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Sample records for alpha 1-antitrypsin

  1. Alpha1-antitrypsin deficiency

    DEFF Research Database (Denmark)

    Stolk, Jan; Seersholm, Niels; Kalsheker, Noor

    2006-01-01

    The Alpha One International Registry (AIR), a multinational research program focused on alpha1-antitrypsin (AAT) deficiency, was formed in response to a World Health Organization recommendation. Each of the nearly 20 participating countries maintains a national registry of patients with AAT defic...... epidemiology, inflammatory and signalling processes, therapeutic advances, and lung imaging techniques....

  2. Alpha-1-antitrypsin deficiency.

    Science.gov (United States)

    Bals, Robert

    2010-10-01

    Alpha-1-antitrypsin deficiency (AATD) is a rare genetic disorder associated with the development of liver and lung disease. AAT is a 52-kD glycoprotein, produced mainly by hepatocytes and secreted into the blood. Agglomeration of the AAT-protein in hepatocytes can result in liver disease. Exposure to smoke is the major risk factor for the development of lung disease characterised as early chronic obstructive lung disease (COPD). Diagnosis is based on the analysis of the AAT genotype and phenotype. The measurement of the AAT serum level is useful as screening test. Liver biopsy is not necessary to establish the diagnosis. Therapy for AAT-related liver disease is supportive, a specific therapy is not available. AATD is a rare condition (1:5000-10000) and, as a consequence, data and information on diagnosis and treatment are not easily accessible. This chapter provides a comprehensive overview on AATD, covering basic biology, diagnostic and therapeutic approaches. Copyright © 2010 Elsevier Ltd. All rights reserved.

  3. Liver replacement for alpha1-antitrypsin deficiency

    Science.gov (United States)

    Putnam, Charles W.; Porter, Kendrick A.; Peters, Robert L.; Ashcavai, Mary; Redeker, Allan G.; Starzl, Thomas E.

    2010-01-01

    A 16-year-old girl with advanced cirrhosis and severe alpha1-antitrypsin deficiency of the homozygous PiZZ phenotype was treated by orthotopic liver transplantation. After replacement of the liver with a homograft from a donor with the normal PiMM phenotype, the alpha1-antitrypsin concentration in the recipient’s serum rose to normal; it had the PiMM phenotype. Two and a third years later, chronic rejection necessitated retransplantation. Insertion of a homograft from a heterozygous PiMZ donar was followed by the identification of that phenotype in the recipient’s serum. Neither liver graft developed the alpha1-antitrypsin glycoprotein deposits seen with the deficiency state. These observations confirm that this hepatic- based inborn error metabolism is metabolically cured by liver replacement. PMID:320694

  4. Alpha-1 Antitrypsin Deficiency (Inherited Emphysema)

    Science.gov (United States)

    ... antitrypsin inactivates elastase once it has finished its job. Without alpha 1 antitrypsin, elastase can destroy the air sacs of the lung. How is the diagnosis made? Because Alpha-1 related disease is COPD, the diagnosis is made by the same methods. Your doctor may have you do a number ...

  5. Association of polymorphism in the alpha-1-antitrypsin gene with ...

    African Journals Online (AJOL)

    Sahand Rayaneh

    2014-06-11

    Jun 11, 2014 ... Association of polymorphism in the alpha-1-antitrypsin gene with milk production traits in ... Abstract. Alpha-1-antitrypsin (A1AT) as a strong protease inhibitor plays a major role in the protection of tissues ..... populations over generations; iii) Different statistical models used to analyse the data. For the traits ...

  6. Intravenous alpha-1 antitrypsin augmentation therapy: systematic review

    DEFF Research Database (Denmark)

    Gøtzsche, Peter C; Johansen, Helle Krogh

    2010-01-01

    We reviewed the benefits and harms of augmentation therapy with alpha-1 antitrypsin in patients with alpha-1 antitrypsin deficiency and lung disease. We searched for randomised trials comparing augmentation therapy with placebo or no treatment in PubMed and ClinicalTrials (7 January 2010). Two...

  7. Therapeutics: Gene Therapy for Alpha-1 Antitrypsin Deficiency.

    Science.gov (United States)

    Gruntman, Alisha M; Flotte, Terence R

    2017-01-01

    This review seeks to give an overview of alpha-1 antitrypsin deficiency, including the different disease phenotypes that it encompasses. We then describe the different therapeutic endeavors that have been undertaken to address these different phenotypes. Lastly we discuss future potential therapeutics, such as genome editing, and how they may play a role in treating alpha-1 antitrypsin deficiency.

  8. Gene therapy for alpha-1 antitrypsin deficiency.

    Science.gov (United States)

    Flotte, Terence R; Mueller, Christian

    2011-04-15

    Alpha-1 antitrypsin (AAT) deficiency is a common single-gene disorder among Northern Europeans and North Americans. The carrier frequency for the common missense mutation (Z-AAT) ranges from 4% in the US to nearly 25% in the Republic of Ireland. Severe AAT deficiency (plasma levels below 11 μm) is most commonly associated with an adult-onset lung disease, with pan-acinar emphysema and airway inflammation, which is thought to be primarily owing to the loss of function of AAT in neutralizing neutrophil elastase and other pro-inflammatory enzymes. In 5-10% of patients, severe liver disease may develop. This may occur at any time from infancy to adulthood, and is thought to be owing to toxicity from the Z-AAT mutant protein that folds poorly and forms insoluble polymers within the hepatocyte, which is the primary site for AAT production. Thus, gene therapy for AAT lung disease is conceived of as augmentation of serum levels (a prolonged form of protein replacement, which is currently in use), while gene therapy for liver disease presents the problem of also having to downregulate the production of Z-AAT protein. Over the years, numerous strategies have been employed for the gene therapy of both AAT-deficient lung disease and liver disease. These will be reviewed with an emphasis on modalities that have reached clinical trials recently.

  9. Fibrinogen and alpha(1)-antitrypsin in COPD exacerbations

    DEFF Research Database (Denmark)

    Sylvan Ingebrigtsen, Truls; Marott, J. L.; Rode, L.

    2015-01-01

    Background We tested the hypotheses that fibrinogen and alpha(1)-antitrypsin are observationally and genetically associated with exacerbations in COPD. Methods We studied 13 591 individuals with COPD from the Copenhagen General Population Study (2003-2013), of whom 6857 were genotyped for FGB -455...... and exacerbations in instrumental variable analyses. Results Elevated fibrinogen and alpha(1)-antitrypsin levels were associated with increased risk of exacerbations in COPD, HR=1.14 (1.07 to 1.22, p...

  10. Deficiency of a alpha-1-antitrypsin influences systemic iron homeostasis

    Science.gov (United States)

    Abstract Background: There is evidence that proteases and anti-proteases participate in the iron homeostasis of cells and living systems. We tested the postulate that alpha-1 antitrypsin (A1AT) polymorphism and the consequent deficiency of this anti-protease in humans are asso...

  11. Association of polymorphism in the alpha-1-antitrypsin gene with ...

    African Journals Online (AJOL)

    Alpha-1-antitrypsin (A1AT) as a strong protease inhibitor plays a major role in the protection of tissues against proteolytic destruction by neutrophil elastase. Existence of this protein in the mammary gland may increase the survival of milk proteins such as lactoferrin and lysozyme. The biological role of A1AT in tissues such ...

  12. Alpha-1-antitrypsin studies: canine serum and canine surfactant protein

    International Nuclear Information System (INIS)

    Tuttle, W.C.; Slauson, D.O.; Dahlstrom, M.; Gorman, C.

    1974-01-01

    Canine serum alpha-1-antitrypsin was isolated by gel filtration and affinity chromatography and characterized by polyacrylamide gel electrophoresis and immunoelectrophoresis. Measurement of the trypsin inhibitory capacity of the separated protein indicated a ninefold concentration of functional trypsin inhibitor during the isolation procedure. Electrophoresis demonstrated the presence of a single protein with alpha-globulin mobility and a molecular weight near that of human alpha-1-antitrypsin. The trypsin inhibitory capacity of pulmonary surfactant protein from five Beagle dogs was measured, related to total surfactant protein concentration, and compared with similar measurements on whole serum from the same animals. Results indicated a variable concentration of trypsin inhibitor in the canine pulmonary surfactant protein. However, the concentration in the surfactant protein was always significantly higher than that in the corresponding serum sample. Preliminary experiments designed to separate the trypsin inhibitory fraction(s) from the other surfactant proteins by gel filtration chromatography indicated that the trypsin inhibitor was probably a single protein with a molecular weight near that of alpha-1-antitrypsin. (U.S.)

  13. The prevalence of alpha-1 antitrypsin deficiency in Ireland

    OpenAIRE

    Morris Valerie B; Dimitrov Borislav D; O'Brien Geraldine; Kelleher Dermot P; McPartlin Joseph; Floyd Olwen; O'Connor Catherine A; Carroll Tomás P; Taggart Clifford C; McElvaney Noel G

    2011-01-01

    PUBLISHED Background: Alpha-1 antitrypsin deficiency (AATD) results from mutations in the SERPINA1 gene and classically presents with early-onset emphysema and liver disease. The most common mutation presenting with clinical evidence is the Z mutation, while the S mutation is associated with a milder plasma deficiency. AATD is an under-diagnosed condition and the World Health Organisation recommends targeted detection programmes for AATD in patients with chronic obstructive pulmonary disea...

  14. Genetics Home Reference: alpha-1 antitrypsin deficiency

    Science.gov (United States)

    ... rapid heartbeat upon standing. Affected individuals often develop emphysema, which is a lung disease caused by damage to the small air ... exposure to tobacco smoke accelerates the appearance of emphysema symptoms and damage to the lungs. About 10 percent of infants with alpha-1 ...

  15. The promise of gene therapy for the treatment of alpha-1 antitrypsin deficiency.

    Science.gov (United States)

    Cruz, Pedro E; Mueller, Christian; Flotte, Terence R

    2007-09-01

    In the last 13 years, three gene therapy trials for the treatment of alpha-1 antitrypsin deficiency have been conducted. The first trial delivered plasmid encoding the alpha-1 antitrypsin cDNA to the nasal epithelium using cationic liposomes. The last two trials delivered recombinant adeno-associated vectors encoding the alpha-1 antitrypsin cDNA by intramuscular injection. In this review, the progress of ongoing clinical trials and new gene therapy technologies is discussed.

  16. 5 Year Expression and Neutrophil Defect Repair after Gene Therapy in Alpha-1 Antitrypsin Deficiency.

    Science.gov (United States)

    Mueller, Christian; Gernoux, Gwladys; Gruntman, Alisha M; Borel, Florie; Reeves, Emer P; Calcedo, Roberto; Rouhani, Farshid N; Yachnis, Anthony; Humphries, Margaret; Campbell-Thompson, Martha; Messina, Louis; Chulay, Jeffrey D; Trapnell, Bruce; Wilson, James M; McElvaney, Noel G; Flotte, Terence R

    2017-06-07

    Alpha-1 antitrypsin deficiency is a monogenic disorder resulting in emphysema due principally to the unopposed effects of neutrophil elastase. We previously reported achieving plasma wild-type alpha-1 antitrypsin concentrations at 2.5%-3.8% of the purported therapeutic level at 1 year after a single intramuscular administration of recombinant adeno-associated virus serotype 1 alpha-1 antitrypsin vector in alpha-1 antitrypsin deficient patients. We analyzed blood and muscle for alpha-1 antitrypsin expression and immune cell response. We also assayed previously reported markers of neutrophil function known to be altered in alpha-1 antitrypsin deficient patients. Here, we report sustained expression at 2.0%-2.5% of the target level from years 1-5 in these same patients without any additional recombinant adeno-associated virus serotype-1 alpha-1 antitrypsin vector administration. In addition, we observed partial correction of disease-associated neutrophil defects, including neutrophil elastase inhibition, markers of degranulation, and membrane-bound anti-neutrophil antibodies. There was also evidence of an active T regulatory cell response (similar to the 1 year data) and an exhausted cytotoxic T cell response to adeno-associated virus serotype-1 capsid. These findings suggest that muscle-based alpha-1 antitrypsin gene replacement is tolerogenic and that stable levels of M-AAT may exert beneficial neutrophil effects at lower concentrations than previously anticipated. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  17. Origins and spreads of Alpha 1 antitrypsin variants in world human ...

    African Journals Online (AJOL)

    This alpha 1 antitrypsin deficiency (AATD) represents a common hereditary disorder that mainly manifests as obstructive lung diseases and less common liver ... Anthropological history of Alpha 1 antitrypsin variants / Denden et al. ..... PIZ allele to be 2000 years or 66 generations, by analyzing STR and RFLP markers on.

  18. Quantification of Total Human Alpha-1 Antitrypsin by Sandwich ELISA.

    Science.gov (United States)

    Tang, Qiushi; Gruntman, Alisha M; Flotte, Terence R

    2017-01-01

    In this chapter we describe an enzyme-linked immunosorbent assay (ELISA) to quantitatively measure human alpha-1 antitrypsin (AAT) protein levels in serum, other body fluids or liquid media. This assay can be used to measure the expression of the human AAT (hAAT) gene in a variety of gene transfer or gene downregulation experiments.A hAAT-specific capture antibody and a HRP-conjugated anti-AAT detection antibody are used in this assay. The conjugated anti-AAT used in this protocol, instead of the typical sandwich which employs an unconjugated antibody followed by a specifically conjugated IgG, makes the assay simpler and decreases variability. This provides a useful tool to evaluate the AAT levels in clinical and research samples and can allow fairly rapid testing of a large number of samples.

  19. Gene-based therapy for alpha-1 antitrypsin deficiency.

    Science.gov (United States)

    Mueller, Christian; Flotte, Terence R

    2013-03-01

    Alpha-1 antitrypsin Deficiency (AATD) has been an attractive target for the development of gene therapy because it is a common single gene disorder, for which there would appear to be significant benefit to be gained for lung disease patients by augmentation of plasma levels of wild-type (M) alpha-1 antitrypsin (AAT). While a significant proportion of patients also have liver disease, which is unlikely to be benefitted by augmentation, the potential to treat or prevent lung disease by replacement of plasma levels to at least 11 microMolar (571 mcg/ml) is the basis upon which several protein replacement therapies have been licensed for human use. Further enhancing the likelihood of success of gene therapy is the fact that the AAT coding sequence is relatively short and the protein appears to function primarily in the plasma and extracellular space. This means that AAT production from any cell or tissue capable of secreting it could be useful therapeutically for augmentation. Based on these considerations, attempts have been made to develop AAT therapies using nonviral gene transfer, gammaretrovirus, recombinant adenovirus (rAd), and recombinant adeno-associated virus (rAAV) vectors. These have resulted in three phase I clinical trials (one of cationic liposome, one of rAAV2, and one of rAAV1) and one phase II clinical trial (with rAAV1). The results of the latter trial, while promising, demonstrated levels were only 3 to 5% of the target range. This indicates the need to further increase the dose of the vector and/or to increase the levels to within the therapeutic range.

  20. Diagnosis of alpha-1-antitrypsin deficiency by DNA analysis of children with liver disease

    Directory of Open Access Journals (Sweden)

    De TOMMASO Adriana Maria Alves

    2001-01-01

    Full Text Available Background - Alpha-1-antitrypsin deficiency is a genetic disorder which is transmitted in a co-dominant, autosomal form. Alpha-1-antitrypsin deficiency affects mainly the lungs and the liver leading, in the latter case, to neonatal cholestasis, chronic hepatitis or cirrhosis. A precise diagnosis of Alpha-1-antitrypsin deficiency may be obtained by biochemical or molecular analysis. Objective - The purpose of this study was to use DNA analysis to examine the presence of an alpha-1-antitrypsin deficiency in 12 children suspected of having this deficiency and who showed laboratory and clinical characteristics of the disease. Patients and Methods - Twelve patients, aged 3 months to 19 years, who had serum alpha-1-antitrypsin levels lower than normal and/or had hepatic disease of undefined etiology were studied. The mutant alleles S and Z of the alpha-1-antitrypsin gene were investigated in the 12 children. Alpha-1-antitrypsin gene organization was analyzed by amplification of genoma through the polymerase chain reaction and digestion with the restriction enzymes Xmnl (S allele and Taq 1 (Z allele. Results - Seven of the 12 patients had chronic liver disease of undefined etiology and the other five patients had low serum levels of alpha-1-antitrypsin as well as a diagnosis of neonatal cholestasis and/or chronic liver disease of undefined etiology. Five of the 12 patients were homozygous for the Z allele (ZZ and two had the S allele with another allele (*S different from Z. Conclusion - These results show that alpha-1-antitrypsin deficiency is relatively frequent in children with chronic hepatic disease of undefined etiology and/or low alpha-1-antitrypsin levels (41.6%. A correct diagnosis is important for effective clinical follow-up and for genetic counseling.

  1. Blood pressure, risk of ischemic cerebrovascular and ischemic heart disease, and longevity in alpha(1)-antitrypsin deficiency

    DEFF Research Database (Denmark)

    Dahl, Morten; Tybjaerg-Hansen, Anne; Sillesen, Henrik

    2003-01-01

    Because elastase in alpha(1)-antitrypsin deficiency may attack elastin in the arterial wall, we tested whether alpha(1)-antitrypsin deficiency is associated with reduced blood pressure, risk of ischemic cerebrovascular (ICVD) and ischemic heart disease (IHD), and longevity.......Because elastase in alpha(1)-antitrypsin deficiency may attack elastin in the arterial wall, we tested whether alpha(1)-antitrypsin deficiency is associated with reduced blood pressure, risk of ischemic cerebrovascular (ICVD) and ischemic heart disease (IHD), and longevity....

  2. Environmental arsenic exposure, selenium and sputum alpha-1 antitrypsin

    DEFF Research Database (Denmark)

    Burgess, Jefferey L; Kurzius-Spencer, Margaret; Poplin, Gerald S

    2014-01-01

    Exposure to arsenic in drinking water is associated with increased respiratory disease. Alpha-1 antitrypsin (AAT) protects the lung against tissue destruction. The objective of this study was to determine whether arsenic exposure is associated with changes in airway AAT concentration and whether...... this relationship is modified by selenium. A total of 55 subjects were evaluated in Ajo and Tucson, Arizona. Tap water and first morning void urine were analyzed for arsenic species, induced sputum for AAT and toenails for selenium and arsenic. Household tap-water arsenic, toenail arsenic and urinary inorganic...... arsenic and metabolites were significantly higher in Ajo (20.6±3.5 μg/l, 0.54±0.77 μg/g and 27.7±21.2 μg/l, respectively) than in Tucson (3.9±2.5 μg/l, 0.16±0.20 μg/g and 13.0±13.8 μg/l, respectively). In multivariable models, urinary monomethylarsonic acid (MMA) was negatively, and toenail selenium...

  3. Active trafficking of alpha 1 antitrypsin across the lung endothelium.

    Directory of Open Access Journals (Sweden)

    Angelia D Lockett

    Full Text Available The homeostatic lung protective effects of alpha-1 antitrypsin (A1AT may require the transport of circulating proteinase inhibitor across an intact lung endothelial barrier. We hypothesized that uninjured pulmonary endothelial cells transport A1AT to lung epithelial cells. Purified human A1AT was rapidly taken up by confluent primary rat pulmonary endothelial cell monolayers, was secreted extracellularly, both apically and basolaterally, and was taken up by adjacent rat lung epithelial cells co-cultured on polarized transwells. Similarly, polarized primary human lung epithelial cells took up basolaterally-, but not apically-supplied A1AT, followed by apical secretion. Evidence of A1AT transcytosis across lung microcirculation was confirmed in vivo by two-photon intravital microscopy in mice. Time-lapse confocal microscopy indicated that A1AT co-localized with Golgi in the endothelium whilst inhibition of the classical secretory pathway with tunicamycin significantly increased intracellular retention of A1AT. However, inhibition of Golgi secretion promoted non-classical A1AT secretion, associated with microparticle release. Polymerized A1AT or A1AT supplied to endothelial cells exposed to soluble cigarette smoke extract had decreased transcytosis. These results suggest previously unappreciated pathways of A1AT bidirectional uptake and secretion from lung endothelial cells towards the alveolar epithelium and airspaces. A1AT trafficking may determine its functional bioavailablity in the lung, which could be impaired in individuals exposed to smoking or in those with A1AT deficiency.

  4. Cardiovascular risk in patients with alpha-1-antitrypsin deficiency.

    Science.gov (United States)

    Fähndrich, Sebastian; Biertz, Frank; Karch, Annika; Kleibrink, Björn; Koch, Armin; Teschler, Helmut; Welte, Tobias; Kauczor, Hans-Ulrich; Janciauskiene, Sabina; Jörres, Rudolf A; Greulich, Timm; Vogelmeier, Claus F; Bals, Robert

    2017-09-15

    Alpha-1-antitrypsin deficiency (AATD) is a rare inherited condition caused by mutations of the SERPINA1 gene that is associated with the development of a COPD like lung disease. The comorbidities in patients with AATD-related lung diseases are not well defined. The aim of this study was to analyze the clinical phenotype of AATD patients within the German COPD cohort study COSYCONET ("COPD and SYstemic consequences-COmorbidities NETwork") cohort focusing on the distribution of comorbidities. The data from 2645 COSYCONET patients, including 139 AATD patients (110 with and 29 without augmentation therapy), were analyzed by descriptive statistics and regression analyses. We found significantly lower prevalence of cardiovascular comorbidities in AATD patients as compared to non-AATD COPD patients. After correction for age, pack years, body mass index, and sex, the differences were still significant for coronary artery disease (p = 0.002) and the prevalence of peripheral artery disease as determined by an ankle-brachial-index <= 0.9 (p = 0.035). Also the distribution of other comorbidities such as bronchiectasis differed between AATD and non-deficient COPD. AATD is associated with a lower prevalence of cardiovascular disease, the underlying mechanisms need further investigation.

  5. Alpha-1 antitrypsin is a potential biomarker for hepatitis B

    Directory of Open Access Journals (Sweden)

    Chen Zhi

    2011-06-01

    Full Text Available Abstract Background Function exertion of specific proteins are key factors in disease progression, thus the systematical identification of those specific proteins is a prerequisite to understand various diseases. Though many proteins have been verified to impact on hepatitis, no systematical protein screening has been documented to hepatitis B virus (HBV induced hepatitis, hindering the comprehensive understanding to this severe disease. Aim To identify the major proteins in the progression of HBV infection from mild stage to severe stage. Methods We performed an integrated strategy by combining two-dimensional electrophoresis (2-DE, peptide mass fingerprinting (PMF analysis, and tissue microarray techniques to screen the functional proteins and detect the localization of those proteins. Results Interestingly, MS/MS identification revealed the expression level of alpha-1 antitrypsin (AAT was significantly elevated in serum samples from patients with severe chronic hepatitis. Immunoblotting with a specific AAT antibody confirmed that AAT is highly expressed in serum samples from patients with hepatic carcinoma and severe chronic hepatitis. Furthermore, we observed that AAT is with highest expression in normal tissue and cells, but lowest in hepatic carcinoma and severe chronic hepatitis tissues and cells, suggesting the specific secretion of AAT from tissues and cells to serum. Conclusion These results suggest the possibility of AAT as a potential biomarker for hepatitis B in diagnosis.

