like reactive power compensation, voltage interruption and harmonics. DVR is connected in series to deliver the active and reactive power to distribution network. DC-link capacitors stay high as a result of the DVR needs a minimum amount of DC-link voltage to compensate sag. So, DC –link voltage is connected with PV module to reduce the cost. Design of UPQC device with multi-bus system obtained using MATLAB/SIMULINK and simulation results are mentioned to support the developed conception.

  13. Improved Active Vibration Isolation Systems

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The control force, feedback gain, and actuator stroke of several active vibration isolation systems were analyzed based on a single-layer active vibration isolation system. The analysis shows that the feedback gain and actuator stroke cannot be selected independently and the active isolation system design must make a compromise between the feedback gain and actuator stroke. The performance of active isolation systems can be improved by the joint vibration reduction using an active vibration isolation system with an adaptive dynamic vibration absorber. The results show that the joint vibration reduction method can successfully avoid the compromise between the feedback gain and actuator stroke. The control force and the object vibration amplitude are also greatly reduced.

  14. Improving the firm's environmental conduct

    DEFF Research Database (Denmark)

    Knudsen, Thorbjørn; Koed Madsen, Tage

    2001-01-01

    lead to strategic advantage and, thus, economic gains at the firm level. In view of the great importance of this claim, the purpose of the present article was to apply resource-based insights in order to develop this reasoning further and provide an empirical test of three hypotheses related...... to the claim. Our empirical test filled a gap in previous research and offered evidence in support of this claim as well as support for two related hypotheses developed on the basis of the resource-based view.......  It has recently been argued that growing societal pressures for better environmental conduct could induce environmental innovation, thereby entailing lower costs due to increased value and/or more efficient resource allocation. This has led to the claim that improved environmental conduct may...

  15. [Improving healthcare and its manageability].

    Science.gov (United States)

    Eddes, Eric Hans

    2013-01-01

    Healthcare in the Netherlands is facing serious challenges. With an ageing population, the consumption of healthcare is on the rise. Quality needs to go up while costs have to go down. The Netherlands Institute for Social Research estimates that healthcare costs, as a percentage of the Gross Domestic Product, will rise from 13% in 2011 (90 billion euros) up to 31% in 2040. Clear choices need to be made in the near future; otherwise, the cost of healthcare will become prohibitive. This commentary explains why volume-directed healthcare alone is not the magic answer. Besides criteria related to process and structure, we are also in need of robust and valid data. Clinical auditing combined with patient-reported outcome measures (PROMs) and financial data will give the additional tools needed to improve and manage healthcare.

  16. International Sport Events: Improving Marketing

    Directory of Open Access Journals (Sweden)

    Margarita Kerzaitė

    2014-04-01

    Full Text Available The report and the article will be a comprehensive analysis ofthe needs to improve the international sport events marketing.Highlighting the role of international sport events in contemporarysociety and the challenges in the context of globalization,comparing opinions of various authors about aspects of classificationand the benefits for host country. The article and the reportreveals the main existing problem encountered in organizinginternational sport events, estimated perspectives for solutionof this problem. Summarizes the international sport eventsopportunities, basically modernize marketing tools according tothe marketing mix correction based on systematic synthesis ofmarketing concepts and adaptation/standardization needs, themost important factors in the marketing mix for the excretion ofthe main marketing objectives. The article is based on the latestscientific literature analysis.

  17. Automobile accessories: Assessment and improvement

    Energy Technology Data Exchange (ETDEWEB)

    Jackson, M. [Univ. of Nevada, Las Vegas, NV (United States)

    1995-11-01

    With mandates and regulatory policies to meet both the California Air Resources Board (CARB) and the Partnership for a New Generation of Vehicles (PNGV), designing vehicles of the future will become a difficult task. As we look into the use of electric and hybrid vehicles, reduction of the required power demand by influential automobile components is necessary in order to obtain performance and range goals. Among those automobile components are accessories. Accessories have a profound impact on the range and mileage of future vehicles with limited amounts of energy or without power generating capabilities such as conventional vehicles. Careful assessment of major power consuming accessories helps us focus on those that need improvement and contributes to attainment of mileage and range goals for electric and hybrid vehicles.

  18. Environmental improvement through product development

    DEFF Research Database (Denmark)

    McAloone, Tim C.; Bey, Niki

    new business opportunities, where sustainable development and value creation are integrated early in the design of new products and services. There is a great opportunity for businesses to create a new and positive agenda, where the focus is on all the good that companies can do for the environment...... and aid the establishment of such a new agenda. We place our focus on how products and services can be designed so not to harm humans, the environment and nature. With this Guide to environmental improvement through product development, we take the first step in this collaboration. The Guide gives...... inspiration and a stepwise approach to integrating positive environmental effects into companies’ design and product development processes. The Guide is intended primarily for product developers who have the task of building environmental thinking into the product development process. However environmental...

  19. Quality Improvement Practices and Trends

    DEFF Research Database (Denmark)

    Dahlgaard, Jens J.; Hartz, Ove; Edgeman, Rick L.

    1998-01-01

    professor, as well as key individuals from various industries. In addition to the above activities, Rick will be working with the European Foundation for Quality Management on their "European Master's Programme in Total Quality Management." That program involves a consortium of European universities. Rick......The following article, "Quality Improvement Practices and Trends in Denmark," is the first in a series of papers arranged for and co-authored by Dr. Rick L. Edgeman. Rick is a member of QE's Editorial Board and is on sabbatical from Colorado State University. During the year, Rick and his family...... has begun the process of developing a comparable consortium of American universities for the same purpose-- an activity which is cosponsored by the Education Division of the American Society for Quality (ASQ)....

  20. Improved cylindrical mirror energy analyzer

    Science.gov (United States)

    Baranova, L. A.

    2017-03-01

    A study has been carried out of the electron-optical properties of improved design of the cylindrical mirror energy analyzer. Both external and internal electrodes of the analyzer are divided into three isolated parts, whereby the potentials on the individual parts can be regulated independently from each other. In symmetric operating mode at identical potentials on the side parts of the electrodes, a significant increase has been obtained in resolving power and light-gathering power of the analyzer compared to the standard design of the cylindrical mirror. In asymmetric operating mode, which is implemented in a linear potential distribution on the external electrode, the conditions have been found under which the linear dispersion of the analyzer increases several times.