  6. Chronic obstructive pulmonary disease in alpha1-antitrypsin PI MZ heterozygotes

    DEFF Research Database (Denmark)

    Hersh, C P; Dahl, Morten; Ly, N P

    2004-01-01

    Severe alpha(1)-antitrypsin deficiency, usually related to homozygosity for the protease inhibitor (PI) Z allele, is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD). The risk of COPD in PI MZ heterozygous individuals is controversial.......Severe alpha(1)-antitrypsin deficiency, usually related to homozygosity for the protease inhibitor (PI) Z allele, is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD). The risk of COPD in PI MZ heterozygous individuals is controversial....

  7. Deficiency Mutations of Alpha-1 Antitrypsin. Effects on Folding, Function, and Polymerization.

    Science.gov (United States)

    Haq, Imran; Irving, James A; Saleh, Aarash D; Dron, Louis; Regan-Mochrie, Gemma L; Motamedi-Shad, Neda; Hurst, John R; Gooptu, Bibek; Lomas, David A

    2016-01-01

    Misfolding, polymerization, and defective secretion of functional alpha-1 antitrypsin underlies the predisposition to severe liver and lung disease in alpha-1 antitrypsin deficiency. We have identified a novel (Ala336Pro, Baghdad) deficiency variant and characterized it relative to the wild-type (M) and Glu342Lys (Z) alleles. The index case is a homozygous individual of consanguineous parentage, with levels of circulating alpha-1 antitrypsin in the moderate deficiency range, but is a biochemical phenotype that could not be classified by standard methods. The majority of the protein was present as functionally inactive polymer, and the remaining monomer was 37% active relative to the wild-type protein. These factors combined indicate an 85 to 95% functional deficiency, similar to that seen with ZZ homozygotes. Biochemical, biophysical, and computational studies further defined the molecular basis of this deficiency. These studies demonstrated that native Ala336Pro alpha-1 antitrypsin could populate the polymerogenic intermediate-and therefore polymerize-more readily than either wild-type alpha-1 antitrypsin or the Z variant. In contrast, folding was far less impaired in Ala336Pro alpha-1 antitrypsin than in the Z variant. The data are consistent with a disparate contribution by the "breach" region and "shutter" region of strand 5A to folding and polymerization mechanisms. Moreover, the findings demonstrate that, in these variants, folding efficiency does not correlate directly with the tendency to polymerize in vitro or in vivo. They therefore differentiate generalized misfolding from polymerization tendencies in missense variants of alpha-1 antitrypsin. Clinically, they further support the need to quantify loss-of-function in alpha-1 antitrypsin deficiency to individualize patient care.

  8. The prevalence of alpha-1 antitrypsin deficiency in Ireland.

    LENUS (Irish Health Repository)

    Carroll, Tomas P

    2012-02-01

    BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) results from mutations in the SERPINA1 gene and classically presents with early-onset emphysema and liver disease. The most common mutation presenting with clinical evidence is the Z mutation, while the S mutation is associated with a milder plasma deficiency. AATD is an under-diagnosed condition and the World Health Organisation recommends targeted detection programmes for AATD in patients with chronic obstructive pulmonary disease (COPD), non-responsive asthma, cryptogenic liver disease and first degree relatives of known AATD patients. METHODS: We present data from the first 3,000 individuals screened following ATS\\/ERS guidelines as part of the Irish National Targeted Detection Programme (INTDP). We also investigated a DNA collection of 1,100 individuals randomly sampled from the general population. Serum and DNA was collected from both groups and mutations in the SERPINA1 gene detected by phenotyping or genotyping. RESULTS: The Irish National Targeted Detection Programme identified 42 ZZ, 44 SZ, 14 SS, 430 MZ, 263 MS, 20 IX and 2 rare mutations. Analysis of 1,100 randomly selected individuals identified 113 MS, 46 MZ, 2 SS and 2 SZ genotypes. CONCLUSION: Our findings demonstrate that AATD in Ireland is more prevalent than previously estimated with Z and S allele frequencies among the highest in the world. Furthermore, our targeted detection programme enriched the population of those carrying the Z but not the S allele, suggesting the Z allele is more important in the pathogenesis of those conditions targeted by the detection programme.

  9. The prevalence of alpha-1 antitrypsin deficiency in Ireland.

    LENUS (Irish Health Repository)

    Carroll, Tomas P

    2011-07-13

    Abstract Background Alpha-1 antitrypsin deficiency (AATD) results from mutations in the SERPINA1 gene and classically presents with early-onset emphysema and liver disease. The most common mutation presenting with clinical evidence is the Z mutation, while the S mutation is associated with a milder plasma deficiency. AATD is an under-diagnosed condition and the World Health Organisation recommends targeted detection programmes for AATD in patients with chronic obstructive pulmonary disease (COPD), non-responsive asthma, cryptogenic liver disease and first degree relatives of known AATD patients. Methods We present data from the first 3,000 individuals screened following ATS\\/ERS guidelines as part of the Irish National Targeted Detection Programme (INTDP). We also investigated a DNA collection of 1,100 individuals randomly sampled from the general population. Serum and DNA was collected from both groups and mutations in the SERPINA1 gene detected by phenotyping or genotyping. Results The Irish National Targeted Detection Programme identified 42 ZZ, 44 SZ, 14 SS, 430 MZ, 263 MS, 20 IX and 2 rare mutations. Analysis of 1,100 randomly selected individuals identified 113 MS, 46 MZ, 2 SS and 2 SZ genotypes. Conclusion Our findings demonstrate that AATD in Ireland is more prevalent than previously estimated with Z and S allele frequencies among the highest in the world. Furthermore, our targeted detection programme enriched the population of those carrying the Z but not the S allele, suggesting the Z allele is more important in the pathogenesis of those conditions targeted by the detection programme.

  10. Muramidase, alpha-1 antitrypsin, alpha-1 antichymotrypsin, and S-100 protein immunoreactivity in giant cell lesions.

    Science.gov (United States)

    Regezi, J A; Zarbo, R J; Lloyd, R V

    1987-01-01

    A spectrum of giant cell lesions was evaluated for muramidase, alpha-1 antitrypsin, alpha-1 antichymotrypsin, and S-100 protein immunoreactivity using an avidin-biotin-complex immunoperoxidase method. Peripheral giant cell granuloma, central giant cell granuloma, giant cell tumor, osteitis fibrosa cystica, cherubism, and giant cell tumor of tendon sheath showed similar patterns of reactivity. Granulomatous inflammatory lesions stained more intensely for muramidase than did noninflammatory lesions. Alpha-1-antichymotrypsin was a slightly better marker of giant cell lesions than was alpha-1-antitrypsin. Positive S-100 protein staining in half the lesions was thought to be due to the presence of Langerhans cells. The results supported the belief that giant cell lesions of bone and tendon sheath are differentiated toward cells of the mononuclear-phagocyte system and that multinucleated giant cells are derived from macrophages.

  11. ALPHA1 ANTITRYPSIN IN SMOKERS AND NON SMOKERS CHRONIC OBSTRUCTIVE PULMONARY DISEASE

    Directory of Open Access Journals (Sweden)

    Panchal Mittal A, Shaikh Sahema M, Sadariya Bhavesh R, Bhoi Bharat K, Sharma Hariom M

    2015-01-01

    Full Text Available Aim: The aim of the present study is to correlate and compare alpha-1 antitrypsin level in smoker and non smoker chronic obstructive pulmonary disease patients. Material and Methods: A comparative study was carried out in 200 subjects, more than 40 years of age and having chronic obstructive pulmonary disease for more than 1 year with a history of smoking at least 20 cigarettes per day (Group A and without a history of smoking (Group B. Pulmonary function tests were used to diagnose the disease as per the Global Initiative for Chronic Obstructive Lung Disease (GOLD classification. Alpha-1 antitrypsin level was done by turbidimetry method on fully auto analyzer I-Lab 650 (Instrumentation Laboratory, USA at Clinical Biochemistry Section, Laboratory Services Sir Takhtsinhji Hospital, Bhavnagar. Statistical analysis was done by using unpaired t-test and Pearson’s correlation coefficient. Results: Results of present study shows that alpha-1 antitrypsin level was decreased in smoker chronic obstructive pulmonary disease patients (150.83±18.853 when compared to non smokers (183.97±29.383. There was statistically significant difference in alpha-1 antitrypsin level between the two groups with ‘p’ value of <0.0001. Pearson’s correlation test show negative correlation between smoker and non-smoker chronic obstructive pulmonary disease patients. Conclusion: The values of serum alpha-1 antitrypsin levels were more significantly decreased in smokers indicating an important role of smoking in pathogenesis of chronic obstructive pulmonary disease. Alpha-1 antitrypsin can act as a predictor for future development of chronic obstructive pulmonary disease in smokers and in nonsmokers.

  12. Change in lung function and morbidity from chronic obstructive pulmonary disease in alpha1-antitrypsin MZ heterozygotes

    DEFF Research Database (Denmark)

    Dahl, Morten; Tybjaerg-Hansen, Anne; Lange, Peter

    2002-01-01

    A deteriorating effect of severe alpha(1)-antitrypsin deficiency (ZZ genotype) on lung function is well known, whereas the role of intermediate deficiency (MZ genotype) remains uncertain.......A deteriorating effect of severe alpha(1)-antitrypsin deficiency (ZZ genotype) on lung function is well known, whereas the role of intermediate deficiency (MZ genotype) remains uncertain....

  13. Alpha-1 antitrypsin reduces ovariectomy-induced bone loss in mice

    Science.gov (United States)

    Alpha-1antitrypsin (AAT) is a multifunctional protein with proteinase inhibitor and anti-inflammatory activities. Recent studies showed that AAT has therapeutic effect for diseases associated with inflammation, such as type 1 diabetes and arthritis. Proinflammatory cytokines are primary mediators of...

  14. Hepatic-targeted RNA interference provides persistent knockdown of alpha-1 antitrypsin levels in ZZ patients.

    Science.gov (United States)

    Turner, Alice M; Stolk, Jan; Bals, Robert; Lickliter, Jason; Hamilton, James; Christianson, Dawn R; Given, Bruce D; Burdon, Jonathan G; Loomba, Rohit; Stoller, James K; Teckman, Jeffery H

    2018-03-20

    Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder causing pulmonary and liver disease. The PiZ mutation results in mis-folded alpha-1 antitrypsin protein (Z-AAT) leading to hepatocyte accumulation, fibrosis and cirrhosis. RNAi-based therapeutics silencing production of hepatic Z-AAT might benefit patients with AATD-associated liver disease. This study evaluated an RNAi therapeutic to silence production of alpha-1 antitrypsin. Part A of this double-blind first-in-human study randomized 54 healthy volunteers (HVs) into single dose cohorts (2 placebo: 4 active), receiving escalating doses of the investigational agent ARC-AAT from 0.38 to 8.0 mg/kg or placebo. Part B randomized 11 PiZZ genotype AATD patients who received up to 4.0 mg/kg or placebo. Patients with baseline FibroScan® >11 kPa or FEV 1 (forced expiratory volume in one second) < 60% were excluded. Assessments included safety, pharmacokinetics, and change in serum alpha-1 antitrypsin (AAT) concentrations. 36 healthy volunteers received ARC-AAT and 18 received placebo (Part A). Seven PiZZ individuals received ARC-AAT and 4 received placebo (Part B). A dose-response in serum AAT reduction was observed at doses ≥ 4 mg/kg with similar relative reductions in PiZZ patients and HVs at 4 mg/kg and a maximum reduction of 76.1% (HVs) vs. 78.8% (PiZZ) at this dose. Time for serum AAT return to baseline was similar for HV and PiZZ. There were no notable differences between HV and PiZZ safety parameters. The study was terminated early due to toxicity findings related to the delivery vehicle (ARC-EX1) seen in a non-human primate study. PiZZ and HV responded similarly to ARC-AAT. Deep and durable knockdown of hepatic AAT production based on observed reduction in serum AAT concentrations was demonstrated. Accumulation of abnormal proteins in the livers of patients with alpha-1 antitrypsin deficiency may lead to decreased liver function and potentially liver failure. Therapeutics targeting the production of

  15. Progress with Recombinant Adeno-Associated Virus Vectors for Gene Therapy of Alpha-1 Antitrypsin Deficiency.

    Science.gov (United States)

    Gruntman, Alisha M; Flotte, Terence R

    2015-06-01

    The pathway to a clinical gene therapy product often involves many changes of course and strategy before obtaining successful results. Here we outline the methodologies, both clinical and preclinical, that went into developing a gene therapy approach to the treatment of alpha-1 antitrypsin deficiency lung disease using muscle-targeted recombinant adeno-associated virus. From initial gene construct development in mouse models through multiple rounds of safety and biodistribution studies in rodents, rabbits, and nonhuman primates to ultimate human trials, this review seeks to provide insight into what clinical translation entails and could thereby inform the process for future investigators.

  16. Prevalence of alpha-1 antitrypsin deficiency and allele frequency in patients with COPD in Brazil

    OpenAIRE

    Russo, Rodrigo; Zillmer, Laura Russo; Nascimento, Oliver Augusto; Manzano, Beatriz; Ivanaga, Ivan Teruaki; Fritscher, Leandro; Lundgren, Fernando; Miravitlles, Marc; Gondim, Heicilainy Del Carlos; Santos Junior, Gildo; Alves, Marcela Amorim; Oliveira, Maria Vera; Souza, Altay Alves Lino de; Sales, Maria Penha Uchoa; Jardim, José Roberto

    2016-01-01

    ABSTRACT Objective: To determine the prevalence of alpha 1-antitrypsin (AAT) deficiency (AATD), as well as allele frequency, in COPD patients in Brazil. Methods: This was a cross-sectional study involving 926 COPD patients 40 years of age or older, from five Brazilian states. All patients underwent determination of AAT levels in dried blood spot (DBS) samples by nephelometry. Those with DBS AAT levels ≤ 2.64 mg/dL underwent determination of serum AAT levels. Those with serum AAT levels of <...

  17. Inhibition of activated protein C by recombinant alpha 1-antitrypsin variants with substitution of arginine or leucine for methionine358

    NARCIS (Netherlands)

    Heeb, M.J.; Bischoff, Rainer; Courtney, M.; Griffin, J.H.

    1990-01-01

    alpha 1-Antitrypsin (alpha 1-AT) was recently identified as a major physiologic plasma inhibitor of activated protein C. The reaction with activated protein C of recombinant alpha 1-AT containing amino acid substitutions at the reactive center was studied. The substitution of Arg358 for Met, as

  18. Alpha-1 antitrypsin Pi*SZ genotype: estimated prevalence and number of SZ subjects worldwide

    Directory of Open Access Journals (Sweden)

    Blanco I

    2017-06-01

    Full Text Available Ignacio Blanco,1 Patricia Bueno,2 Isidro Diego,3 Sergio Pérez-Holanda,4 Beatriz Lara,5 Francisco Casas-Maldonado,6 Cristina Esquinas,7 Marc Miravitlles7,8 1Alpha1-Antitrypsin Deficiency Spanish Registry (REDAAT, Lung Foundation Breathe, Spanish Society of Pneumology (SEPAR, Barcelona, Spain; 2Internal Medicine Department, County Hospital of Jarrio, Principality of Asturias, Spain; 3Materials and Energy Department, School of Mining Engineering, Oviedo University, Principality of Asturias, Spain; 4Surgical Department, University Central Hospital of Asturias, Oviedo, Spain; 5Respiratory Medicine Department, Coventry and Warwickshire University Hospital, Coventry, UK; 6Pneumology Department, University Hospital San Cecilio, Granada, Spain; 7Pneumology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 8CIBER de Enfermedades Respiratorias (CIBERES, Barcelona, Spain Abstract: The alpha-1 antitrypsin (AAT haplotype Pi*S, when inherited along with the Pi*Z haplotype to form a Pi*SZ genotype, can be associated with pulmonary emphysema in regular smokers, and less frequently with liver disease, panniculitis, and systemic vasculitis in a small percentage of people, but this connection is less well established. Since the detection of cases can allow the application of preventive measures in patients and relatives with this congenital disorder, the objective of this study was to update the prevalence of the SZ genotype to achieve accurate estimates of the number of Pi*SZ subjects worldwide, based on studies performed according to the following criteria: 1 samples representative of the general population, 2 AAT phenotyping characterized by adequate methods, and 3 selection of studies with reliable results assessed with a coefficient of variation calculated from the sample size and 95% confidence intervals. Studies fulfilling these criteria were used to develop tables and maps with an inverse distance-weighted (IDW interpolation method, to

  19. Alpha-1 antitrypsin: a potent anti-inflammatory and potential novel therapeutic agent.

    LENUS (Irish Health Repository)

    Bergin, David A

    2012-04-01

    Alpha-1 antitrypsin (AAT) has long been thought of as an important anti-protease in the lung where it is known to decrease the destructive effects of major proteases such as neutrophil elastase. In recent years, the perception of this protein in this simple one dimensional capacity as an anti-protease has evolved and it is now recognised that AAT has significant anti-inflammatory properties affecting a wide range of inflammatory cells, leading to its potential therapeutic use in a number of important diseases. This present review aims to discuss the described anti-inflammatory actions of AAT in modulating key immune cell functions, delineate known signalling pathways and specifically to identify the models of disease in which AAT has been shown to be effective as a therapy.

  20. Prognosis of patients with alpha1-antitrypsine deficiency on long-term oxygen therapy

    DEFF Research Database (Denmark)

    Ringbaek, Thomas J; Seersholm, Niels; Perch, Michael

    2014-01-01

    : Compared with COPD without AATD, AATD patients are younger, more often males, have a lower prevalence of cardio-vascular diseases and diabetes mellitus, and higher prevalence of osteoporosis. Moreover, they have better prognosis, partly due to greater chance of receiving a lung transplantation....... on average about 17 years younger than patients without AATD. Cardio-vascular diseases and diabetes mellitus were significantly less prevalent among patients with AATD (60.4% versus 70.3% (P ...INTRODUCTION: Data on patients with alpha1-antitrypsine deficiency (AATD) on long-term oxygen therapy (LTOT) is sparse. The aim of this study was to present the incidence of patients with AATD on LTOT, and compare their characteristics, comorbidities and prognosis (lung transplantation, termination...

  1. Gene targeted therapeutics for liver disease in alpha-1 antitrypsin deficiency

    Directory of Open Access Journals (Sweden)

    Caitriona McLean

    2009-01-01

    Full Text Available Caitriona McLean*, Catherine M Greene*, Noel G McElvaneyRespiratory Research Division, Dept. Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland; *Each of these authors contributed equally to this workAbstract: Alpha-1 antitrypsin (A1AT is a 52 kDa serine protease inhibitor that is synthesized in and secreted from the liver. Although it is present in all tissues in the body the present consensus is that its main role is to inhibit neutrophil elastase in the lung. A1AT deficiency occurs due to mutations of the A1AT gene that reduce serum A1AT levels to <35% of normal. The most clinically significant form of A1AT deficiency is caused by the Z mutation (Glu342Lys. ZA1AT polymerizes in the endoplasmic reticulum of liver cells and the resulting accumulation of the mutant protein can lead to liver disease, while the reduction in circulating A1AT can result in lung disease including early onset emphysema. There is currently no available treatment for the liver disease other than transplantation and therapies for the lung manifestations of the disease remain limited. Gene therapy is an evolving field which may be of use as a treatment for A1AT deficiency. As the liver disease associated with A1AT deficiency may represent a gain of function possible gene therapies for this condition include the use of ribozymes, peptide nucleic acids (PNAs and RNA interference (RNAi, which by decreasing the amount of aberrant protein in cells may impact on the pathogenesis of the condition.Keywords: alpha-1 antitrypsin deficiency, siRNA, peptide nucleic acid, ribozymes

  2. Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels

    DEFF Research Database (Denmark)

    Thun, Gian Andri; Imboden, Medea; Ferrarotti, Ilaria

    2013-01-01

    Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onse...

  3. alpha-1-Antitrypsin (AAT)-modified donor cells suppress GVHD but enhance the GVL effect: a role for mitochondrial bioenergetics

    NARCIS (Netherlands)

    Marcondes, A.M.; Karoopongse, E.; Lesnikova, M.; Margineantu, D.; Welte, T.; Dinarello, C.A.; Hockenbery, D.; Janciauskiene, S.; Deeg, H.J.

    2014-01-01

    Hematopoietic cell transplantation is curative in many patients. However, graft-versus-host disease (GVHD), triggered by alloreactive donor cells, has remained a major complication. Here, we show an inverse correlation between plasma alpha-1-antitrypsin (AAT) levels in human donors and the

  4. Alpha-1 antitrypsin and granulocyte colony-stimulating factor as serum biomarkers of disease severity in ulcerative colitis

    DEFF Research Database (Denmark)

    Soendergaard, Christoffer; Nielsen, Ole Haagen; Seidelin, Jakob Benedict

    2015-01-01

    -stimulating factor produced a predictive model with an AUC of 0.72 when differentiating mild and moderate UC, and an AUC of 0.96 when differentiating moderate and severe UC, the latter being as reliable as CRP. CONCLUSIONS: Alpha-1 antitrypsin is identified as a potential serum biomarker of mild-to-moderate disease...

  5. Functional unfolding of alpha1-antitrypsin probed by hydrogen-deuterium exchange coupled with mass spectrometry.

    Science.gov (United States)

    Baek, Je-Hyun; Yang, Won Suk; Lee, Cheolju; Yu, Myeong-Hee

    2009-05-01

    The native state of alpha(1)-antitrypsin (alpha(1)AT), a member of the serine protease inhibitor (serpin) family, is considered a kinetically trapped folding intermediate that converts to a more stable form upon complex formation with a target protease. Although previous structural and mutational studies of alpha(1)AT revealed the structural basis of the native strain and the kinetic trap, the mechanism of how the native molecule overcomes the kinetic barrier to reach the final stable conformation during complex formation remains unknown. We hypothesized that during complex formation, a substantial portion of the molecule undergoes unfolding, which we dubbed functional unfolding. Hydrogen-deuterium exchange coupled with ESI-MS was used to analyze this serpin in three forms: native, complexing, and complexed with bovine beta-trypsin. Comparing the deuterium content at the corresponding regions of these three samples, we probed the unfolding of alpha(1)AT during complex formation. A substantial portion of the alpha(1)AT molecule unfolded transiently during complex formation, including not only the regions expected from previous structural studies, such as the reactive site loop, helix F, and the following loop, but also regions not predicted previously, such as helix A, strand 6 of beta-sheet B, and the N terminus. Such unfolding of the native interactions may elevate the free energy level of the kinetically trapped native serpin sufficiently to cross the transition state during complex formation. In the current study, we provide evidence that protein unfolding has to accompany functional execution of the protein molecule.

  6. Anti-apoptotic effects of Z alpha1-antitrypsin in human bronchial epithelial cells.

    LENUS (Irish Health Repository)

    Greene, C M

    2010-05-01

    alpha(1)-antitrypsin (alpha(1)-AT) deficiency is a genetic disease which manifests as early-onset emphysema or liver disease. Although the majority of alpha(1)-AT is produced by the liver, it is also produced by bronchial epithelial cells, amongst others, in the lung. Herein, we investigate the effects of mutant Z alpha(1)-AT (ZAAT) expression on apoptosis in a human bronchial epithelial cell line (16HBE14o-) and delineate the mechanisms involved. Control, M variant alpha(1)-AT (MAAT)- or ZAAT-expressing cells were assessed for apoptosis, caspase-3 activity, cell viability, phosphorylation of Bad, nuclear factor (NF)-kappaB activation and induced expression of a selection of pro- and anti-apoptotic genes. Expression of ZAAT in 16HBE14o- cells, like MAAT, inhibited basal and agonist-induced apoptosis. ZAAT expression also inhibited caspase-3 activity by 57% compared with control cells (p = 0.05) and was a more potent inhibitor than MAAT. Whilst ZAAT had no effect on the activity of Bad, its expression activated NF-kappaB-dependent gene expression above control or MAAT-expressing cells. In 16HBE14o- cells but not HEK293 cells, ZAAT upregulated expression of cIAP-1, an upstream regulator of NF-kappaB. cIAP1 expression was increased in ZAAT versus MAAT bronchial biopsies. The data suggest a novel mechanism by which ZAAT may promote human bronchial epithelial cell survival.

  7. Treatment of lung disease in alpha-1 antitrypsin deficiency: a systematic review

    Directory of Open Access Journals (Sweden)

    Edgar RG

    2017-05-01

    Full Text Available Ross G Edgar,1,2 Mitesh Patel,3 Susan Bayliss,4 Diana Crossley,2,5 Elizabeth Sapey,2,5 Alice M Turner4,6 1Therapy Services, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; 2Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK; 3Division of Primary Care, University of Nottingham, Nottingham, UK; 4Institute of Applied Health Research, University of Birmingham, Birmingham, UK; 5Department of Respiratory Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; 6Department of Respiratory Medicine, Heart of England NHS Foundation Trust, Birmingham, UK Background: Alpha-1 antitrypsin deficiency (AATD is a rare genetic condition predisposing individuals to chronic obstructive pulmonary disease (COPD. The treatment is generally extrapolated from COPD unrelated to AATD; however, most COPD trials exclude AATD patients; thus, this study sought to systematically review AATD-specific literature to assist evidence-based patient management.Methods: Standard review methodology was used with meta-analysis and narrative synthesis (PROSPERO-CRD42015019354. Eligible studies were those of any treatment used in severe AATD. Randomized controlled trials (RCTs were the primary focus; however, case series and uncontrolled studies were eligible. All studies had ≥10 participants receiving treatment or usual care, with baseline and follow-up data (>3 months. Risk of bias was assessed appropriately according to study methodology.Results: In all, 7,296 studies were retrieved from searches; 52 trials with 5,632 participants met the inclusion criteria, of which 26 studies involved alpha-1 antitrypsin augmentation and 17 concerned surgical treatments (largely transplantation. Studies were grouped into four management themes: COPD medical, COPD surgical, AATD specific, and other treatments. Computed tomography (CT density, forced expiratory volume in 1 s, diffusing capacity of the lungs for carbon monoxide

  8. Alpha-1-antitrypsin is an endogenous inhibitor of proinflammatory cytokine production in whole blood.

    Science.gov (United States)

    Pott, Gregory B; Chan, Edward D; Dinarello, Charles A; Shapiro, Leland

    2009-05-01

    Several observations suggest endogenous suppressors of inflammatory mediators are present in human blood. alpha-1-Antitrypsin (AAT) is the most abundant serine protease inhibitor in blood, and AAT possesses anti-inflammatory activity in vitro and in vivo. Here, we show that in vitro stimulation of whole blood from persons with a genetic AAT deficiency resulted in enhanced cytokine production compared with blood from healthy subjects. Using whole blood from healthy subjects, dilution of blood with RPMI tissue-culture medium, followed by incubation for 18 h, increased spontaneous production of IL-8, TNF-alpha, IL-1 beta, and IL-1R antagonist (IL-1Ra) significantly, compared with undiluted blood. Dilution-induced cytokine production suggested the presence of one or more circulating inhibitors of cytokine synthesis present in blood. Serially diluting blood with tissue-culture medium in the presence of cytokine stimulation with heat-killed Staphylococcus epidermidis (S. epi) resulted in 1.2- to 55-fold increases in cytokine production compared with S. epi stimulation alone. Diluting blood with autologous plasma did not increase the production of IL-8, TNF-alpha, IL-1 beta, or IL-1Ra, suggesting that the endogenous, inhibitory activity of blood resided in plasma. In whole blood, diluted and stimulated with S. epi, exogenous AAT inhibited IL-8, IL-6, TNF-alpha, and IL-1 beta significantly but did not suppress induction of the anti-inflammatory cytokines IL-1Ra and IL-10. These ex vivo and in vitro observations suggest that endogenous AAT in blood contributes to the suppression of proinflammatory cytokine synthesis.

  9. In vivo genome editing partially restores alpha1-antitrypsin in a murine model of AAT deficiency.

    Science.gov (United States)

    Song, Chun-Qing; Wang, Dan; Jiang, Tingting; O'Connor, Kevin; Tang, Qiushi; Cai, Lingling; Li, Xiangrui; Weng, Zhiping; Yin, Hao; Gao, Guangping; Mueller, Christian; Flotte, Terence R; Xue, Wen

    2018-03-29

    CRISPR genome editing holds promise in the treatment of genetic diseases that currently lack effective long-term therapies. Patients with Alpha-1 Antitrypsin (AAT) deficiency develop progressive lung disease due to the loss of AAT's antiprotease function and liver disease due to a toxic gain of function of the common mutant allele. However, it remains unknown whether CRISPR-mediated AAT correction in the liver, where AAT is primarily expressed, can correct either or both defects. Here we show that AAV delivery of CRISPR can effectively correct Z-AAT mutation in the liver of a transgenic mouse model. Specifically, we co-injected two AAV: one expressing Cas9 and another encoding an AAT guide RNA and homology-dependent repair template. In both neonate and adult mice, this treatment partially restored M-AAT in the serum. Furthermore, deep sequencing confirmed both indel mutations and precise gene correction in the liver, permitting careful analysis of gene editing events in vivo. This study demonstrates a proof-of-concept for the application of CRISPR-Cas9 technology to correct AAT mutations in vivo and validates continued exploration of this approach for the treatment of patients with AAT deficiency.

  10. Alpha-1-antitrypsin deficiency in Madeira (Portugal): the highest prevalence in the world.

    Science.gov (United States)

    Spínola, Carla; Bruges-Armas, Jácome; Pereira, Conceição; Brehm, António; Spínola, Hélder

    2009-10-01

    Alpha-1-antitrypsin (AAT) deficiency is a common genetic disease which affects both lung and liver. Early diagnosis can help asymptomatic patients to adjust their lifestyle choices in order to reduce the risk of Chronic Obstructive Pulmonary Disease (COPD). The determination of this genetic deficiency prevalence in Madeira Island (Portugal) population is important to clarify susceptibility and define the relevance of performing genetic tests for AAT on individuals at risk for COPD. Two hundred samples of unrelated individuals from Madeira Island were genotyped for the two most common AAT deficiency alleles, PI*S and PI*Z, using Polymerase Chain Reaction-Mediated Site-Directed Mutagenesis. Our results show one of the highest frequencies for both mutations when compared to any already studied population in the world. In fact, PI*S mutation has the highest prevalence (18%), and PI*Z mutation (2.5%) was the third highest worldwide. The frequency of AAT deficiency genotypes in Madeira (PI*ZZ, PI*SS, and PI*SZ) is estimated to be the highest in the world: 41 per 1000. This high prevalence of AAT deficiency on Madeira Island reveals an increased genetic susceptibility to COPD and suggests a routine genetic testing for individuals at risk.

  11. Alpha 1 Antitrypsin Inhibits Dendritic Cell Activation and Attenuates Nephritis in a Mouse Model of Lupus.

    Directory of Open Access Journals (Sweden)

    Ahmed S Elshikha

    Full Text Available Systemic lupus erythematosus (SLE is an autoimmune disorder with a worldwide distribution and considerable mortality and morbidity. Although the pathogenesis of this disease remains elusive, over-reactive dendritic cells (DCs play a critical role in the disease development. It has been shown that human alpha-1 antitrypsin (hAAT has protective effects in type 1 diabetes and rheumatoid arthritis mouse models. In the present study, we tested the effect of AAT on DC differentiation and functions, as well as its protective effect in a lupus-prone mouse model. We showed that hAAT treatment significantly inhibited LPS (TLR4 agonist and CpG (TLR9 agonist -induced bone-marrow (BM-derived conventional and plasmacytoid DC (cDC and pDC activation and reduced the production of inflammatory cytokines including IFN-I, TNF-α and IL-1β. In MRL/lpr mice, hAAT treatment significantly reduced BM-derived DC differentiation, serum autoantibody levels, and importantly attenuated renal pathology. Our results for the first time demonstrate that hAAT inhibits DC activation and function, and it also attenuates autoimmunity and renal damage in the MRL/lpr lupus model. These results imply that hAAT has a therapeutic potential for the treatment of SLE in humans.

  12. Evidence for unfolded protein response activation in monocytes from individuals with alpha-1 antitrypsin deficiency.

    LENUS (Irish Health Repository)

    Carroll, Tomás P

    2010-04-15

    The hereditary disorder alpha-1 antitrypsin (AAT) deficiency results from mutations in the SERPINA1 gene and presents with emphysema in young adults and liver disease in childhood. The most common form of AAT deficiency occurs because of the Z mutation, causing the protein to fold aberrantly and accumulate in the endoplasmic reticulum (ER). This leads to ER stress and contributes significantly to the liver disease associated with the condition. In addition to hepatocytes, AAT is also synthesized by monocytes, neutrophils, and epithelial cells. In this study we show for the first time that the unfolded protein response (UPR) is activated in quiescent monocytes from ZZ individuals. Activating transcription factor 4, X-box binding protein 1, and a subset of genes involved in the UPR are increased in monocytes from ZZ compared with MM individuals. This contributes to an inflammatory phenotype with ZZ monocytes exhibiting enhanced cytokine production and activation of the NF-kappaB pathway when compared with MM monocytes. In addition, we demonstrate intracellular accumulation of AAT within the ER of ZZ monocytes. These are the first data showing that Z AAT protein accumulation induces UPR activation in peripheral blood monocytes. These findings change the current paradigm regarding lung inflammation in AAT deficiency, which up until now was derived from the protease-anti-protease hypothesis, but which now must include the exaggerated inflammatory response generated by accumulated aberrantly folded AAT in circulating blood cells.

  13. Alpha-1 Antitrypsin Deficiency Targeted Testing and Augmentation Therapy: A Canadian Thoracic Society Clinical Practice Guideline

    Directory of Open Access Journals (Sweden)

    DD Marciniuk

    2012-01-01

    Full Text Available Alpha-1 antitrypsin (A1AT functions primarily to inhibit neutrophil elastase, and deficiency predisposes individuals to the development of chronic obstructive pulmonary disease (COPD. Severe A1AT deficiency occurs in one in 5000 to one in 5500 of the North American population. While the exact prevalence of A1AT deficiency in patients with diagnosed COPD is not known, results from small studies provide estimates of 1% to 5%. The present document updates a previous Canadian Thoracic Society position statement from 2001, and was initiated because of lack of consensus and understanding of appropriate patients suitable for targeted testing for A1AT deficiency, and for the use of A1AT augmentation therapy. Using revised guideline development methodology, the present clinical practice guideline document systematically reviews the published literature and provides an evidence-based update. The evidence supports the practice that targeted testing for A1AT deficiency be considered in individuals with COPD diagnosed before 65 years of age or with a smoking history of <20 pack years. The evidence also supports consideration of A1AT augmentation therapy in nonsmoking or exsmoking patients with COPD (forced expiratory volume in 1 s of 25% to 80% predicted attributable to emphysema and documented A1AT deficiency (level ≤11 μmol/L who are receiving optimal pharmacological and nonpharmacological therapies (including comprehensive case management and pulmonary rehabilitation because of benefits in computed tomography scan lung density and mortality.

  14. Diagnosing alpha-1 antitrypsin deficiency: the first step in precision medicine [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Craig P. Hersh

    2017-11-01

    Full Text Available Severe alpha-1 antitrypsin (AAT deficiency is one of the most common serious genetic diseases in adults of European descent. Individuals with AAT deficiency have a greatly increased risk for emphysema and liver disease. Other manifestations include bronchiectasis, necrotizing panniculitis and granulomatosis with polyangiitis. Despite the frequency and potential severity, AAT deficiency remains under-recognized, and there is often a delay in diagnosis. This review will focus on three recent updates that should serve to encourage testing and diagnosis of AAT deficiency: first, the publication of a randomized clinical trial demonstrating the efficacy of intravenous augmentation therapy in slowing the progression of emphysema in AAT deficiency; second, the mounting evidence showing an increased risk of lung disease in heterozygous PI MZ genotype carriers; last, the recent publication of a clinical practice guideline, outlining diagnosis and management. Though it has been recognized for more than fifty years, AAT deficiency exemplifies the modern paradigm of precision medicine, with a diagnostic test that identifies a genetic subtype of a heterogeneous disease, leading to a targeted treatment.

  15. Alpha-1 antitrypsin prevents the development of preeclampsia through suppression of oxidative stress

    Directory of Open Access Journals (Sweden)

    Yaling eFeng

    2016-05-01

    Full Text Available Preeclampsia (PE and its complications have become the leading cause of maternal and fetal morbidity and mortality in the world. And the development of PE is still barely predictable and thus challenging to prevent and manage clinically. Oxidative stress contributes to the development of the disease. Our previous study demonstrated that exogenous Alpha-1 antitrypsin (AAT played a cytoprotective role in vascular endothelial cell by suppressing oxidative stress. In this study, we aim to investigate whether AAT contributes to the development of PE, and to identify the mechanism behind these effects. We found that AAT levels were significantly decreased in placenta tissues from women with PE compared that of healthy women. Notably, we demonstrate that AAT injection is able to relieve the high blood pressure and reduce urine protein levels in a dose-dependent manner in PE mice. In addition, our results showed that AAT injection exhibited an anti-oxidative stress role by significantly reducing PE mediated-upregulation of ROS, MMP9 and MDA, and increasing the levels of SOD, eNOS and GPx with increased dosage of AAT. Furthermore, we found that AAT injection inactivated PE mediated activation of PAK/STAT1/p38 signaling. These findings were confirmed in human samples. In conclusion, our study suggests that exogenous AAT injection increases the antioxidants and suppresses oxidative stress, and subsequent prevention of PE development through inactivation of STAT1/p38 signaling. Thus, AAT would become a potential strategy for PE therapy.

  16. Alpha-1 Antitrypsin Prevents the Development of Preeclampsia Through Suppression of Oxidative Stress.

    Science.gov (United States)

    Feng, Yaling; Xu, Jianjuan; Zhou, Qin; Wang, Rong; Liu, Nin; Wu, Yanqun; Yuan, Hua; Che, Haisha

    2016-01-01

    Preeclampsia (PE) and its complications have become the leading cause of maternal and fetal morbidity and mortality in the world. And the development of PE is still barely predictable and thus challenging to prevent and manage clinically. Oxidative stress contributes to the development of the disease. Our previous study demonstrated that exogenous Alpha-1 antitrypsin (AAT) played a cytoprotective role in vascular endothelial cell by suppressing oxidative stress. In this study, we aim to investigate whether AAT contributes to the development of PE, and to identify the mechanism behind these effects. We found that AAT levels were significantly decreased in placenta tissues from women with PE compared that of healthy women. Notably, we demonstrate that AAT injection is able to relieve the high blood pressure and reduce urine protein levels in a dose-dependent manner in PE mice. In addition, our results showed that AAT injection exhibited an anti-oxidative stress role by significantly reducing PE mediated-upregulation of ROS, MMP9 and MDA, and increasing the levels of SOD, eNOS, and GPx with increased dosage of AAT. Furthermore, we found that AAT injection inactivated PE mediated activation of PAK/STAT1/p38 signaling. These findings were confirmed in human samples. In conclusion, our study suggests that exogenous AAT injection increases the antioxidants and suppresses oxidative stress, and subsequent prevention of PE development through inactivation of STAT1/p38 signaling. Thus, AAT would become a potential strategy for PE therapy.

  17. Diabetic retinopathy: could the alpha-1 antitrypsin be a therapeutic option?

    Directory of Open Access Journals (Sweden)

    Gustavo Ortiz

    2014-01-01

    Full Text Available Diabetic retinopathy is one of the most important causes of blindness. The underlying mechanisms of this disease include inflammatory changes and remodeling processes of the extracellular-matrix (ECM leading to pericyte and vascular endothelial cell damage that affects the retinal circulation. In turn, this causes hypoxia leading to release of vascular endothelial growth factor (VEGF to induce the angiogenesis process. Alpha-1 antitrypsin (AAT is the most important circulating inhibitor of serine proteases (SERPIN. Its targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, proteinase 3 (PR-3 and plasminogen activator (PAI. AAT modulates the effect of protease-activated receptors (PARs during inflammatory responses. Plasma levels of AAT can increase 4-fold during acute inflammation then is so-called acute phase protein (APPs. Individuals with low serum levels of AAT could develop disease in lung, liver and pancreas. AAT is involved in extracellular matrix remodeling and inflammation, particularly migration and chemotaxis of neutrophils. It can also suppress nitric oxide (NO by nitric oxide sintase (NOS inhibition. AAT binds their targets in an irreversible way resulting in product degradation. The aim of this review is to focus on the points of contact between multiple factors involved in diabetic retinopathy and AAT resembling pleiotropic effects that might be beneficial.

  18. Antigen-specific tolerance of human alpha1-antitrypsin induced by helper-dependent adenovirus.

    Science.gov (United States)

    Cerullo, V; McCormack, W; Seiler, M; Mane, V; Cela, R; Clarke, C; Rodgers, J R; Lee, B

    2007-12-01

    As efficient and less toxic virus-derived gene therapy vectors are developed, a pressing problem is to avoid immune response to the therapeutic gene product. Secreted therapeutic proteins potentially represent a special problem, as they are readily available to professional antigen-presenting cells throughout the body. Some studies suggest that immunity to serum proteins can be avoided in some mouse strains by using tissue-specific promoters. Here we show that expression of human alpha1-antitrypsin (AAT) was nonimmunogenic in the immune-responsive strain C3H/HeJ, when expressed from helper-dependent (HD) vectors using ubiquitous as well as tissue-specific promoters. Coadministration of less immunogenic HD vectors with an immunogenic first-generation vector failed to immunize, suggesting immune suppression rather than immune stealth. Indeed, mice primed with HD vectors were tolerant to immune challenge with hAAT emulsified in complete Freund's adjuvant. Such animals developed high-titer antibodies to coemulsified human serum albumin, showing that tolerance was antigen specific. AAT-specific T cell responses were depressed in tolerized animals, suggesting that tolerance affects both T and B cells. These results are consistent with models of high-dose tolerance of B cells and certain other suppressive mechanisms, and suggest that a high level of expression from HD vectors can be sufficient to induce specific immune tolerance to serum proteins.

  19. Gene targeted therapeutics for liver disease in alpha-1 antitrypsin deficiency.

    LENUS (Irish Health Repository)

    McLean, Caitriona

    2009-01-01

    Alpha-1 antitrypsin (A1AT) is a 52 kDa serine protease inhibitor that is synthesized in and secreted from the liver. Although it is present in all tissues in the body the present consensus is that its main role is to inhibit neutrophil elastase in the lung. A1AT deficiency occurs due to mutations of the A1AT gene that reduce serum A1AT levels to <35% of normal. The most clinically significant form of A1AT deficiency is caused by the Z mutation (Glu342Lys). ZA1AT polymerizes in the endoplasmic reticulum of liver cells and the resulting accumulation of the mutant protein can lead to liver disease, while the reduction in circulating A1AT can result in lung disease including early onset emphysema. There is currently no available treatment for the liver disease other than transplantation and therapies for the lung manifestations of the disease remain limited. Gene therapy is an evolving field which may be of use as a treatment for A1AT deficiency. As the liver disease associated with A1AT deficiency may represent a gain of function possible gene therapies for this condition include the use of ribozymes, peptide nucleic acids (PNAs) and RNA interference (RNAi), which by decreasing the amount of aberrant protein in cells may impact on the pathogenesis of the condition.

  20. Endothelial alpha-1-antitrypsin attenuates cigarette smoke induced apoptosis in vitro.

    Science.gov (United States)

    Aldonyte, Ruta; Hutchinson, Tarun Edgar; Hutchinson, Edgar Tarun; Jin, Bilian; Brantly, Mark; Block, Edward; Patel, Jawaharlal; Zhang, Jianliang

    2008-06-01

    Deficiency of the antiprotease alpha-1-antitrypsin (AAT) and exposure to cigarette smoke (CS) contribute to the development of early onset emphysema. CS-induced apoptosis of alveolar cells including endothelial cells plays critical role in the lung destruction. AAT deficiency is associated with increased lung tissue destruction as well. We hypothesize that AAT protects lung alveoli from noxious environmental stimuli such as CS-induced apoptosis. Porcine pulmonary artery endothelial cells (PAEC) were exposed to CS in the presence or absence of AAT (20 microM). AAT internalization and markers for apoptosis were assessed by confocal microscopy. Flow cytometry was performed in parallel to quantify the number of AAT-loaded and apoptotic cells. We demonstrated that exogenous AAT accumulated in PAEC and protected cells from CS-induced apoptosis. AAT-loaded CS-exposed cells exhibited increased amounts of chaperone HSP-70 in their cytosol and less apoptosis inducing factor in their nuclei compared to AAT-untreated, CS-exposed cells. Our results suggest that AAT is taken up by endothelial cells via two mechanisms and that intracellular AAT may have a protective role in CS-induced endothelial apoptosis. This may open new insights into the field of endothelial serpins as agents capable of protecting the vasculature from environment-derived noxious substances.

  1. Alpha-1 antitrypsin gene polymorphism in Chronic Obstructive Pulmonary Disease (COPD

    Directory of Open Access Journals (Sweden)

    Sabri Denden

    2010-01-01

    Full Text Available Alpha-1-antitrypsin (AAT plays an important role in the pathogenesis of emphysema, the pathological lesion underlying the majority of the manifestations of Chronic Obstructive Pulmonary Disease (COPD. In this study we tested the hypothesis that common AAT polymorphisms influence the risk of developing COPDs. We investigated PiM1 (Ala213Val, PiM2 (Arg101His, PiM3 (Glu376Asp, PiS (Glu264Val and PiZ (Glu342Lys SERPINA1 alleles in 100 COPD patients and 200 healthy controls. No significant differences were observed in allele frequencies between COPD patients and controls, neither did haplotype analysis show significant differences between the two groups. A cross-sectional study revealed no significant relationship between common SERPINA1 polymorphisms (PiM1, PiM2, PiM3 and the emphysematous type of COPD. In addition, FEV1 annual decline, determined during a two-year follow up period, revealed no difference among carriers of the tested polymorphisms.

  2. SVIP regulates Z variant alpha-1 antitrypsin retro-translocation by inhibiting ubiquitin ligase gp78.

    Directory of Open Access Journals (Sweden)

    Nazli Khodayari

    Full Text Available Alpha-1 antitrypsin deficiency (AATD is an inherited disorder characterized by early-onset emphysema and liver disease. The most common disease-causing mutation is a single amino acid substitution (Glu/Lys at amino acid 342 of the mature protein, resulting in disruption of the 290-342 salt bridge (an electrophoretic abnormality defining the mutation [Z allele, or ZAAT], protein misfolding, polymerization, and accumulation in the endoplasmic reticulum of hepatocytes and monocytes. The Z allele causes a toxic gain of function, and the E3 ubiquitin ligase gp78 promotes degradation and increased solubility of endogenous ZAAT. We hypothesized that the accumulation of ZAAT is influenced by modulation of gp78 E3 ligase and SVIP (small VCP-interacting protein interaction with p97/VCP in ZAAT-expressing hepatocytes. We showed that the SVIP inhibitory effect on ERAD due to overexpression causes the accumulation of ZAAT in a human Z hepatocyte-like cell line (AT01. Overexpression of gp78, as well as SVIP suppression, induces gp78-VCP/p97 interaction in AT01 cells. This interaction leads to retro-translocation of ZAAT and reduction of the SVIP inhibitory role in ERAD. In this context, overexpression of gp78 or SVIP suppression may eliminate the toxic gain of function associated with polymerization of ZAAT, thus providing a potential new therapeutic approach to the treatment of AATD.

  3. Selenoprotein S/SEPS1 modifies endoplasmic reticulum stress in Z variant alpha1-antitrypsin deficiency.

    LENUS (Irish Health Repository)

    Kelly, Emer

    2009-06-19

    Z alpha(1)-antitrypsin (ZAAT) deficiency is a disease associated with emphysematous lung disease and also with liver disease. The liver disease of AAT deficiency is associated with endoplasmic reticulum (ER) stress. SEPS1 is a selenoprotein that, through a chaperone activity, decreases ER stress. To determine the effect of SEPS1 on ER stress in ZAAT deficiency, we measured activity of the grp78 promoter and levels of active ATF6 as markers of the unfolded protein response in HepG2 cells transfected with the mutant form of AAT, a ZAAT transgene. We evaluated levels of NFkappaB activity as a marker of the ER overload response. To determine the effect of selenium supplementation on the function of SEPS1, we investigated glutathione peroxidase activity, grp78 promoter activity, and NFkappaB activity in the presence or absence of selenium. SEPS1 reduced levels of active ATF6. Overexpression of SEPS1 also inhibited grp78 promoter and NFkappaB activity, and this effect was enhanced in the presence of selenium supplementation. This finding demonstrates a role for SEPS1 in ZAAT deficiency and suggests a possible therapeutic potential for selenium supplementation.

  4. Sex differences in alpha-1-antitrypsin deficiency lung disease-analysis from the German registry.

    Science.gov (United States)

    Fähndrich, Sebastian; Herr, Christian; Greulich, Timm; Seibert, Martina; Lepper, Philipp M; Bernhard, Nikolas; Lützow, Cindy; Vogelmeier, Claus; Bals, Robert

    2015-05-01

    Alpha-1-antitrypsin deficiency (AATD) is a rare condition with clinical manifestations of the lung and the liver. There is evidence that the gender affects the clinical presentation of non-AATD chronic obstructive lung disease (COPD). The aim of this study was to analyze gender-dependent disease pattern in AATD-based COPD. Data from 1066 individuals from the German AATD registry were analyzed by descriptive and analytical statistics. The AAT genotypes comprised 820 individuals with PiZZ (male 56%, female 45%), 109 with PI SZ (male 55%; female 45%), and others (n = 137). A subgroup of 422 patients with available post-bronchodilator FEV1% predicted was analyzed in detail after stratification in spirometric GOLD stages I-IV. The age of the registered individuals is 52.2 ± 13.4 years (male: 51.91 ± 13.86 years; female: 52.76 ± 13.39 years). Female patients with GOLD I-IV showed lower numbers of pack-years and lower BMI. The time between the first symptom and the establishment of the correct diagnosis was significantly longer in female (14.47 ± 16.46 years) as compared to male individuals (12.39 ± - 14.38 years, p = 0.04). In conclusion, the data of the registry allow to characterize the natural course of the disease and highlight differences in the clinical presentation of patients with AATD-dependent COPD.

  5. Circulating alpha1-antitrypsin in the general population: Determinants and association with lung function

    Directory of Open Access Journals (Sweden)

    Berger Wolfgang

    2008-04-01

    Full Text Available Abstract Background Severe alpha1-antitrypsin (AAT deficiency associated with low AAT blood concentrations is an established genetic COPD risk factor. Less is known about the respiratory health impact of variation in AAT serum concentrations in the general population. We cross-sectionally investigated correlates of circulating AAT concentrations and its association with FEV1. Methods In 5187 adults (2669 females with high-sensitive c-reactive protein (CRP levels ≤ 10 mg/l from the population-based Swiss SAPALDIA cohort, blood was collected at the time of follow-up examination for measuring serum AAT and CRP. Results Female gender, hormone intake, systolic blood pressure, age in men and in postmenopausal women, as well as active and passive smoking were positively, whereas alcohol intake and BMI inversely correlated with serum AAT levels, independent of CRP adjustment. We observed an inverse association of AAT with FEV1 in the total study population (p Conclusion The results of this population-based study reflect a complex interrelationship between tobacco exposure, gender related factors, circulating AAT, systemic inflammatory status and lung function.

  6. The Influence of Cigarette Smoking on Gingival Bleeding and Serum Concentrations of Haptoglobin and Alpha 1-Antitrypsin

    Directory of Open Access Journals (Sweden)

    Fouad H. Al-Bayaty

    2013-01-01

    Full Text Available The objectives of this study were to evaluate the influence of cigarette smoking on gingival bleeding and serum concentrations of cotinine, haptoglobin, and alpha 1-antitrypsin in Malaysian smokers. A total of 197 male smokers and nonsmokers were recruited for this study. Plaque index, bleeding on probing (BOP, and levels of serum cotinine, haptoglobin, and alpha 1-antitrypsin were evaluated. The data were analyzed using SPSS version 20.0, with the significance level set at α≤0.05. Linear regression analyses were performed. The mean cigarette consumption per day was 13.39±5.75 cigarettes; the mean duration was 16.03±8.78 years. Relatively low BOP values (26.05±1.48 and moderate plaque indexes (51.35±11.27 were found. The levels of serum cotinine (106.9±30.71 ng/dL, haptoglobin (76.04±52.48 mg/dL, and alpha 1-antitrypsin (141.90±18.40 mg/dL were significantly higher in smokers compared to non-smokers. Multiple logistic regression models for all variables and smokers demonstrated observed differences between BOP, the number of cigarettes per day, and duration of smoking, while serum cotinine, haptoglobin and alpha-1 antitrypsin levels showed no significant differences. Duration of smoking (years and the cotinine level in serum showed a significant correlation with plaque index. The present analysis demonstrated that the duration of smoking in years, but not the number of cigarettes smoked per day, was associated with reduced gingival bleeding in smokers.

  7. Alpha-1 Antitrypsin Gene Therapy Ameliorates Bone Loss in Ovariectomy-Induced Osteoporosis Mouse Model.

    Science.gov (United States)

    Akbar, Mohammad Ahsanul; Cao, Jay J; Lu, Yuanqing; Nardo, David; Chen, Mong-Jen; Elshikha, Ahmed S; Ahamed, Rubina; Brantly, Mark; Holliday, L Shannon; Song, Sihong

    2016-09-01

    Osteoporosis is a major healthcare burden affecting mostly postmenopausal women characterized by compromised bone strength and increased risk of fragility fracture. Although pathogenesis of this disease is complex, elevated proinflammatory cytokine production is clearly involved in bone loss at menopause. Therefore, anti-inflammatory strategies hold a great potential for the prevention of postmenopausal osteoporosis. In this study, we investigated the effect of gene therapy of recombinant adeno-associated virus (rAAV)-mediated human alpha-1 antitrypsin (hAAT), a multifunctional protein that has anti-inflammatory property, on bone loss in an ovariectomy-induced osteoporosis mouse model. Adult ovariectomized (OVX) mice were intraperitoneally (i.p.) injected with hAAT (protein therapy), rAAV8-CB-hAAT (gene therapy), or phosphate buffer saline (PBS). Age-matched and sham-operated animals were used as controls. Eight weeks after the treatment, animals were sacrificed and bone-related biomarkers and vertebral bone structure were evaluated. Results showed that hAAT gene therapy significantly decreased serum IL-6 level and receptor activator of NF-κB (RANK) gene expression in bone. Importantly, hAAT gene therapy increased bone volume/total volume and decreased structure model index (SMI) compared to PBS injection in OVX mice. These results demonstrate that hAAT gene therapy by rAAV vector efficiently mitigates bone loss possibly through inhibition of proinflammatory cytokine IL-6 and RANK gene expression. Considering the safety profile of hAAT and rAAV vector in humans, our results provide a new alternative for the treatment of osteoporosis.

  8. Serum Proteins Associated with Emphysema Progression in Severe Alpha-1 Antitrypsin Deficiency.

    Science.gov (United States)

    Beiko, Tatsiana; Janech, Michael G; Alekseyenko, Alexander V; Atkinson, Carl; Coxson, Harvey O; Barth, Jeremy L; Stephenson, Sarah E; Wilson, Carole L; Schnapp, Lynn M; Barker, Alan; Brantly, Mark; Sandhaus, Robert A; Silverman, Edwin K; Stoller, James K; Trapnell, Bruce; Charlie, Strange

    2017-07-15

    Computed tomography (CT) lung density is an accepted biomarker for emphysema in alpha-1 antitrypsin deficiency (AATD), although concerns for radiation exposure limit its longitudinal use. Serum proteins associated with emphysema, particularly in early disease, may provide additional pathogenic insights. We investigated whether distinct proteomic signatures characterize the presence and progression of emphysema in individuals with severe AATD and normal forced expiratory volume in 1 second (FEV 1 ). QUANT itative lung CT U n M asking emphysema progression in AATD (QUANTUM-1) is a multicenter, prospective 3-year study of 49 adults with severe AATD and FEV 1 post-bronchodilator values (Post-BD) ≥ 80% predicted. All participants received chest CT, serial spirometry, and contributed to the serum biobank. Volumetric imaging display and analysis (VIDA) software defined the baseline 15 th percentile density (PD15) which was indexed to CT-derived total lung capacity (TLC). We measured 317 proteins using a multiplexed immunoassay (Myriad Discovery MAP ® panel) in 31 individuals with a complete dataset. We analyzed associations between initial PD15/TLC, PD15/TLC annual decline, body mass index (BMI), and protein levels using Pearson's product moment correlation. C-reactive protein (CRP), adipocyte fatty acid-binding protein (AFBP), leptin, and tissue plasminogen activator (tPA) were found to be associated with baseline emphysema and all but leptin were associated with emphysema progression after adjustments were made for age and sex. All 4 proteins were associated with BMI after further adjustment for multiple comparisons was made. The relationship between these proteins and BMI, and further validation of these findings in replicative cohorts require additional studies.

  9. Rapid renal alpha-1 antitrypsin gene induction in experimental and clinical acute kidney injury.

    Directory of Open Access Journals (Sweden)

    Richard A Zager

    Full Text Available Alpha-1-antitrypsin (AAT is a hepatic stress protein with protease inhibitor activity. Recent evidence indicates that ischemic or toxic injury can evoke selective changes within kidney that resemble a hepatic phenotype. Hence, we tested the following: i Does acute kidney injury (AKI up-regulate the normally renal silent AAT gene? ii Does rapid urinary AAT excretion result? And iii Can AAT's anti-protease/anti-neutrophil elastase (NE activity protect injured proximal tubule cells? CD-1 mice were subjected to ischemic or nephrotoxic (glycerol, maleate, cisplatin AKI. Renal functional and biochemical assessments were made 4-72 hrs later. Rapidly following injury, 5-10 fold renal cortical and isolated proximal tubule AAT mRNA and protein increases occurred. These were paralleled by rapid (>100 fold increases in urinary AAT excretion. AKI also induced marked increases in renal cortical/isolated proximal tubule NE mRNA. However, sharp NE protein levels declines resulted, which strikingly correlated (r, -0.94 with rising AAT protein levels (reflecting NE complexing by AAT/destruction. NE addition to HK-2 cells evoked ∼95% cell death. AAT completely blocked this NE toxicity, as well as Fe induced oxidant HK-2 cell attack. Translational relevance of experimental AAT gene induction was indicated by ∼100-1000 fold urinary AAT increases in 22 AKI patients (matching urine NGAL increases. We conclude: i AKI rapidly up-regulates the renal cortical/proximal tubule AAT gene; ii NE gene induction also results; iii AAT can confer cytoprotection, potentially by blocking/reducing cytotoxic NE accumulation; and iv marked increases in urinary AAT excretion in AKI patients implies clinical relevance of the AKI- AAT induction pathway.

  10. Alpha-1 antitrypsin protein and gene therapies decrease autoimmunity and delay arthritis development in mouse model

    Directory of Open Access Journals (Sweden)

    Atkinson Mark A

    2011-02-01

    Full Text Available Abstract Background Alpha-1 antitrypsin (AAT is a multi-functional protein that has anti-inflammatory and tissue protective properties. We previously reported that human AAT (hAAT gene therapy prevented autoimmune diabetes in non-obese diabetic (NOD mice and suppressed arthritis development in combination with doxycycline in mice. In the present study we investigated the feasibility of hAAT monotherapy for the treatment of chronic arthritis in collagen-induced arthritis (CIA, a mouse model of rheumatoid arthritis (RA. Methods DBA/1 mice were immunized with bovine type II collagen (bCII to induce arthritis. These mice were pretreated either with hAAT protein or with recombinant adeno-associated virus vector expressing hAAT (rAAV-hAAT. Control groups received saline injections. Arthritis development was evaluated by prevalence of arthritis and arthritic index. Serum levels of B-cell activating factor of the TNF-α family (BAFF, antibodies against both bovine (bCII and mouse collagen II (mCII were tested by ELISA. Results Human AAT protein therapy as well as recombinant adeno-associated virus (rAAV8-mediated hAAT gene therapy significantly delayed onset and ameliorated disease development of arthritis in CIA mouse model. Importantly, hAAT therapies significantly reduced serum levels of BAFF and autoantibodies against bCII and mCII, suggesting that the effects are mediated via B-cells, at least partially. Conclusion These results present a new drug for arthritis therapy. Human AAT protein and gene therapies are able to ameliorate and delay arthritis development and reduce autoimmunity, indicating promising potential of these therapies as a new treatment strategy for RA.

  11. Improving adherence to alpha-1 antitrypsin deficiency screening guidelines using the pulmonary function laboratory

    Directory of Open Access Journals (Sweden)

    Luna Diaz LV

    2017-07-01

    Full Text Available Landy V Luna Diaz,1 Isabella Iupe,1 Bruno Zavala,1 Kira C Balestrini,1 Andrea Guerrero,1 Gregory Holt,1,2 Rafael Calderon-Candelario,1,2 Mehdi Mirsaeidi,1,2 Michael Campos1,21Miami Veterans Administration Medical Center, Miami, FL, 2Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Miami School of Medicine, Miami, FL, USAAlpha-1 antitrypsin deficiency (AATD is the only well-recognized genetic disorder associated with an increased risk of emphysema and COPD.1 Identifying AATD allows genetic counseling and the chance to offer specific augmentation therapy to slow emphysema progression. Despite specific recommendations from the World Health Organization, American Thoracic Society and European Respiratory Society to screen all patients with COPD and other at-risk conditions,2–4 testing rates are low (<15%.5We conducted a project to improve AATD screening at the Miami VA Medical Center using the pulmonary function test (PFT laboratory. We instructed the PFT personnel to perform reflex testing on all patients with pre-bronchodilator airflow obstruction (forced expiratory volume in 1 second/forced vital capacity <70% and then evaluated if the screening was appropriate according to guidelines. Trained PFT personnel explained AATD disease to patients and provided them with an informational brochure. After obtaining verbal consent, AATD screening was performed using dried blood spot kits provided by the Alpha-1 Foundation as part of the Florida Screening Program (noncommercial.6 The PFT lab director was the responsible physician of record, in charge of discussing positive results to patients and documenting results in the electronic medical record. The Miami Veterans Affairs Medical Center Institutional Review Board approved the protocol as a quality improvement project.

  12. Prevalence of alpha-1 antitrypsin deficiency and allele frequency in patients with COPD in Brazil.

    Science.gov (United States)

    Russo, Rodrigo; Zillmer, Laura Russo; Nascimento, Oliver Augusto; Manzano, Beatriz; Ivanaga, Ivan Teruaki; Fritscher, Leandro; Lundgren, Fernando; Miravitlles, Marc; Gondim, Heicilainy Del Carlos; Santos, Gildo; Alves, Marcela Amorim; Oliveira, Maria Vera; Souza, Altay Alves Lino de; Sales, Maria Penha Uchoa; Jardim, José Roberto

    2016-01-01

    To determine the prevalence of alpha 1-antitrypsin (AAT) deficiency (AATD), as well as allele frequency, in COPD patients in Brazil. This was a cross-sectional study involving 926 COPD patients 40 years of age or older, from five Brazilian states. All patients underwent determination of AAT levels in dried blood spot (DBS) samples by nephelometry. Those with DBS AAT levels ≤ 2.64 mg/dL underwent determination of serum AAT levels. Those with serum AAT levels of sangue seco por meio de nefelometria. Aqueles em que a concentração de AAT no sangue seco foi ≤ 2,64 mg/dl foram submetidos a dosagem sérica de AAT. Aqueles em que a concentração sérica de AAT foi sangue seco ≤ 2,64 mg/dl, e 24 (2,6% da amostra) apresentaram concentração sérica de AAT < 113 mg/dl. A distribuição genotípica nesse subgrupo de 24 pacientes foi a seguinte: PI*MS, em 3 (12,5%); PI*MZ, em 13 (54,2%); PI*SZ, em 1 (4,2%); PI*SS, em 1 (4,2%); e PI*ZZ, em 6 (25,0%). Na amostra estudada, a prevalência global da deficiência de AAT foi de 2,8% e a prevalência do genótipo PI*ZZ (deficiência grave de AAT) foi de 0,8%. A prevalência da deficiência de AAT em pacientes com DPOC no Brasil é semelhante àquela encontrada na maioria dos países e reforça a recomendação de que se deve medir a concentração de AAT em todos pacientes com DPOC.

  13. Prevalence of alpha-1 antitrypsin deficiency and allele frequency in patients with COPD in Brazil

    Science.gov (United States)

    Russo, Rodrigo; Zillmer, Laura Russo; Nascimento, Oliver Augusto; Manzano, Beatriz; Ivanaga, Ivan Teruaki; Fritscher, Leandro; Lundgren, Fernando; Miravitlles, Marc; Gondim, Heicilainy Del Carlos; Santos, Gildo; Alves, Marcela Amorim; Oliveira, Maria Vera; de Souza, Altay Alves Lino; Sales, Maria Penha Uchoa; Jardim, José Roberto

    2016-01-01

    ABSTRACT Objective: To determine the prevalence of alpha 1-antitrypsin (AAT) deficiency (AATD), as well as allele frequency, in COPD patients in Brazil. Methods: This was a cross-sectional study involving 926 COPD patients 40 years of age or older, from five Brazilian states. All patients underwent determination of AAT levels in dried blood spot (DBS) samples by nephelometry. Those with DBS AAT levels ≤ 2.64 mg/dL underwent determination of serum AAT levels. Those with serum AAT levels of < 113 mg/dL underwent genotyping. In case of conflicting results, SERPINA1 gene sequencing was performed. Results: Of the 926 COPD patients studied, 85 had DBS AAT levels ≤ 2.64 mg/dL, and 24 (2.6% of the study sample) had serum AAT levels of < 113 mg/dL. Genotype distribution in this subset of 24 patients was as follows: PI*MS, in 3 (12.5%); PI*MZ, in 13 (54.2%); PI*SZ, in 1 (4.2%); PI*SS, in 1 (4.2%); and PI*ZZ, in 6 (25.0%). In the sample as a whole, the overall prevalence of AATD was 2.8% and the prevalence of the PI*ZZ genotype (severe AATD) was 0.8% Conclusions: The prevalence of AATD in COPD patients in Brazil is similar to that found in most countries and reinforces the recommendation that AAT levels be measured in all COPD patients. PMID:27812629

  14. Augmentation therapy with alpha1-antitrypsin: patterns of use and adverse events.

    Science.gov (United States)

    Stoller, James K; Fallat, Robert; Schluchter, Mark D; O'Brien, Ralph G; Connor, Jason T; Gross, Nicholas; O'Neil, Kevin; Sandhaus, Robert; Crystal, Ronald G

    2003-05-01

    To describe patterns of prescribing augmentation therapy, and types and rates of adverse events in the National Heart, Lung, and Blood Institute Registry for Individuals with Severe Deficiency of Alpha(1)-Antitrypsin. Observational cohort study with follow-up visits every 6 to 12 months for up to 7 years. The rate and dosing frequency with which Registry participants were prescribed to receive augmentation therapy by their managing physicians, and the type and frequency of adverse events, classified in two ways: severity of self-reported symptoms, and actions taken as a consequence of the symptom. Over the course of Registry follow-up, 66% (n = 747) of the participants received augmentation therapy at some time. In keeping with recommendations made in the 1989 American Thoracic Society (ATS) statement, 75% of participants with airflow obstruction at first visit (defined as FEV(1) or = 80% predicted (14%) also received augmentation therapy. Among those with COPD for whom augmentation therapy was not prescribed, financial constraints were the reported cause in 30%. Observed patterns also varied from approved practice, in that dosing frequencies other than the US Food and Drug Administration-approved, once-weekly regimen were frequently prescribed. The overall rate of reported adverse events was 0.02 per patient-month, with 83% of participants reporting no events. This overall rate was composed of 16% considered mild events, 76% moderate events, and 9% severe events. We conclude that augmentation therapy was generally well tolerated and, consistent with ATS guidelines, physicians generally did not prescribe augmentation therapy for subjects with FEV(1) > or = 80% predicted. However, the large percentage of subjects with FEV(1) <80% predicted not receiving augmentation therapy and the frequent use of 2- to 3-week or monthly dosing reflects variation of practice from suggested treatment guidelines.

  15. Alpha-1 antitrypsin is elevated in exhaled breath condensate and serum in exacerbated COPD patients.

    Science.gov (United States)

    Koczulla, A Rembert; Noeske, Sarah; Herr, Christian; Koepke, Janine; Jörres, Rudolf A; Nell, Christoph; Schmid, Severin; Vogelmeier, Claus; Bals, Robert

    2012-01-01

    Exacerbations of chronic obstructive pulmonary disease (COPD) significantly contribute to COPD-related morbidity. Diagnosis of COPD exacerbations may be improved by analyzing biomarkers such as alpha-1 antitrypsin (AAT). AAT is an acute-phase protein and inhibitor of neutrophil elastase. Deficiency of AAT may result in early-onset respiratory symptoms. Measurement of exhaled breath condensate (EBC) is a noninvasive method to investigate biomarkers present in the epithelial lining fluid, such as AAT. To investigate whether AAT can be detected and quantified in EBC and to compare AAT levels in the EBC of healthy controls, patients with COPD, and during exacerbations of COPD. EBC from 10 healthy controls, 17 subjects with COPD, and 18 subjects with exacerbations of COPD was collected with the RTube™ device. AAT from EBC and serum were quantified by ELISA. AAT in EBC was detectable in every individual. Patients with exacerbations of COPD had significantly increased AAT values (mean, 514.33 pg/mL, [SD 279.41 ]) compared with healthy controls (mean, 251.32 pg/mL, [SD 44.71]) and stable COPD patients (mean, 242.01 pg/mL [SD 65.74]) (P=0.0003; P=0.00003). EBC AAT showed only a correlation trend with serum AAT (r=0.3, P=0.054). AAT in EBC was detectable and quantifiable. AAT measured in EBC was significantly increased during exacerbations of COPD and can potentially be used as a biomarker in exacerbations. Copyright © 2011 Elsevier Ltd. All rights reserved.

  16. Gastric clearance of alpha-1-antitrypsin under cimetidine perfusion. New test to detect protein-losing gastropathy

    International Nuclear Information System (INIS)

    Florent, C.; Vidon, N.; Flourie, B.; Carmantrand, A.; Zerbani, A.; Maurel, M.; Bernier, J.J.

    1986-01-01

    Gastric losses of plasma are usually measured with radiolabeled macromolecules. This method is expensive and cumbersome. Direct measurement of exudated plasma proteins are ineffective since proteins are denaturated by acidic gastric juice and pepsin. It was recently shown that albumin measurement after immediate neutralization allowed detection of gastric protein losses, but this method is quite complex and time consuming. We studied alpha 1-antitrypsin and 51Cr-labeled protein clearance in gastric juice during normal saline and cimetidine (1.5 mg/kg/hr) infusion in six healthy volunteers and six patients with exudative gastropathy. alpha 1-Antitrypsin was measurable in all samples during cimetidine infusion: alpha 1-AT and 51Cr losses were significantly correlated (P less than 0.001). The upper limit of gastric alpha 1-AT clearance in controls was 0.86 ml/hr (mean + 2 SD). Using this value, there was no overlapping between patients and controls. The upper limit of 51Cr test was 1.87 ml/hr (mean + 2 SD) in controls but gastric clearance of 51Cr was below this value in one patient. This suggests that the measurement of alpha 1-AT gastric clearance during cimetidine perfusion is a good test to detect an exudative gastropathy. This test is inexpensive and lasts only 3 hr

  17. Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiency

    DEFF Research Database (Denmark)

    Dirksen, A; Piitulainen, E; Parr, D G

    2009-01-01

    Assessment of emphysema-modifying therapy is difficult, but newer outcome measures offer advantages over traditional methods. The EXAcerbations and Computed Tomography scan as Lung End-points (EXACTLE) trial explored the use of computed tomography (CT) densitometry and exacerbations...... for the assessment of the therapeutic effect of augmentation therapy in subjects with alpha(1)-antitrypsin (alpha(1)-AT) deficiency. In total, 77 subjects (protease inhibitor type Z) were randomised to weekly infusions of 60 mg x kg(-1) human alpha(1)-AT (Prolastin) or placebo for 2-2.5 yrs. The primary end...... was unaltered by treatment, but a reduction in exacerbation severity was observed. In patients with alpha(1)-AT deficiency, CT is a more sensitive outcome measure of emphysema-modifying therapy than physiology and health status, and demonstrates a trend of treatment benefit from alpha(1)-AT augmentation....

  18. Alpha-1-antitrypsin is produced by human neutrophil granulocytes and their precursors and liberated during granule exocytosis

    DEFF Research Database (Denmark)

    Clemmensen, Stine N; Jacobsen, Lars C; Rørvig, Sara

    2011-01-01

    Alpha-1-antitrypsin (A1AT) is an important inhibitor of neutrophil proteases including elastase, cathepsin G, and proteinase 3. Transcription profiling data suggest that A1AT is expressed by human neutrophil granulocytes during all developmental stages. A1AT has hitherto only been found associated....... Neutrophils from patients with A1AT-deficiency carrying the (PI)ZZ mutation in the A1AT gene appeared structurally and functionally normal, but A1AT produced in leukocytes of these patients lacked the ability to bind proteases efficiently. We conclude that A1AT generation and release from neutrophils add...

  19. Massive ascites and the heterozygous alpha 1 antitrypsin (α1AT) living related donor liver in the homozygous child.

    Science.gov (United States)

    Khorsandi, Shirin E; Thompson, Richard; Vilca-Melendez, Hector; Dhawan, Anil; Heaton, Nigel

    2018-02-01

    The following is a short report on the use of a heterozygous (PiMZ) alpha 1 antitrypsin (α1AT) living related donor liver in a homozygous (PiZ) child that was complicated by massive ascites early after transplant. This clinical report is then followed by a brief summary of present knowledge on the α 1 AT protein and management of massive ascites in the pediatric liver transplant recipient. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Extinction of alpha1-antitrypsin expression in cell hybrids is independent of HNF1alpha and HNF4 and involves both promoter and internal DNA sequences.

    OpenAIRE

    Bulla, G A

    1999-01-01

    In rat hepatoma x fibroblast somatic cell hybrids, extinction of rat alpha1-antitrypsin (alpha1AT) gene expression is accompanied by the loss of liver-enriched transcription factors hepatocyte nuclear factor 1 (HNF1alpha) and hepatocyte nuclear factor 4 (HNF4). Previous analysis showed that forced expression of functional HNF1alpha failed to prevent extinction of the rat alpha1AT locus in cell hybrids. Here I show that ectopic co-expression of HNF1alpha plus HNF4 fails to prevent extinction o...

  1. SP-A binds alpha1-antitrypsin in vitro and reduces the association rate constant for neutrophil elastase

    Directory of Open Access Journals (Sweden)

    Carrabino Natalia

    2005-12-01

    Full Text Available Abstract Background α1-antitrypsin and surfactant protein-A (SP-A are major lung defense proteins. With the hypothesis that SP-A could bind α1-antitrypsin, we designed a series of in vitro experiments aimed at investigating the nature and consequences of such an interaction. Methods and results At an α1-antitrypsin:SP-A molar ratio of 1:1, the interaction resulted in a calcium-dependent decrease of 84.6% in the association rate constant of α1-antitrypsin for neutrophil elastase. The findings were similar when SP-A was coupled with the Z variant of α1-antitrypsin. The carbohydrate recognition domain of SP-A appeared to be a major determinant of the interaction, by recognizing α1-antitrypsin carbohydrate chains. However, binding of SP-A carbohydrate chains to the α1-antitrypsin amino acid backbone and interaction between carbohydrates of both proteins are also possible. Gel filtration chromatography and turnover per inactivation experiments indicated that one part of SP-A binds several molar parts of α1-antitrypsin. Conclusion We conclude that the binding of SP-A to α1-antitrypsin results in a decrease of the inhibition of neutrophil elastase. This interaction could have potential implications in the physiologic regulation of α1-antitrypsin activity, in the pathogenesis of pulmonary emphysema, and in the defense against infectious agents.

  2. Long-term evolution of lung function in individuals with alpha-1 antitrypsin deficiency from the Spanish registry (REDAAT

    Directory of Open Access Journals (Sweden)

    Esquinas C

    2018-03-01

    Full Text Available Cristina Esquinas,1,2,* Sonia Serreri,3,* Miriam Barrecheguren,1 Esther Rodriguez,1 Alexa Nuñez,1 Francisco Casas-Maldonado,4 Ignacio Blanco,5 Pietro Pirina,3 Beatriz Lara,6 Marc Miravitlles1,7 1Pneumology Department, University Hospital Vall d’Hebron, Barcelona, Spain; 2Public Health, Mental, Maternal and Child Health Nursing Department, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain; 3Università di Sassari, Sassari, Italy; 4Pneumology Department, University Hospital San Cecilio, Granada, Spain; 5Alpha-1 Antitrypsin Deficiency Spanish Registry (REDAAT, Spanish Society of Pneumology (SEPAR, Barcelona, Spain; 6Coventry and Warwickshire University Hospital, Coventry, UK; 7CIBER de Enfermedades Respiratorias (CIBERES, Spain *These authors contributed equally to this work Background: The clinical course of alpha-1 antitrypsin deficiency (AATD is very heterogeneous. It is estimated that 60% of individuals with severe AATD (Pi*ZZ develop emphysema. The main objective of this study was to describe the outcomes of long-term lung function in individuals with AATD-associated emphysema after at least 8 years of follow-up. Materials and methods: We performed a retrospective analysis of longitudinal follow-up data of AATD PiZZ patients from the Spanish registry (AATD Spanish Registry [REDAAT]. The main follow-up outcome was the annual rate of decline in forced expiratory volume in 1 second (FEV1 calculated using the FEV1 values at baseline and in the last post-bronchodilator spirometry available. Results: One hundred and twenty-two AATD PiZZ patients were analyzed. The median follow-up was 11 years (interquartile range =9–14. The mean FEV1 decline was 28 mL/year (SD=54, with a median of 33 mL/year. Tobacco consumption (β=19.8, p<0.001, previous pneumonia (β=27.8, p=0.026 and higher baseline FEV1% (β=0.798, p=0.016 were independently related to a faster FEV1 decline. Conclusion: In this large cohort with a long

  3. Tumor necrosis factor alpha and alpha-1 antitrypsin gene variants in Serbian pediatric arterial ischemic stroke patients

    Directory of Open Access Journals (Sweden)

    Đorđević Valentina

    2013-01-01

    Full Text Available The etiology of arterial ischemic stroke (AIS in children is complex, and different from that in adults. Although rare, stroke in children is an important cause of mortality and morbidity. There is increasing evidence that genetic factors, including inflammation mediators, have a role in occurrence and outcome of stroke. We have chosen to assess the role of polymorphism -308G/A in the promoter of tumor necrosis factor α (TNFα gene and S and Z mutations in alpha 1-antitrypsin (AAT gene in the etiology of stroke in children. TNFα polymorphism affects plasma levels of this proinflamatory cytokine, and this could contribute to stroke pathology. It has been shown that increased AAT concentration may present a risk for AIS in children. Since S and Z mutations in AAT gene reduce its levels in plasma they could have a protective role in pediatric stroke. In this study twenty six children with AIS and 100 unrelated individuals from Serbian general population were investigated by PCR/RFLP for these gene variations. No statistically significant difference was observed between patients and general population in distribution of genotypes for -308G/A TNFα polymorphism, so its contributory role in the etiology of stroke was not evident in our group of patients. None of the tested AAT gene mutations were found in patients, which is in concordance with the proposed protective role of deficient AAT variants. AIS is a multifactorial disease, with many genes having a modest role in its pathophysiology, so further analyses of their combined effect are needed to elucidate genetic risk factors in the etiology and outcome of stroke in pediatric patients.

  4. A novel SERPINA1 mutation causing serum alpha(1-antitrypsin deficiency.

    Directory of Open Access Journals (Sweden)

    Darren N Saunders

    Full Text Available Mutations in the SERPINA1 gene can cause deficiency in the circulating serine protease inhibitor α(1-Antitrypsin (α(1AT. α(1AT deficiency is the major contributor to pulmonary emphysema and liver disease in persons of European ancestry, with a prevalence of 1 in 2500 in the USA. We present the discovery and characterization of a novel SERPINA1 mutant from an asymptomatic Middle Eastern male with circulating α(1AT deficiency. This 49 base pair deletion mutation (T379Δ, originally mistyped by IEF, causes a frame-shift replacement of the last sixteen α(1AT residues and adds an extra twenty-four residues. Functional analysis showed that the mutant protein is not secreted and prone to intracellular aggregation.

  5. Fluphenazine reduces proteotoxicity in C. elegans and mammalian models of alpha-1-antitrypsin deficiency.

    Directory of Open Access Journals (Sweden)

    Jie Li

    Full Text Available The classical form of α1-antitrypsin deficiency (ATD is associated with hepatic fibrosis and hepatocellular carcinoma. It is caused by the proteotoxic effect of a mutant secretory protein that aberrantly accumulates in the endoplasmic reticulum of liver cells. Recently we developed a model of this deficiency in C. elegans and adapted it for high-content drug screening using an automated, image-based array scanning. Screening of the Library of Pharmacologically Active Compounds identified fluphenazine (Flu among several other compounds as a drug which reduced intracellular accumulation of mutant α1-antitrypsin Z (ATZ. Because it is representative of the phenothiazine drug class that appears to have autophagy enhancer properties in addition to mood stabilizing activity, and can be relatively easily re-purposed, we further investigated its effects on mutant ATZ. The results indicate that Flu reverses the phenotypic effects of ATZ accumulation in the C. elegans model of ATD at doses which increase the number of autophagosomes in vivo. Furthermore, in nanomolar concentrations, Flu enhances the rate of intracellular degradation of ATZ and reduces the cellular ATZ load in mammalian cell line models. In the PiZ mouse model Flu reduces the accumulation of ATZ in the liver and mediates a decrease in hepatic fibrosis. These results show that Flu can reduce the proteotoxicity of ATZ accumulation in vivo and, because it has been used safely in humans, this drug can be moved rapidly into trials for liver disease due to ATD. The results also provide further validation for drug discovery using C. elegans models that can be adapted to high-content drug screening platforms and used together with mammalian cell line and animal models.

  6. Alpha-1-Antitrypsin Antagonizes Cisplatin-Induced Cytotoxicity in Prostate Cancer (PC3) and Melanoma Cancer (A375) Cell Lines.

    Science.gov (United States)

    Ljujic, Mila; Mijatovic, Sanja; Bulatovic, Mirna Z; Mojic, Marija; Maksimovic-Ivanic, Danijela; Radojkovic, Dragica; Topic, Aleksandra

    2017-04-01

    Increased circulating alpha-1-antitrypsin (AAT) correlates with cancer stage/aggressiveness, but its role in cancer biology is unclear. We revealed antagonistic effect of AAT to cisplatin-induced cytotoxicity in prostate (PC3) and melanoma (A375) cancer cell lines. Moreover, AAT abrogated cytotoxicity of MEK inhibitor U0126 in PC3 cell line. Weaker antagonistic effect of AAT on cytotoxicity of PI3/Akt and NF-kB inhibitors was also observed. In addition, cisplatin increased AAT gene expression in transfected PC3 cells. However, AAT derived from transfected PC3 cells did not antagonize cisplatin-induced cytotoxicity. In conclusion, these results suggest possible association between high circulating AAT and cisplatin resistance.

  7. Human Alpha-1-Antitrypsin (hAAT) therapy reduces renal dysfunction and acute tubular necrosis in a murine model of bilateral kidney ischemia-reperfusion injury

    NARCIS (Netherlands)

    Maicas, Nuria; van der Vlag, Johan; Bublitz, Janin; Florquin, Sandrine; Bakker-van Bebber, Marinka; Dinarello, Charles A; Verweij, Vivienne; Masereeuw, Roos|info:eu-repo/dai/nl/155644033; Joosten, Leo A; Hilbrands, Luuk B

    2017-01-01

    Several lines of evidence have demonstrated the anti-inflammatory and cytoprotective effects of alpha-1-antitrypsin (AAT), the major serum serine protease inhibitor. The aim of the present study was to investigate the effects of human AAT (hAAT) monotherapy during the early and recovery phase of

  8. Effect of Recombinant alpha1-Antitrypsin Fc-Fused (AAT-Fc)Protein on the Inhibition of Inflammatory Cytokine Production and Streptozotocin-Induced Diabetes

    NARCIS (Netherlands)

    Lee, S.; Lee, Y.; Hong, K.; Hong, J.; Bae, S.; Choi, J.; Jhun, H.; Kwak, A.; Kim, E.; Jo, S.; Dinarello, C.A.; Kim, S.

    2013-01-01

    alpha1-Antitrypsin (AAT) is a member of the serine proteinase inhibitor family that impedes the enzymatic activity of serine proteinases, including human neutrophil elastase, cathepsin G and neutrophil proteinase 3. Here, we expressed recombinant AAT by fusing the intact AAT gene to the constant

  9. Deficiência de alfa-1 antitripsina: diagnóstico e tratamento Alpha-1 antitrypsin deficiency: diagnosis and treatment

    Directory of Open Access Journals (Sweden)

    Aquiles A Camelier

    2008-07-01

    Full Text Available A deficiência de alfa-1 antitripsina é um distúrbio genético de descoberta recente e que ocorre com freqüência comparável à da fibrose cística. Resulta de diferentes mutações no gene SERPINA1 e tem diversas implicações clínicas. A alfa-1 antitripsina é produzida principalmente no fígado e atua como uma antiprotease. Tem como principal função inativar a elastase neutrofílica, impedindo a ocorrência de dano tecidual. A mutação mais freqüentemente relacionada à doença clínica é o alelo Z, que determina polimerização e acúmulo dentro dos hepatócitos. O acúmulo e a conseqüente redução dos níveis séricos de alfa-1 antitripsina determinam, respectivamente, doença hepática e pulmonar, sendo que esta se manifesta principalmente sob a forma de enfisema de aparecimento precoce, habitualmente com predomínio basal. O diagnóstico envolve a detecção de níveis séricos reduzidos de alfa-1 antitripsina e a confirmação fenotípica. Além do tratamento usual para doença pulmonar obstrutiva crônica, existe atualmente uma terapia específica com infusão de concentrados de alfa-1 antitripsina. Essa terapia de reposição, aparentemente segura, ainda não teve a eficácia clínica definitivamente comprovada, e o custo-efetividade também é um tema controverso e ainda pouco abordado. Apesar da sua importância, não existem dados epidemiológicos brasileiros a respeito da prevalência da doença ou da freqüência de ocorrência dos alelos deficientes. O subdiagnóstico também tem sido uma importante limitação tanto para o estudo da doença quanto para o tratamento adequado dos pacientes. Espera-se que a criação do Registro Internacional de Alfa-1 venha a resolver essas e outras importantes questões.Alpha-1 antitrypsin deficiency is a recently identified genetic disease that occurs almost as frequently as cystic fibrosis. It is caused by various mutations in the SERPINA1 gene, and has numerous clinical

  10. Recombinant AAV serotype and capsid mutant comparison for pulmonary gene transfer of alpha-1-antitrypsin using invasive and noninvasive delivery.

    Science.gov (United States)

    Liqun Wang, Rejean; McLaughlin, Thomas; Cossette, Travis; Tang, Qiushi; Foust, Kevin; Campbell-Thompson, Martha; Martino, Ashley; Cruz, Pedro; Loiler, Scott; Mueller, Christian; Flotte, Terence R

    2009-01-01

    Recombinant adeno-associated viral (rAAV) vectors have been widely used in pulmonary gene therapy research. In this study, we evaluated the transduction and expression efficiencies of several AAV serotypes and AAV2 capsid mutants with specific pulmonary targeting ligands in the mouse lung. The noninvasive intranasal delivery was compared with the traditional intratracheal lung delivery. The rAAV8 was the most efficient serotype at expressing alpha-1-antitrypsin (AAT) in the lung among all the tested serotypes and mutants. A dose of 1 x 10(10) vg of rAAV8-CB-AAT transduced a high percentage of cells in the lung when delivered intratrachealy. The serum and the broncho-alveolar lavage fluid (BALF) levels of human AAT (hAAT) were about 6- and 2.5-fold higher, respectively, than those of rAAV5 group. Among the rAAV2 capsid mutants, the rAAV2 capsid mutants that display a peptide sequence from hAAT ("long serpin") indicated a twofold increase in transgene expression. For most vectors, the serum hAAT levels achieved after intranasal delivery were 1/2 to 1/3 of those with the intratracheal method. Overall, rAAV8 was the most promising vector for the future application in gene therapy of pulmonary diseases such as AAT deficiency-related emphysema.

  11. Three new alpha1-antitrypsin deficiency variants help to define a C-terminal region regulating conformational change and polymerization.

    Directory of Open Access Journals (Sweden)

    Anna M Fra

    Full Text Available Alpha1-antitrypsin (AAT deficiency is a hereditary disorder associated with reduced AAT plasma levels, predisposing adults to pulmonary emphysema. The most common genetic AAT variants found in patients are the mildly deficient S and the severely deficient Z alleles, but several other pathogenic rare alleles have been reported. While the plasma AAT deficiency is a common trait of the disease, only a few AAT variants, including the prototypic Z AAT and some rare variants, form cytotoxic polymers in the endoplasmic reticulum of hepatocytes and predispose to liver disease. Here we report the identification of three new rare AAT variants associated to reduced plasma levels and characterize their molecular behaviour in cellular models. The variants, called Mpisa (Lys259Ile, Etaurisano (Lys368Glu and Yorzinuovi (Pro391His, showed reduced secretion compared to control M AAT, and accumulated to different extents in the cells as ordered polymeric structures resembling those formed by the Z variant. Structural analysis of the mutations showed that they may facilitate polymerization both by loosening 'latch' interactions constraining the AAT reactive loop and through effects on core packing. In conclusion, the new AAT deficiency variants, besides increasing the risk of lung disease, may predispose to liver disease, particularly if associated with the common Z variant. The new mutations cluster structurally, thus defining a region of the AAT molecule critical for regulating its conformational state.

  12. Alpha-1 antitrypsin deficiency caused by a novel mutation (p.Leu263Pro: Pi*ZQ0gaia – Q0gaia allele

    Directory of Open Access Journals (Sweden)

    M.J. Oliveira

    2015-11-01

    Full Text Available Severe alpha-1 antitrypsin deficiency (AATD is generally associated with PI*ZZ genotype and less often with combinations of PI*Z, PI*S, and other rarer deficiency or null (Q0 alleles. Severe AATD predisposes patients to various diseases, including pulmonary emphysema. Presented here is a case report of a young man with COPD and AATD. The investigation of the AATD showed a novel mutation p.Leu263Pro (c.860T>C, which was named Q0gaia (Pi*ZQ0gaia. Q0gaia is associated with very low or no detectable serum concentrations of AAT. Keywords: Alpha-1 antitrypsin deficiency, Null allele, COPD

  13. Bioequivalence of a Liquid Formulation of Alpha1-Proteinase Inhibitor Compared with Prolastin®-C (Lyophilized Alpha1-PI) in Alpha1-Antitrypsin Deficiency.

    Science.gov (United States)

    Barker, Alan F; Campos, Michael A; Brantly, Mark L; Stocks, James M; Sandhaus, Robert A; Lee, Douglas; Steinmann, Kimberly; Lin, Jiang; Sorrells, Susan

    2017-12-01

    This study evaluated the bioequivalence, safety, and immunogenicity of a new liquid formulation of human plasma-derived alpha 1 -proteinase inhibitor, Liquid Alpha 1 -PI, compared with the Lyophilized Alpha 1 -PI formulation (Prolastin®-C), for augmentation therapy in patients with alpha 1 -antitrypsin deficiency (AATD). In this double-blind, randomized, 20-week crossover study, 32 subjects with AATD were randomized to receive 8 weekly infusions of 60 mg/kg of Liquid Alpha 1 -PI or Lyophilized Alpha 1 -PI. Serial blood samples were drawn for 7 days after the last dose followed by 8 weeks of the alternative treatment. The primary endpoint was bioequivalence at steady state, as measured by area under the concentration versus time curve from 0 to 7 days (AUC 0-7 days ) postdose using an antigenic content assay. Bioequivalence was defined as 90% confidence interval (CI) for the ratio of the geometric least squares (LS) mean of AUC 0-7 days for both products within the limits of 0.80 and 1.25. Safety and immunogenicity were assessed. Mean alpha 1 -PI concentration versus time curves for both formulations were superimposable. Mean AUC 0-7 days was 20 320 versus 19 838 mg × h/dl for Liquid Alpha 1 -PI and Lyophilized Alpha 1 -PI, respectively. The LS mean ratio of AUC 0-7 days (90% CI) for Liquid Alpha 1 -PI versus Lyophilized Alpha 1 -PI was 1.05 (1.03-1.08), indicating bioequivalence. Liquid Alpha 1 -PI was well tolerated and adverse events were consistent with Lyophilized Alpha 1 -PI. Immunogenicity to either product was not detected. In conclusion, Liquid Alpha 1 -PI is bioequivalent to Lyophilized Alpha 1 -PI, with a similar safety profile. The liquid formulation would eliminate the need for reconstitution and shorten preparation time for patients receiving augmentation therapy for AATD.

  14. Alpha-1 antitrypsin phenotypes in patients with lung, prostate and breast cancer

    International Nuclear Information System (INIS)

    El-Akawi, Zeyad J.; Al-Hindawi, Fatin K.

    2004-01-01

    Determination of Alpha1-antitryspin (AT) phenotypes in Jordanian patients with lung, prostate and breast cancerto find a prevalent phenotype that could be recommended for the diagnosis of cancer. This study was conducted at Jordan University of Science and Technology, School of Medicine Jordan during the period May 2001 to May 2002. Alpha1-antitryspin (AT) phenotypes for 83 Jordanian cancer patients distributed as follows, 25 lung cancer, 25 prostate cancer and 33 with breast cancer were tested using isoelectric focusing gel electrophoresis and immunofluxation techniques. Isoelectric focusing results demonstrated that 96% of lung cancer patients were of PiMM phenotype and 4% of PiFM phenotype. All prostate cancer patients (100%) were found to be of PiMM and 3% PiMS. These findings demonstrated that there was no significant differences in the distribution of AT phenotypes among Jordanian patients with lung, prostae and breast cancerand they matched those reported for healthy individuals. Thus, we can nor recommand a given AT phentype for early diagnosis of the above mentioned types of cancer. (author)

  15. Sustained secretion of human alpha-1-antitrypsin from murine muscle transduced with adeno-associated virus vectors

    Science.gov (United States)

    Song, Sihong; Morgan, Michael; Ellis, Tamir; Poirier, Amy; Chesnut, Kye; Wang, Jianming; Brantly, Mark; Muzyczka, Nicholas; Byrne, Barry J.; Atkinson, Mark; Flotte, Terence R.

    1998-01-01

    Recombinant adeno-associated virus (AAV) vectors have been used to transduce murine skeletal muscle as a platform for secretion of therapeutic proteins. The utility of this approach for treating alpha-1-antitrypsin (AAT) deficiency was tested in murine myocytes in vitro and in vivo. AAV vectors expressing the human AAT gene from either the cytomegalovirus (CMV) promoter (AAV-C-AT) or the human elongation factor 1-α promoter (AAV-E-AT) were examined. In vitro in C2C12 murine myoblasts, the expression levels in transient transfections were similar between the two vectors. One month after transduction, however, the human elongation factor 1 promoter mediated 10-fold higher stable human AAT expression than the CMV promoter. In vivo transduction was performed by injecting doses of up to 1.4 × 1013 particles into skeletal muscles of several mouse strains (C57BL/6, BALB/c, and SCID). In vivo, the CMV vector mediated higher levels of expression, with sustained serum levels over 800 μg/ml in SCID and over 400 μg/ml in C57BL/6 mice. These serum concentrations are 100,000-fold higher than those previously observed with AAV vectors in muscle and are at levels which would be therapeutic if achieved in humans. High level expression was delayed for several weeks but was sustained for over 15 wk. Immune responses were dependent upon the mouse strain and the vector dosage. These data suggest that recombinant AAV vector transduction of skeletal muscle could provide a means for replacing AAT or other essential serum proteins but that immune responses may be elicited under certain conditions. PMID:9826709

  16. Characteristics of candidates for lung transplantation due to chronic obstructive pulmonary disease and alpha-1 antitrypsin deficiency emphysema.

    Science.gov (United States)

    Giacoboni, Daniela; Barrecheguren, Miriam; Esquinas, Cristina; Rodríguez, Esther; Berastegui, Cristina; López-Meseguer, Manuel; Monforte, Víctor; Bravo, Carlos; Pirina, Pietro; Miravitlles, Marc; Román, Antonio

    2015-08-01

    COPD and emphysema due to alpha-1 antitrypsin deficiency (AATD) are the first and fourth indications for lung transplantation worldwide, respectively. Despite this, there is little information regarding the health status of these patients at the time of transplantation. Patients who received a lung transplant in the Hospital Vall d'Hebron between July 1993 and August 2013 were identified and data from the evaluation prior to the transplant were collected. A total of 217 patients who received a lung transplant for COPD and 19 in whom the indication was AATD were included. These patients were severely impaired at the time of the evaluation for lung transplantation, although the trend in recent years has been to evaluate patients at earlier stages of the disease. Baseline characteristics were similar in both groups except that patients with AATD were younger [43 (7.7) vs. 53.6 (6.1) years old, P<.001], with less exposure to tobacco [23.9 (15) vs. 50 (29) packs-year, P<002] and lower PCO2 [41.7 (7.6) vs. 47.9 (9.7) mmHg, P<.004]. The number of patients receiving a lung transplant for COPD has progressively increased and the tendency is to perform the evaluation in earlier stages of the disease. Patients receiving transplants for COPD and AATD had similar characteristics at the time of the evaluation, although AATD patients were younger and had less exposure to tobacco and lower PCO2. Copyright © 2014 SEPAR. Published by Elsevier Espana. All rights reserved.

  17. Rationale and Design of the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) Study. Sarcoidosis Protocol.

    Science.gov (United States)

    Moller, David R; Koth, Laura L; Maier, Lisa A; Morris, Alison; Drake, Wonder; Rossman, Milton; Leader, Joseph K; Collman, Ronald G; Hamzeh, Nabeel; Sweiss, Nadera J; Zhang, Yingze; O'Neal, Scott; Senior, Robert M; Becich, Michael; Hochheiser, Harry S; Kaminski, Naftali; Wisniewski, Stephen R; Gibson, Kevin F

    2015-10-01

    Sarcoidosis is a systemic disease characterized by noncaseating granulomatous inflammation with tremendous clinical heterogeneity and uncertain pathobiology and lacking in clinically useful biomarkers. The Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study is an observational cohort study designed to explore the role of the lung microbiome and genome in these two diseases. This article describes the design and rationale for the GRADS study sarcoidosis protocol. The study addresses the hypothesis that distinct patterns in the lung microbiome are characteristic of sarcoidosis phenotypes and are reflected in changes in systemic inflammatory responses as measured by peripheral blood changes in gene transcription. The goal is to enroll 400 participants, with a minimum of 35 in each of 9 clinical phenotype subgroups prioritized by their clinical relevance to understanding of the pathobiology and clinical heterogeneity of sarcoidosis. Participants with a confirmed diagnosis of sarcoidosis undergo a baseline visit with self-administered questionnaires, chest computed tomography, pulmonary function tests, and blood and urine testing. A research or clinical bronchoscopy with a research bronchoalveolar lavage will be performed to obtain samples for genomic and microbiome analyses. Comparisons will be made by blood genomic analysis and with clinical phenotypic variables. A 6-month follow-up visit is planned to assess each participant's clinical course. By the use of an integrative approach to the analysis of the microbiome and genome in selected clinical phenotypes, the GRADS study is powerfully positioned to inform and direct studies on the pathobiology of sarcoidosis, identify diagnostic or prognostic biomarkers, and provide novel molecular phenotypes that could lead to improved personalized approaches to therapy for sarcoidosis.

  18. Clinical utility of alpha-1 proteinase inhibitor in the management of adult patients with severe alpha-1 antitrypsin deficiency: a review of the current literature

    Directory of Open Access Journals (Sweden)

    Parr DG

    2017-07-01

    Full Text Available David G Parr, Beatriz Lara Department of Respiratory Medicine, Cardio-Respiratory Division, University Hospital Coventry, Coventry, UK Abstract: Alpha-1 antitrypsin (AAT functions primarily to inhibit neutrophil elastase, and its deficiency predisposes individuals to the development of chronic obstructive pulmonary disease (COPD. The putative protective serum concentration is generally considered to be above a threshold of 11 µM/L, and therapeutic augmentation of AAT above this value is believed to retard the progression of emphysema. Several AAT preparations, all derived from human donor plasma, have been commercialized since approval by the US Food and Drug Administration (FDA in 1987. Biochemical efficacy has been demonstrated by augmentation of pulmonary antiprotease activity, but demonstration of clinical efficacy in randomized, placebo-controlled trials has been hampered by the practical difficulties of performing conventional studies in a rare disease with a relatively long natural history. Computed tomography has been applied to measure lung density as a more specific and sensitive surrogate outcome measure of emphysema than physiologic indices, such as forced expiratory volume in 1 second, and studies consistently show a therapeutic reduction in the rate of lung density decline. However, convincing evidence of benefit using traditional clinical measures remains elusive. Intravenous administration of AAT at a dose of 60 mg/kg/week is the commonest regime in use and has well-documented safety and tolerability. International and national guidelines on the management of AAT deficiency recommend intravenous augmentation therapy to supplement optimized usual COPD treatment in patients with severe deficiency and evidence of lung function impairment. Keywords: alpha-1 antitrypsin deficiency, augmentation or replacement therapy, computed tomography, emphysema, COPD

  19. Alpha-1 Antitrypsin Deficiency

    Science.gov (United States)

    ... the Liver Galactosemia Gilbert’s Syndrome Diseases of the Liver Glycogen Storage Disease Type 1 (von Gierke) Hemochromatosis Hepatic Encephalopathy Hepatitis A Hepatitis B Hepatitis C Intrahepatic Cholestasis of Pregnancy (ICP) Jaundice In Newborns ...

  20. Alpha-1 Antitrypsin Deficiency

    Science.gov (United States)

    ... and Clinical Studies to hear experts, parents, and children talk about their experiences with clinical research. More Information Related Health Topics Cough How the Lungs Work Lung Transplant Oxygen Therapy Pulmonary Function Tests Pulmonary Rehabilitation Other Resources Non- ...

  1. Alpha-1 Antitrypsin Test

    Science.gov (United States)

    ... Culture Blood Gases Blood Ketones Blood Smear Blood Typing Blood Urea Nitrogen (BUN) BNP and NT-proBNP ... Luteinizing Hormone (LH) Lyme Disease Tests Magnesium Maternal Serum Screening, Second Trimester Measles and Mumps Tests Mercury ...

  2. Culture of Impure Human Islet Fractions in the Presence of Alpha-1-Antitrypsin Prevents Insulin Cleavage and Improves Islet Recovery

    Science.gov (United States)

    Loganathan, G.; Dawra, R.K.; Pugazhenthi, S.; Wiseman, A.C.; Sanders, M.A.; Saluja, A.K.; Sutherland, D.E.R.; Hering, B.J.; Balamurugan, A.N.

    2010-01-01

    Background Exocrine tissue is commonly cotransplanted with islets in autografting and allotransplantation of impure preparations. Proteases and insulin are released by acinar cells and islets, respectively, during pretransplantation culture and also systemically after transplantation. We hypothesized that released proteases could cleave insulin molecules and that addition of alpha 1 antitrypsin (A1AT) to impure islet cultures would block this cleavage, improving islet recovery and function. Methods Trypsin, chymotrypsin, and elastase (TCE) activity and insulin levels were measured in culture supernates of pure (n = 5) and impure (n = 5) islet fractions, which were isolated from deceased donors. SDS-PAGE was used to detect insulin after incubation with proteases. We assessed the effects of A1AT supplementation (0.5 mg/mL; n = 4] on TCE activity, insulin levels, culture recovery, and islet quality. The ultrastructure of islets exposed to TCE versus control medium was examined using electron microscopy (EM). Results Protease (TCE) activity in culture supernates was directly proportional to the percentage purity of islets: pure, impure, or highly impure. Increasingly lower levels of insulin were detected in culture supernates with higher protease activity levels. Insulin levels measured in supernates of 2000 IE aliquots of impure and highly impure islet preparations were 61 ± 23.7% and 34 ± 33% of that in pure preparations, respectively. Incubation with commercially available proteases (TCE) or exocrine acinar cell supernates cleaved insulin molecules as assessed using SDS-PAGE. Addition of A1AT to impure islet preparations reduced protease activity and restored normal insulin levels as detected using enzyme-linked immunosorbent assay (ELISA) and SDS-PAGE of culture supernates. A1AT improved insulin levels to 98% ± 1.3% in impure and 78% ± 34.2% in highly impure fractions compared with pure islet fractions. A1AT supplementation improved postculture recovery of

  3. Encapsulation of Alpha-1 antitrypsin in PLGA nanoparticles: In Vitro characterization as an effective aerosol formulation in pulmonary diseases

    Directory of Open Access Journals (Sweden)

    Pirooznia Nazanin

    2012-05-01

    Full Text Available Abstract Background Alpha 1- antitrypsin (α1AT belongs to the superfamily of serpins and inhibits different proteases. α1AT protects the lung from cellular inflammatory enzymes. In the absence of α1AT, the degradation of lung tissue results to pulmonary complications. The pulmonary route is a potent noninvasive route for systemic and local delivery. The aerosolized α1AT not only affects locally its main site of action but also avoids remaining in circulation for a long period of time in peripheral blood. Poly (D, L lactide-co glycolide (PLGA is a biodegradable and biocompatible polymer approved for sustained controlled release of peptides and proteins. The aim of this work was to prepare a wide range of particle size as a carrier of protein-loaded nanoparticles to deposit in different parts of the respiratory system especially in the deep lung. Various lactide to glycolide ratio of the copolymer was used to obtain different release profile of the drug which covers extended and rapid drug release in one formulation. Results Nonaqueous and double emulsion techniques were applied for the synthesis of nanoparticles. Nanoparticles were characterized in terms of surface morphology, size distribution, powder X-ray diffraction (XRD, encapsulation efficiency, in vitro drug release, FTIR spectroscopy and differential scanning calorimetry (DSC. To evaluate the nanoparticles cytotoxicity, cell cytotoxicity test was carried out on the Cor L105 human epithelial lung cancer cell line. Nanoparticles were spherical with an average size in the range of 100 nm to 1μ. The encapsulation efficiency was found to be higher when the double emulsion technique was applied. XRD and DSC results indicated that α1AT encapsulated in the nanoparticles existed in an amorphous or disordered-crystalline status in the polymer matrix. The lactic acid to glycolic acid ratio affects the release profile of α1AT. Hence, PLGA with a 50:50 ratios exhibited the ability to release

  4. Effects of Prolastin C (Plasma-Derived Alpha-1 Antitrypsin) on the acute inflammatory response in patients with ST-segment elevation myocardial infarction (from the VCU-alpha 1-RT pilot study)

    NARCIS (Netherlands)

    Abbate, A.; Tassell, B.W. Van; Christopher, S.; Abouzaki, N.A.; Sonnino, C.; Oddi, C.; Carbone, S.; Melchior, R.D.; Gambill, M.L.; Roberts, C.S.; Kontos, M.C.; Peberdy, M.A.; Toldo, S.; Vetrovec, G.W.; Biondi-Zoccai, G.; Dinarello, C.A.

    2015-01-01

    Alpha-1 antitrypsin (AAT) has broad anti-inflammatory and immunomodulating properties in addition to inhibiting serine proteases. Administration of human plasma-derived AAT is protective in models of acute myocardial infarction in mice. The objective of this study was to determine the safety and

  5. Identification of a novel SERPINA-1 mutation causing alpha-1 antitrypsin deficiency in a patient with severe bronchiectasis and pulmonary embolism

    Directory of Open Access Journals (Sweden)

    Milger K

    2015-05-01

    Full Text Available Katrin Milger,1 Lesca Miriam Holdt,2 Daniel Teupser,2 Rudolf Maria Huber,1 Jürgen Behr,1 Nikolaus Kneidinger1 1Department of Internal Medicine V, University of Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, 2Institute of Laboratory Medicine, University of Munich, Munich, Germany Abstract: Deficiency in the serine protease inhibitor, alpha-1 antitrypsin (AAT, is known to cause emphysema and liver disease. Other manifestations, including airway disease or skin disorders, have also been described. A 44-year-old woman presented to our emergency department with dyspnea and respiratory insufficiency. She had never smoked, and had been diagnosed with COPD 9 years earlier. Three months previously, she had suffered a pulmonary embolism. Chest computed tomography scan revealed severe cystic bronchiectasis with destruction of the lung parenchyma. The sweat test was normal and there was no evidence of the cystic fibrosis transmembrane conductance regulator (CFTR mutation. Capillary zone electrophoresis showed a decrease of alpha-1 globin band and AAT levels were below the quantification limit (<25 mg/dL. No S or Z mutation was identified, but sequencing analysis found a homozygous cytosine and adenine (CA insertion in exon 2 of the SERPINA-1 gene, probably leading to a dysfunctional protein (PI Null/Null. This mutation has not been previously identified. The atypical presentation of the patient, with severe cystic bronchiectasis, highlights AAT deficiency as a differential diagnosis in bronchiectasis. Further, awareness should be raised regarding a possible increased risk of thromboembolism associated with AAT deficiency. Keywords: alpha-1 antitrypsin deficiency, bronchiectasis, SERPINA-1 mutation, pulmonary embolism

  6. Exploring the optimum approach to the use of CT densitometry in a randomised placebo-controlled study of augmentation therapy in alpha 1-antitrypsin deficiency

    DEFF Research Database (Denmark)

    Parr, David G; Dirksen, Asger; Piitulainen, Eeva

    2009-01-01

    BACKGROUND: Computed tomography (CT) lung densitometry has been demonstrated to be the most sensitive and specific outcome measure for the assessment of emphysema-modifying therapy, but the optimum densitometric index has yet to be determined and targeted sampling may be more sensitive than whole...... lung assessment. The EXAcerbations and CT scan as Lung Endpoints (EXACTLE) trial aimed to clarify the optimum approach to the use of CT densitometry data for the assessment of alpha 1-antitrypsin (AAT) augmentation therapy on the progression of emphysema in AAT deficiency (AATD). METHODS: Patients...... of emphysema in the apical, middle and basal regions of the lung by measurement with PD15 showed that this treatment effect was more evident when the basal third was sampled (1.722 g/L, p = 0.040). A comparison between different densitometric indices indicated that the influence of inspiratory variability...

  7. Synthetic Cannabinoid Abuse and a Rare Alpha-1-Antitrypsin Mutant Causing Acute Fulminant Hepatitis: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Kurt J. Knowles

    2017-01-01

    Full Text Available Synthetic cannabinoids (SCs abuse is on the rise because they are easily obtained over the counter; they are potent psychoactive compounds and routine drug testing does not detect them. As their abuse is on the rise, so are their detrimental side effects; however, the occurrence of acute hepatitis due to SCs abuse has been reported only once before. In this case, testing revealed that the patient was also heterozygous for alpha-1-antitrypsin (A-1-AT with the phenotype of PI⁎EM. This mutant phenotype has never been reported as a cause of A-1-AT disease and the abuse of SCs in a patient with this phenotype has also never been reported. This case illustrates the possible need to expand routine drug testing for SCs and consider A-1-AT phenotyping in certain clinical scenarios.

  8. Intensive smoking diminishes the differences in quality of life and exacerbation frequency between the alpha-1-antitrypsin deficiency genotypes PiZZ and PiSZ.

    Science.gov (United States)

    Bernhard, Nikolas; Lepper, Philipp M; Vogelmeier, Claus; Seibert, Martina; Wagenpfeil, Stefan; Bals, Robert; Fähndrich, Sebastian

    2017-09-01

    Alpha-1-antitrypsin deficiency (AATD) is a rare genetic disorder that is associated with low levels of circulating alpha-1-antitrypsin in serum. In comparison to the genotype PiZZ, PiSZ usually leads to lower risk of emphysema, better lung function and better survival. The aim of this study was to analyze the relationship between cigarette smoking (packyears) and the AATD genotypes (PiZZ and PiSZ) concerning quality of life (SGRQ), transfer factor of the lung for carbon monoxide (TLCO), forced expiratory volume in one second (FEV 1 ) and exacerbation rate. We compared PiZZ and PiSZ individuals from the German registry for individuals with AATD (AATDR) in univariate analysis and multivariate linear regression models. All subjects were stratified into three groups according to their cumulative nicotine consumption (0 py; 0 < py < 30; ?30 py). 868 PiZZ individuals (mean age 52.6 ± 12.8 years (43.5% female)) and 114 PiSZ individuals (mean age 50.3 ± 17.4 years (46.5% female)) were compared. In contrast to never- and intensive (ex-) smokers, moderate (ex-) smoking PiSZ individuals had a significantly better SGRQ total score (B = ?8.148; p = 0.020) and less exacerbations (B = ?0.354; p = 0.037) than individuals with PiZZ in multivariate analysis. The differences in quality of life and exacerbation frequency between PiZZ and PiSZ individuals diminish by intensive (ex-) smoking. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Exacerbations and duration of smoking abstinence are associated with the annual loss of FEV1 in individuals with PiZZ alpha-1-antitrypsin deficiency.

    Science.gov (United States)

    Fähndrich, Sebastian; Bernhard, Nikolas; Lepper, Philipp M; Vogelmeier, Claus; Seibert, Martina; Wagenpfeil, Stefan; Bals, Robert

    2017-08-01

    Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder that is associated with a higher risk of chronic obstructive pulmonary disease (COPD) and emphysema. The annual declines in lung function (FEV 1 ) and transfer factor of the lung for carbon monoxide (TLCO) predict all-cause mortality. We investigated the longitudinal follow-up data over 11 years (mean follow-up period of 4.89 years) from the German AATD registry and analyzed the relationship between annual loss of FEV 1 and TLCO and sex, age, body mass index (BMI), nicotine consumption, occupational dust exposure, St. George's Respiratory Questionnaire (SGRQ) score, baseline FEV 1 or TLCO, alpha-1-antitrypsin (AAT) serum level, exacerbation frequency and the duration of smoking abstinence by multiple linear generalized estimating equations models (GEE-models). We evaluated the data of 100 individuals with post-bronchodilator FEV 1 measurements and from 116 individuals with TLCO measurements. The mean overall decline was -54.06 ± 164.62 ml/year in FEV 1 and -0.17 ± 0.70 mmol/min/kPa/year in TLCO. Accelerated deterioration of FEV 1 was associated with occupational dust exposure (p = 0.026), shorter duration of smoking abstinence (p = 0.008), higher baseline FEV 1 (p = 0.003), higher annual exacerbation frequency (p = 0.003) and higher frequency of glucocorticoids intake (p = 0.004). Furthermore, patients with an elevated decline in TLCO showed significant impaired health-related quality of life at baseline (p = 0.039) and lower AAT serum levels (p < 0.001) in multivariate analysis. Annual decline in FEV 1 is related to the exacerbation rate, occupational dust exposure and the duration of smoking abstinence. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Progression of emphysema evaluated by MRI using hyperpolarized (3)He (HP (3)He) measurements in patients with alpha-1-antitrypsin (A1AT) deficiency compared with CT and lung function tests

    DEFF Research Database (Denmark)

    Stavngaard, T; Søgaard, L Vejby; Batz, M

    2009-01-01

    as compared to yearly decline. PURPOSE: To investigate the progression of emphysema over a period of 2 years using diffusion-weighted hyperpolarized (HP) (3)He magnetic resonance imaging (MRI) in patients with alpha-1-antitrypsin (A1AT) deficiency. MATERIAL AND METHODS: Nine patients with severe A1AT...

  11. Health status and lung function in the Swedish alpha 1-antitrypsin deficient cohort, identified by neonatal screening, at the age of 37-40 years

    Directory of Open Access Journals (Sweden)

    Piitulainen E

    2017-02-01

    Full Text Available Eeva Piitulainen, Behrouz Mostafavi, Hanan A Tanash Department of Respiratory Medicine and Allergology, Skåne University Hospital, Lund University, Malmö, Sweden Background: Severe alpha 1-antitrypsin (AAT deficiency (genotype PiZZ is a well-known risk factor for COPD. A cohort of PiZZ and PiSZ individuals was identified by the Swedish national neonatal AAT screening program in 1972–1974 and followed up regularly since birth. Our aim was to study the lung function, respiratory symptoms and health status at the age of 38 years in comparison with a random sample of control subjects selected from the population registry.Methods: The study group included 120 PiZZ, 46 PiSZ and 164 control subjects (PiMM, who answered a questionnaire on smoking habits and symptoms and the Saint George Respiratory Questionnaire (SGRQ on quality of life. A total of 89 PiZZ, 33 PiSZ and 92 PiMM subjects underwent spirometry.Results: Four percent of the PiZZ, 2% of the PiSZ and 12% of the control subjects were current smokers (P=0.008, and 17% of the PiZZ, 9% of the PiSZ and 21% of the control subjects had stopped smoking. The PiZZ current smokers had a significantly higher (ie, poorer median activity score according to the SGRQ than the PiZZ never-smokers (P=0.032. The PiMM current smokers had significantly higher activity score (P<0.001, symptom score (P<0.001, and total score (P=0.001 according to the SGRQ than the PiMM never-smokers. The PiZZ current smokers had a significantly lower postbronchodilator forced expiratory volume in 1 second (FEV1% of predicted value (P=0.019 and FEV1/forced vital capacity (FVC ratio (P=0.032 than the PiZZ never-smokers. The proportion of subjects with a FEV1/FVC ratio of <0.70, indicating COPD, was significantly higher in the PiZZ current smokers than in the PiZZ never-smokers (P=0.001. Among the PiSZ and PiMM subjects, the differences in lung function between the smoking subgroups were insignificant.Conclusion: PiZZ current

  12. TISSUE INHIBITOR OF METALLOPROTEINASE 1, MATRIX METALLOPROTEINASE 9, ALPHA-1 ANTITRYPSIN, METALLOTHIONEIN AND UROKINASE TYPE PLASMINOGEN ACTIVATOR RECEPTOR IN SKIN BIOPSIES FROM PATIENTS AFFECTED BY AUTOIMMUNE BLISTERING DISEASES

    Directory of Open Access Journals (Sweden)

    Ana Maria Abreu Velez

    2013-07-01

    Full Text Available Introduction: Proteinases and proteinase inhibitors have been described to play a role in autoimmune skin blistering diseases. We studied skin lesional biopsies from patients affected by several autoimmune skin blistering diseases for proteinases and proteinase inhibitors. Methods: We utilized immunohistochemistry to evaluate biopsies for alpha-1-antitrypsin, human matrix metalloproteinase 9 (MMP9, human tissue inhibitor of metalloproteinases 1 (TIMP-1, metallothionein and urokinase type plasminogen activator receptor (uPAR. We tested 30 patients affected by endemic pemphigus, 30 controls from the endemic area, and 15 normal controls. We also tested 30 biopsies from patients with bullous pemphigoid (BP, 20 with pemphigus vulgaris (PV, 8 with pemphigus foliaceus, and 14 with dermatitis herpetiformis (DH. Results: Contrary to findings in the current literature, most autoimmune skin blistering disease biopsies were negative for uPAR and MMP9. Only some chronic patients with El Bagre-EPF were positive to MMP9 in the dermis, in proximity to telocytes. TIMP-1 and metallothionein were positive in half of the biopsies from BP patients at the basement membrane of the skin, within several skin appendices, in areas of dermal blood vessel inflammation and within dermal mesenchymal-epithelial cell junctions.

  13. Emergence of a Stage-Dependent Human Liver Disease Signature with Directed Differentiation of Alpha-1 Antitrypsin-Deficient iPS Cells

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    Andrew A. Wilson

    2015-05-01

    Full Text Available Induced pluripotent stem cells (iPSCs provide an inexhaustible source of cells for modeling disease and testing drugs. Here we develop a bioinformatic approach to detect differences between the genomic programs of iPSCs derived from diseased versus normal human cohorts as they emerge during in vitro directed differentiation. Using iPSCs generated from a cohort carrying mutations (PiZZ in the gene responsible for alpha-1 antitrypsin (AAT deficiency, we find that the global transcriptomes of PiZZ iPSCs diverge from normal controls upon differentiation to hepatic cells. Expression of 135 genes distinguishes PiZZ iPSC-hepatic cells, providing potential clues to liver disease pathogenesis. The disease-specific cells display intracellular accumulation of mutant AAT protein, resulting in increased autophagic flux. Furthermore, we detect beneficial responses to the drug carbamazepine, which further augments autophagic flux, but adverse responses to known hepatotoxic drugs. Our findings support the utility of iPSCs as tools for drug development or prediction of toxicity.

  14. iTRAQ-Based Proteomics of Chronic Renal Failure Rats after FuShengong Decoction Treatment Reveals Haptoglobin and Alpha-1-Antitrypsin as Potential Biomarkers

    Directory of Open Access Journals (Sweden)

    Yu Yang

    2017-01-01

    Full Text Available Background. Chronic renal failure (CRF has become a global health problem and bears a huge economic burden. FuShengong Decoction (FSGD as traditional Chinese medicine has multiple pharmacological effects. Objectives. To understand the underlying molecular mechanism and signaling pathway involved in the FSGD treatment of CRF and screen differentially expressed proteins in rats with CRF treated with FSGD. Methods. Thirty-three male Sprague-Dawley rats were randomly divided into control group, CRF group, and FSGD group. Differentially expressed proteins were screened by iTRAQ coupled with nanoLC-MS/MS, and these identified proteins were later analyzed by GO, KEGG, and STRING. Additionally, haptoglobin (HP and alpha-1-antitrypsin (AAT were finally verified by ELISA, Western blot, and real time PCR. Results. A total of 417 proteins were identified. Nineteen differentially expressed proteins were identified in the FSGD group compared with the model group, of which 3 proteins were upregulated and 16 proteins were downregulated. Cluster analysis indicated that inflammatory response was associated with these proteins and complement and coagulation cascade pathways were predominantly involved. The validation methods further confirmed that the levels of HP and AAT were significantly increased. Conclusions. HP and AAT may be the important biomarkers in the pathogenesis of CRF and FSGD therapy.

  15. In vivo post-transcriptional gene silencing of alpha-1 antitrypsin by adeno-associated virus vectors expressing siRNA.

    Science.gov (United States)

    Cruz, Pedro E; Mueller, Christian; Cossette, Travis L; Golant, Alexandra; Tang, Qiushi; Beattie, Stuart G; Brantly, Mark; Campbell-Thompson, Martha; Blomenkamp, Keith S; Teckman, Jeffrey H; Flotte, Terence R

    2007-09-01

    alpha-1 Antitrypsin (AAT) deficiency is one of the most common genetic diseases in North America, with a carrier frequency of approximately 4% in the US population. Homozygosity for the most common mutation (Glu342Lys, PI(*)Z) leads to the synthesis of a mutant protein, which accumulates and polymerizes within hepatocytes rather than being efficiently secreted. This lack of secretion causes severe serum deficiency predisposing to chronic lung disease. Twelve to fifteen percent of patients with PI(*)ZZ also develop liver disease, which can be severe, even in infancy. This is thought to be due to toxic effects of the accumulated mutant Z-AAT within the hepatocyte. Thus, an approach to reduce AAT-deficient liver disease will likely require some mechanism to decrease the amount of Z-AAT within hepatocytes. In this report, we describe studies of small-interfering RNAs (siRNAs) designed to downregulate endogenous AAT within hepatocytes. Three different siRNA sequences were identified and cloned into a recombinant adeno-associated virus (rAAV) backbone, either singly or as a trifunctional (3X) construct. Each had activity independently, but the levels of AAT expression in cell culture models showed the greatest decrease with the 3X construct, resulting in levels that were five-fold lower than controls. The rAAV-3X-siRNA was then packaged into AAV8 capsids and used in vivo to transduce the livers of human Z-AAT overexpressing transgenic mice. Those studies showed a decrease in total human AAT, a clearing of Z-AAT accumulation by immunohistochemistry, and a decrease in monomer Z-AAT within the liver within 3 weeks after vector injection. The rAAV8-3X-siRNA vector may hold promise as a potential therapy for patients with AAT liver disease.

  16. Preclinical evaluation of a recombinant adeno-associated virus vector expressing human alpha-1 antitrypsin made using a recombinant herpes simplex virus production method.

    Science.gov (United States)

    Chulay, Jeffrey D; Ye, Guo-Jie; Thomas, Darby L; Knop, David R; Benson, Janet M; Hutt, Julie A; Wang, Gensheng; Humphries, Margaret; Flotte, Terence R

    2011-02-01

    Recombinant adeno-associated virus (rAAV) vectors offer promise for gene therapy of alpha-1 antitrypsin (AAT) deficiency. A toxicology study in mice evaluated intramuscular injection of an rAAV vector expressing human AAT (rAAV-CB-hAAT) produced using a herpes simplex virus (HSV) complementation system or a plasmid transfection (TFX) method at doses of 3 × 10(11) vg (1.2 × 10(13) vg/kg) for both vectors and 2 × 10(12) vg (8 × 10(13) vg/kg) for the HSV-produced vector. The HSV-produced vector had favorable in vitro characteristics in terms of purity, efficiency of transduction, and hAAT expression. There were no significant differences in clinical findings or hematology and clinical chemistry values between test article and control groups and no gross pathology findings. Histopathological examination demonstrated minimal to mild changes in skeletal muscle at the injection site, consisting of focal chronic interstitial inflammation and muscle degeneration, regeneration, and vacuolization, in vector-injected animals. At the 3 × 10(11) vg dose, serum hAAT levels were higher with the HSV-produced vector than with the TFX-produced vector. With the higher dose of HSV-produced vector, the increase in serum hAAT levels was dose-proportional in females and greater than dose-proportional in males. Vector copy numbers in blood were highest 24 hr after dosing and declined thereafter, with no detectable copies present 90 days after dosing. Antibodies to hAAT were detected in almost all vector-treated animals, and antibodies to HSV were detected in most animals that received the highest vector dose. These results support continued development of rAAV-CB-hAAT for treatment of AAT deficiency.

  17. Ni(ii) ions cleave and inactivate human alpha-1 antitrypsin hydrolytically, implicating nickel exposure as a contributing factor in pathologies related to antitrypsin deficiency.

    Science.gov (United States)

    Wezynfeld, Nina Ewa; Bonna, Arkadiusz; Bal, Wojciech; Frączyk, Tomasz

    2015-04-01

    Human alpha-1 antitrypsin (AAT) is an abundant serum protein present at a concentration of 1.0-1.5 g L(-1). AAT deficiency is a genetic disease that manifests with emphysema and liver cirrhosis due to the accumulation of a misfolded AAT mutant in hepatocytes. Lung AAT amount is inversely correlated with chronic obstructive pulmonary disease (COPD), a serious and often deadly condition, with increasing frequency in the aging population. Exposure to cigarette smoke and products of fossil fuel combustion aggravates AAT deficiency and COPD according to mechanisms that are not fully understood. Taking into account that these fumes contain particles that can release nickel to human airways and skin, we decided to investigate interactions of AAT with Ni(ii) ions within the paradigm of Ni(ii)-dependent peptide bond hydrolysis. We studied AAT protein derived from human blood using HPLC, SDS-PAGE, and mass spectrometry. These studies were aided by spectroscopic experiments on model peptides. As a result, we identified three hydrolysis sites in AAT. Two of them are present in the N-terminal part of the molecule next to each other (before Thr-13 and Ser-14 residues) and effectively form one N-terminal cleavage site. The single C-terminal cleavage site is located before Ser-285. The N-terminal hydrolysis was more efficient than the C-terminal one, but both abolished the ability of AAT to inhibit trypsin in an additive manner. Nickel ions bound to hydrolysis products demonstrated an ability to generate ROS. These results implicate Ni(ii) exposure as a contributing factor in AAT-related pathologies.

  18. The impact of smoke exposure on the clinical phenotype of alpha-1 antitrypsin deficiency in Ireland: exploiting a national registry to understand a rare disease.

    Science.gov (United States)

    O'Brien, M Emmet; Pennycooke, Kevin; Carroll, Tomás P; Shum, Jonathan; Fee, Laura T; O'Connor, Catherine; Logan, P Mark; Reeves, Emer P; McElvaney, Noel G

    2015-05-01

    Individuals with Alpha-1 antitrypsin deficiency (AATD) have mutations in the SERPINA1 gene causing genetic susceptibility to early onset lung and liver disease that may result in premature death. Environmental interactions have a significant impact in determining the disease phenotype and outcome in AATD. The aim of this study was to assess the impact of smoke exposure on the clinical phenotype of AATD in Ireland. Clinical demographics and available thoracic computerised tomography (CT) imaging were detected from 139 PiZZ individuals identified from the Irish National AATD Registry. Clinical information was collected by questionnaire. Data was analysed to assess AATD disease severity and evaluate predictors of clinical phenotype. Questionnaires were collected from 107/139 (77%) and thoracic CT evaluation was available in 72/107 (67.2%). 74% of respondents had severe Chronic Obstructive Pulmonary Disease (COPD) (GOLD stage C or D). Cigarette smoking was the greatest predictor of impairment in FEV1 and DLCO (%predicted) and the extent of emphysema correlated most significantly with DLCO. Interestingly the rate of FEV1 decline was similar in ex-smokers when compared to never-smokers. Passive smoke exposure in childhood resulted in a greater total pack-year smoking history. Radiological evidence of bronchiectasis was a common finding and associated with increasing age. The Irish National AATD Registry facilitates clinical and basic science research of this condition in Ireland. This study illustrates the detrimental effect of smoke exposure on the clinical phenotype of AATD in Ireland and the benefit of immediate smoking cessation at any stage of lung disease.

  19. Urinary alpha-1 antitrypsin and CD59 glycoprotein predict albuminuria development in hypertensive patients under chronic renin-angiotensin system suppression.

    Science.gov (United States)

    Gonzalez-Calero, Laura; Martin-Lorenzo, Marta; de la Cuesta, Fernando; Maroto, Aroa S; Baldan-Martin, Montserrat; Ruiz-Hurtado, Gema; Pulido-Olmo, Helena; Segura, Julian; Barderas, Maria G; Ruilope, Luis M; Vivanco, Fernando; Alvarez-Llamas, Gloria

    2016-01-16

    Hypertension is a multi-factorial disease of increasing prevalence and a major risk factor for cardiovascular mortality even in the presence of adequate treatment. Progression of cardiovascular disease (CVD) occurs frequently during chronic renin-angiotensin-system (RAS) suppression, and albuminuria is a marker of CV risk. High prevalence of albuminuria in treated hypertensive patients has been demonstrated, but there are no available markers able to predict evolution. The aim of this study was the identification of novel indicators of albuminuria progression measurable in urine of diabetic and non-diabetic patients. 1143 hypertensive patients under chronic treatment were followed for a minimum period of 3 years. Among them, 105 diabetic and non-diabetic patients were selected and classified in three groups according to albuminuria development during follow-up: (a) patients with persistent normoalbuminuria; (b) patients developing de novo albuminuria; (c) patients with maintained albuminuria. Differential urine analysis was performed by 2D gel electrophoresis (2D-DIGE) and further confirmed by liquid chromatography-mass spectrometry. Non-parametric statistical tests were applied. CD59 glycoprotein and alpha-1 antitrypsin (AAT) resulted already altered in patients developing albuminuria de novo, with a similar response in those with maintained albuminuria. A prospective study in a sub-group of normoalbuminuric patients who were clinically followed up for at least 1 year from urine sampling, revealed CD59 and AAT proteins significantly varied in the urine collected from normoalbuminurics who will negatively progress, serving as predictors of future albuminuria development. CD59 and AAT proteins are significantly altered in hypertensive patients developing albuminuria. Interestingly, CD59 and AAT are able to predict, in normoalbuminuric individuals, who will develop albuminuria in the future, being potential predictors of vascular damage and CV risk. These findings

  20. Health status and lung function in the Swedish alpha 1-antitrypsin deficient cohort, identified by neonatal screening, at the age of 37-40 years.

    Science.gov (United States)

    Piitulainen, Eeva; Mostafavi, Behrouz; Tanash, Hanan A

    2017-01-01

    Severe alpha 1-antitrypsin (AAT) deficiency (genotype PiZZ) is a well-known risk factor for COPD. A cohort of PiZZ and PiSZ individuals was identified by the Swedish national neonatal AAT screening program in 1972-1974 and followed up regularly since birth. Our aim was to study the lung function, respiratory symptoms and health status at the age of 38 years in comparison with a random sample of control subjects selected from the population registry. The study group included 120 PiZZ, 46 PiSZ and 164 control subjects (PiMM), who answered a questionnaire on smoking habits and symptoms and the Saint George Respiratory Questionnaire (SGRQ) on quality of life. A total of 89 PiZZ, 33 PiSZ and 92 PiMM subjects underwent spirometry. Four percent of the PiZZ, 2% of the PiSZ and 12% of the control subjects were current smokers ( P =0.008), and 17% of the PiZZ, 9% of the PiSZ and 21% of the control subjects had stopped smoking. The PiZZ current smokers had a significantly higher (ie, poorer) median activity score according to the SGRQ than the PiZZ never-smokers ( P =0.032). The PiMM current smokers had significantly higher activity score ( P <0.001), symptom score ( P <0.001), and total score ( P =0.001) according to the SGRQ than the PiMM never-smokers. The PiZZ current smokers had a significantly lower postbronchodilator forced expiratory volume in 1 second (FEV 1 )% of predicted value ( P =0.019) and FEV 1 /forced vital capacity (FVC) ratio ( P =0.032) than the PiZZ never-smokers. The proportion of subjects with a FEV 1 /FVC ratio of <0.70, indicating COPD, was significantly higher in the PiZZ current smokers than in the PiZZ never-smokers ( P =0.001). Among the PiSZ and PiMM subjects, the differences in lung function between the smoking subgroups were insignificant. PiZZ current smokers were found to have signs of COPD before 40 years of age. Smoking is less common among the AAT-deficient subjects identified by neonatal screening than among their peers in the general

  1. Learning about Alpha-1 Antitrypsin Deficiency (AATD)

    Science.gov (United States)

    ... weight loss. Some Individuals with AATD have advanced lung disease and have emphysema, in which the small air sacs (alveoli) in the lungs are damaged. Symptoms of emphysema include difficulty breathing, ...

  2. Deficiency of α-1-antitrypsin influences systemic iron homeostasis

    Directory of Open Access Journals (Sweden)

    Ghio AJ

    2013-01-01

    Full Text Available Andrew J Ghio,1 Joleen M Soukup,1 Judy H Richards,1 Bernard M Fischer,2 Judith A Voynow,2 Donald E Schmechel31US Environmental Protection Agency, Chapel Hill, NC, USA; 2Division of Pediatric Pulmonary Medicine, Department of Pediatrics,3Joseph and Kathleen Bryan Alzheimer Disease Research Center, Department of Medicine (Neurology, Duke University Medical Center, Durham, NC, USAAbstract: There is evidence that proteases and antiproteases participate in the iron homeostasis of cells and living systems. We tested the postulate that α-1 antitrypsin (A1AT polymorphism and the consequent deficiency of this antiprotease in humans are associated with a systemic disruption in iron homeostasis. Archived plasma samples from Alpha-1 Foundation (30 MM, 30 MZ, and 30 ZZ individuals were analyzed for A1AT, ferritin, transferrin, and C-reactive protein (CRP. Plasma samples were also assayed for metals using inductively coupled plasma atomic emission spectroscopy (ICPAES. Plasma levels of A1AT in MZ and ZZ individuals were approximately 60% and 20% of those for MM individuals respectively. Plasma ferritin concentrations in those with the ZZ genotype were greater relative to those individuals with either MM or MZ genotype. Plasma transferrin for MM, MZ, and ZZ genotypes showed no significant differences. Linear regression analysis revealed a significant (negative relationship between plasma concentrations of A1AT and ferritin while that between A1AT and transferrin levels was not significant. Plasma CRP concentrations were not significantly different between MM, MZ, and ZZ individuals. ICPAES measurement of metals confirmed elevated plasma concentrations of nonheme iron among ZZ individuals. Nonheme iron concentrations correlated (negatively with levels of A1AT. A1AT deficiency is associated with evidence of a disruption in iron homeostasis with plasma ferritin and nonheme iron concentrations being elevated among those with the ZZ genotype.Keywords: α-1

  3. Recent advances in understanding and treating COPD related to α1-antitrypsin deficiency.

    Science.gov (United States)

    Henao, Maria Paula; Craig, Timothy J

    2016-12-01

    Alpha-1-antitrypsin deficiency (AATD) is an orphan disease that predisposes individuals to COPD and liver disease. The following is a comprehensive review of AATD from epidemiology to treatment for physicians who treat COPD or asthma. Areas covered: In this comprehensive review of alpha-1-antitrypsin deficiency, we describe the historical perspective, genetics, epidemiology, clinical presentation and symptoms, screening and diagnosis, and treatments of the condition. Expert commentary: The two most important directions for advancing the understanding of AATD involve improving detection of the condition, especially in asymptomatic patients, and advancing knowledge of treatments directed specifically at AATD-related conditions. With regard to treatment for AATD-related conditions, research must continue to explore the implications and importance of augmentation therapy as well as consider new implementations that may prove more successful taking into consideration not only factors of pulmonary function and liver health, but also product availability and financial viability.

  4. Association of polymorphism of the alpha 1-antitrypsin gene with ...

    African Journals Online (AJOL)

    In order to determine the relationship between the polymorphisms of the AAT gene and milk production traits and SCS, the General Linear Model (GLM) procedure from the Statistical Analysis Software was used. SNP5504 affected milk fat percentage, SNP8178 affected milk protein percentage and SNP5609 and SNP5624 ...

  5. Alpha-1 antitrypsin phenotypes in patients with Klinefelter's syndrome

    Indian Academy of Sciences (India)

    Klinefelter's syndrome (KS) is the most common human sex chromosome disorder, with a prevalence of 1 in 660 men. The phenotype is variable, but the most constant findings are small and firm testes, decreased testosterone level, infertility, eunuchoid body proportion, increased height, and learning disabilities, due to the ...

  6. Alpha-1 antitrypsin phenotypes in patients with Klinefelter's syndrome

    Indian Academy of Sciences (India)

    1Department of Human Biology and Genetics, Institute of General and Molecular Pathology,. University of Tartu, Ravila Street 19, Tartu 50411, Estonia. 2Centre of Andrology, Tartu University Hospital, Puusepa Street 1a, Tartu 50406, Estonia. Introduction. Klinefelter's syndrome (KS) is the most common human sex.

  7. Association of polymorphism of alpha 1-antitrypsin gene with milk ...

    African Journals Online (AJOL)

    User

    number of human diseases (Majamaa et al., 2001; Lisowska-Myjak & Pachecka, 2007). Based on the role played by the AAT gene in humans, the aim of this study was to investigate possible associations between variants of the gene and milk production traits as well as SCS in Chinese Holstein dairy cattle. Materials and ...

  8. Characterising the association of latency with α1-antitrypsin polymerisation using a novel monoclonal antibody

    Science.gov (United States)

    Tan, Lu; Perez, Juan; Mela, Marianna; Miranda, Elena; Burling, Keith A; Rouhani, Farshid N; DeMeo, Dawn L; Haq, Imran; Irving, James A; Ordóñez, Adriana; Dickens, Jennifer A; Brantly, Mark; Marciniak, Stefan J; Alexander, Graeme J M; Gooptu, Bibek; Lomas, David A

    2015-01-01

    α1-Antitrypsin is primarily synthesised in the liver, circulates to the lung and protects pulmonary tissues from proteolytic damage. The Z mutant (Glu342Lys) undergoes inactivating conformational change and polymerises. Polymers are retained within the hepatocyte endoplasmic reticulum (ER) in homozygous (PiZZ) individuals, predisposing the individuals to hepatic cirrhosis and emphysema. Latency is an analogous process of inactivating, intra-molecular conformational change and may co-occur with polymerisation. However, the relationship between latency and polymerisation remained unexplored in the absence of a suitable probe. We have developed a novel monoclonal antibody specific for latent α1-antitrypsin and used it in combination with a polymer-specific antibody, to assess the association of both conformers in vitro, in disease and during augmentation therapy. In vitro kinetics analysis showed polymerisation dominated the pathway but latency could be promoted by stabilising monomeric α1-antitrypsin. Polymers were extensively produced in hepatocytes and a cell line expressing Z α1-antitrypsin but the latent protein was not detected despite manipulation of the secretory pathway. However, α1-antitrypsin augmentation therapy contains latent α1-antitrypsin, as did the plasma of 63/274 PiZZ individuals treated with augmentation therapy but 0/264 who were not receiving this medication (p < 10−14). We conclude that latent α1-antitrypsin is a by-product of the polymerisation pathway, that the intracellular folding environment is resistant to formation of the latent conformer but that augmentation therapy introduces latent α1-antitrypsin into the circulation. A suite of monoclonal antibodies and methodologies developed in this study can characterise α1-antitrypsin folding and conformational transitions, and screen methods to improve augmentation therapy. PMID:25462157

  9. Current status of gene therapy for α-1 antitrypsin deficiency.

    Science.gov (United States)

    Loring, Heather S; Flotte, Terence R

    2015-03-01

    As a common monogenic disease, α-1 antitrypsin (AAT) deficiency has undergone thorough investigation for the development of gene therapy. The most common pathology associated with AAT deficiency occurs in the lung, where the loss of function due to impaired secretion of mutant AAT prevents the inhibition of neutrophil elastase and leads to loss of elastin content from the alveolar interstitium. Current treatment in the USA consists of recurrent intravenous protein replacement therapy to augment serum AAT levels. In an attempt to replace recurring treatments with a single dose of gene therapy, recombinant adenovirus, plasmid, and recombinant adeno-associated virus (rAAV) vectors have been investigated as vectors for transgene delivery. Large strides in gene therapy for AAT deficiency lung disease have led to the development of rAAV1-AAT capable of producing sustained serum AAT levels in clinical trials after intramuscular administration in humans at 3% of the target level. Further increases in levels are anticipated as limb perfusion targets greater muscle mass. The future roles of intrapleural and airway delivery, miRNA-expressing vectors, iPS cell platforms, and genome editing are anticipated.

  10. Matrix metalloproteinase-9 predicts pulmonary status declines in α1-antitrypsin deficiency

    Directory of Open Access Journals (Sweden)

    Rames Alexis

    2011-03-01

    Full Text Available Abstract Background Matrix metalloproteinase-9 (MMP-9 may be important in the progression of emphysema, but there have been few longitudinal clinical studies of MMP-9 including pulmonary status and COPD exacerbation outcomes. Methods We utilized data from the placebo arm (n = 126 of a clinical trial of patients with alpha1-antitrypsin deficiency (AATD and emphysema to examine the links between plasma MMP-9 levels, pulmonary status, and COPD exacerbations over a one year observation period. Pulmonary function, computed tomography lung density, incremental shuttle walk test (ISWT, and COPD exacerbations were assessed at regular intervals over 12 months. Prospective analyses used generalized estimating equations to incorporate repeated longitudinal measurements of MMP-9 and all endpoints, controlling for age, gender, race-ethnicity, leukocyte count, and tobacco history. A secondary analysis also incorporated highly-sensitive C-reactive protein levels in predictive models. Results At baseline, higher plasma MMP-9 levels were cross-sectionally associated with lower FEV1 (p = 0.03, FVC (p Conclusions Increased plasma MMP-9 levels generally predicted pulmonary status declines, including worsening transfer factor and lung density as well as greater COPD exacerbations in AATD-associated emphysema.

  11. α-1-Antitrypsin is an endogenous inhibitor of proinflammatory cytokine production in whole blood

    OpenAIRE

    Pott, Gregory B.; Chan, Edward D.; Dinarello, Charles A.; Shapiro, Leland

    2009-01-01

    Several observations suggest endogenous suppressors of inflammatory mediators are present in human blood. α-1-Antitrypsin (AAT) is the most abundant serine protease inhibitor in blood, and AAT possesses anti-inflammatory activity in vitro and in vivo. Here, we show that in vitro stimulation of whole blood from persons with a genetic AAT deficiency resulted in enhanced cytokine production compared with blood from healthy subjects. Using whole blood from healthy subjects, dilution of blood with...

  12. Avaliação da concentração de alfa 1-antitripsina e da presença dos alelos S e Z em uma população de indivíduos sintomáticos respiratórios crônicos Determination of alpha 1-antitrypsin levels and of the presence of S and Z alleles in a population of patients with chronic respiratory symptoms

    Directory of Open Access Journals (Sweden)

    Heliane Guerra Serra

    2008-12-01

    Full Text Available OBJETIVO: Determinar a concentração de alfa 1-antitripsina (AAT e a prevalência dos alelos S e Z em indivíduos sintomáticos respiratórios crônicos. MÉTODOS: Pacientes com tosse crônica e dispnéia foram submetidos à avaliação clínica, espirometria, tomografia computadorizada de tórax, dosagem de AAT por nefelometria e pesquisa das mutações S e Z por reação em cadeia da polimerase. Foram consideradas como variáveis dependentes a concentração de AAT e o tabagismo. RESULTADOS: Dos 89 pacientes incluídos no estudo (44 mulheres; idade média, 51,3 ± 18,2 anos, os alelos S e Z foram detectados em 33,3% e 5,7%, respectivamente, com freqüência gênica dos alelos S e Z de 0,16 e 0,028. Dois pacientes tinham genótipo SZ (AAT 141 mg/dL (normal, Grupo 2, n = 57. A freqüência de fumantes foi igual nos dois grupos, com carga tabágica maior no Grupo 2. O alelo S estava presente em 13 e 14 pacientes dos Grupos 1 e 2, respectivamente, enquanto que o alelo Z estava presente em 2 e 1 paciente dos mesmos grupos. Não houve diferença nos testes de função pulmonar, nem na freqüência de bronquiectasias ou enfisema entre os dois grupos. Os valores espirométricos e as concentrações de AAT foram similares entre fumantes e não-fumantes. Bronquiectasias foram mais freqüentes entre os não fumantes, e enfisema foi mais freqüente entre os fumantes. CONCLUSÕES: Trinta pacientes apresentaram níveis de AAT abaixo da média esperada para os genótipos MM e MS, e este fato não pode ser explicado por uma freqüência maior dos alelos S e Z.OBJECTIVE: To determine the levels of alpha-1 antitrypsin (AAT and the presence of S and Z alleles in patients with chronic respiratory symptoms. METHODS: Patients with chronic cough and dyspnea were submitted to clinical evaluation, pulmonary function tests, high-resolution computed tomography, nephelometric determination of AAT and determination of S and Z alleles by polymerase chain reaction. Smoking

  13. The role of α1 -antitrypsin Deficiency in the Pathogenesis of Antineutrophil Cytoplasmic Antibodies Associated Systemic Necrotizing Vasculitides

    Directory of Open Access Journals (Sweden)

    Alzouki Abdul-Nasser

    1999-01-01

    Full Text Available Alpha1-antitrypsin (D,1AT is the most abundant circulating protease inhibitor (Pi in human plasma. It has central function in controlling tissue degradation by inhibiting a large number of proteases including neutrophil elastase and proteinase 3 (PR3. PR3, the Wegner′s autoantigen, has been suggested to be involved in the pathogenesis of small-vessel systemic vasculitides. α1 AT deficiency (PiZ is frequent in Caucasian populations, and its homozygous state (PiZZ is known to predispose to lung emphysema and chronic liver disease. A strong correlation between heterozygous (PiZ and homozygous (PiZZ α1 AT deficiency and anti-neutrophil cytoplasmic autoantibodies (ANCA associated systemic nocrotizing vasculitides has recently been reported in various populations. In this review the pathogenesis of small-vessel vasculitides is outlined, focusing on the role of α1 AT deficiency. α1 AT has been suggested to have a crucial role as a protective protein in ANCA-associated vasculitic syndromes.

  14. Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID)

    DEFF Research Database (Denmark)

    Chapman, Kenneth R; Burdon, Jonathan G W; Piitulainen, Eeva

    2015-01-01

    -smokers (aged 18-65 years) in 28 international study centres in 13 countries if they had severe α1 antitrypsin deficiency (serum concentration volume in 1 s of 35-70% (predicted). We excluded patients if they had undergone, or were on the waiting list to undergo, lung...... transplantation, lobectomy, or lung volume-reduction surgery, or had selective IgA deficiency. We randomly assigned patients (1:1; done by Accovion) using a computerised pseudorandom number generator (block size of four) with centre stratification to receive A1PI intravenously 60 mg/kg per week or placebo for 24...

  15. Diagnosing α1-antitrypsin deficiency: how to improve the current algorithm

    Directory of Open Access Journals (Sweden)

    Noel G. McElvaney

    2015-03-01

    Full Text Available Over the past 10–15 years, the diagnosis of α1-antitrypsin deficiency (AATD has markedly improved as a result of increasing awareness and the publication of diagnostic recommendations by the American Thoracic Society (ATS/European Respiratory Society (ERS. Nevertheless, the condition remains substantially underdiagnosed. Furthermore, when AATD is diagnosed there is a delay before treatment is introduced. This may help explain why AATD is the fourth most common cause of lung transplantation. Clearly we need to do better. The ATS/ERS recommend testing high-risk groups, such as: all chronic obstructive pulmonary disease patients; all nonresponsive asthmatic adults/adolescents; all cases of cryptogenic cirrhosis/liver disease; subjects with granulomatosis with polyangitis; bronchiectasis of unknown aetiology; panniculitis and first-degree relatives of patients with AATD. In terms of laboratory diagnosis, measurement of α1-antitrypsin levels will identify patients with protein deficiency, but cannot differentiate between the various genetic subtypes of AATD. Phenotyping is the current gold standard for detecting rare variants of AATD (except null variants, while advances in molecular diagnostics are making genotyping more effective. An accurate diagnosis facilitates the physician's ability to actively intervene with measures such as smoking cessation and perhaps augmentation therapy, and it will also help provide a better understanding of the natural history of the disease.

  16. Alpha-1 antitrypsin gene therapy prevented bone loss in ovariectomy induced osteoporosis mouse model

    Science.gov (United States)

    Osteoporosis is a major healthcare burden affecting mostly postmenopausal women characterized by compromised bone strength and increased risk of fragility fracture. Although pathogenesis of this disease is complex, elevated proinflammatory cytokine production is clearly involved in bone loss at meno...

  17. α1-Antitrypsin reduces rhinovirus infection in primary human airway epithelial cells exposed to cigarette smoke

    Directory of Open Access Journals (Sweden)

    Berman R

    2016-06-01

    Full Text Available Reena Berman, Di Jiang, Qun Wu, Hong Wei Chu Department of Medicine, National Jewish Health, Denver, CO, USA Abstract: Human rhinovirus (HRV infections target airway epithelium and are the leading cause of acute exacerbations of COPD. Cigarette smoke (CS increases the severity of viral infections, but there is no effective therapy for HRV infection. We determined whether α1-antitrypsin (A1AT reduces HRV-16 infection in CS-exposed primary human airway epithelial cells. Brushed bronchial epithelial cells from normal subjects and patients diagnosed with COPD were cultured at air–liquid interface to induce mucociliary differentiation. These cells were treated with A1AT or bovine serum albumin for 2 hours and then exposed to air or whole cigarette smoke (WCS with or without HRV-16 (5×104 50% Tissue Culture Infective Dose [TCID50]/transwell infection for 24 hours. WCS exposure significantly increased viral load by an average of fivefold and decreased the expression of antiviral genes interferon-λ1, OAS1, and MX1. When A1AT was added to WCS-exposed cells, viral load significantly decreased by an average of 29-fold. HRV-16 infection significantly increased HRV-16 receptor intercellular adhesion molecule-1 messenger RNA expression in air-exposed cells, which was decreased by A1AT. A1AT-mediated reduction of viral load was not accompanied by increased epithelial antiviral gene expression or by inhibiting the activity of 3C protease involved in viral replication or maturation. Our findings demonstrate that A1AT treatment prevents a WCS-induced increase in viral load and for the first time suggest a therapeutic effect of A1AT on HRV infection. Keywords: α1-antitrypsin, rhinovirus, COPD, cigarette smoke, ICAM-1

  18. Histone Deacetylase Inhibitor (HDACi) Suberoylanilide Hydroxamic Acid (SAHA)-mediated Correction of α1-Antitrypsin Deficiency*

    Science.gov (United States)

    Bouchecareilh, Marion; Hutt, Darren M.; Szajner, Patricia; Flotte, Terence R.; Balch, William E.

    2012-01-01

    α1-Antitrypsin (α1AT) deficiency (α1ATD) is a consequence of defective folding, trafficking, and secretion of α1AT in response to a defect in its interaction with the endoplasmic reticulum proteostasis machineries. The most common and severe form of α1ATD is caused by the Z-variant and is characterized by the accumulation of α1AT polymers in the endoplasmic reticulum of the liver leading to a severe reduction (>85%) of α1AT in the serum and its anti-protease activity in the lung. In this organ α1AT is critical for ensuring tissue integrity by inhibiting neutrophil elastase, a protease that degrades elastin. Given the limited therapeutic options in α1ATD, a more detailed understanding of the folding and trafficking biology governing α1AT biogenesis and its response to small molecule regulators is required. Herein we report the correction of Z-α1AT secretion in response to treatment with the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA), acting in part through HDAC7 silencing and involving a calnexin-sensitive mechanism. SAHA-mediated correction restores Z-α1AT secretion and serpin activity to a level 50% that observed for wild-type α1AT. These data suggest that HDAC activity can influence Z-α1AT protein traffic and that SAHA may represent a potential therapeutic approach for α1ATD and other protein misfolding diseases. PMID:22995909

  19. α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8.

    LENUS (Irish Health Repository)

    Bergin, David A

    2010-12-01

    Hereditary deficiency of the protein α-1 antitrypsin (AAT) causes a chronic lung disease in humans that is characterized by excessive mobilization of neutrophils into the lung. However, the reason for the increased neutrophil burden has not been fully elucidated. In this study we have demonstrated using human neutrophils that serum AAT coordinates both CXCR1- and soluble immune complex (sIC) receptor-mediated chemotaxis by divergent pathways. We demonstrated that glycosylated AAT can bind to IL-8 (a ligand for CXCR1) and that AAT-IL-8 complex formation prevented IL-8 interaction with CXCR1. Second, AAT modulated neutrophil chemotaxis in response to sIC by controlling membrane expression of the glycosylphosphatidylinositol-anchored (GPI-anchored) Fc receptor FcγRIIIb. This process was mediated through inhibition of ADAM-17 enzymatic activity. Neutrophils isolated from clinically stable AAT-deficient patients were characterized by low membrane expression of FcγRIIIb and increased chemotaxis in response to IL-8 and sIC. Treatment of AAT-deficient individuals with AAT augmentation therapy resulted in increased AAT binding to IL-8, increased AAT binding to the neutrophil membrane, decreased FcγRIIIb release from the neutrophil membrane, and normalization of chemotaxis. These results provide new insight into the mechanism underlying the effect of AAT augmentation therapy in the pulmonary disease associated with AAT deficiency.

  20. Directing membrane chromatography to manufacture α1-antitrypsin from human plasma fraction IV.

    Science.gov (United States)

    Fan, Jinxin; Luo, Jianquan; Song, Weijie; Chen, Xiangrong; Wan, Yinhua

    2015-12-04

    The surging demand for plasma proteins, mainly driven by the growing market and the development of new therapeutic indications, is promoting manufacturers to improve the throughput of plasma proteins. Due to the inherent convective mass transfer, membrane chromatography has been proved to be an efficient approach for extracting a small amount of target proteins from large-volume feed. In this study, α1-antitrypsin (AAT) was extracted from human plasma fraction IV by a two-step membrane chromatography. An anion-exchange membrane chromatography (AEMC) was used to capture the plasma proteins in bind/elute mode, and the obtained effluent was further polished by a hydrophobic interaction membrane chromatography (HIMC) in flow-through mode. Under optimal conditions, the recovery and purity of AAT achieved 87.0% and 0.58 AAT/protein (g/g) by AEMC, respectively. After the precise polishing by HIMC, the purity of AAT was 1.22 AAT/protein (g/g). The comparison results showed that membrane chromatography outperformed column chromatography in both steps because of its high throughput. This two-step membrane chromatography could obtain an AAT recovery of 83.3% and an activity recovery of 91.4%. The outcome of this work not only offers an alternative process for protein purification from plasma, but also provides guidelines for manufacturing product from a large-volume feed with multi-components by membrane chromatography. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Z α-1 antitrypsin deficiency and the endoplasmic reticulum stress response.

    LENUS (Irish Health Repository)

    Greene, Catherine M

    2010-10-06

    The serine proteinase inhibitor α-1 antitrypsin (AAT) is produced principally by the liver at the rate of 2 g\\/d. It is secreted into the circulation and provides an antiprotease protective screen throughout the body but most importantly in the lung, where it can neutralise the activity of the serine protease neutrophil elastase. Mutations leading to deficiency in AAT are associated with liver and lung disease. The most notable is the Z AAT mutation, which encodes a misfolded variant of the AAT protein in which the glutamic acid at position 342 is replaced by a lysine. More than 95% of all individuals with AAT deficiency carry at least one Z allele. ZAAT protein is not secreted effectively and accumulates intracellularly in the endoplasmic reticulum (ER) of hepatocytes and other AAT-producing cells. This results in a loss of function associated with decreased circulating and intrapulmonary levels of AAT. However, the misfolded protein acquires a toxic gain of function that impacts on the ER. A major function of the ER is to ensure correct protein folding. ZAAT interferes with this function and promotes ER stress responses and inflammation. Here the signalling pathways activated during ER stress in response to accumulation of ZAAT are described and therapeutic strategies that can potentially relieve ER stress are discussed.

  2. The Z mutation alters the global structural dynamics of α1-antitrypsin.

    Directory of Open Access Journals (Sweden)

    Victoria A Hughes

    Full Text Available α1-Antitrypsin (α1AT deficiency, the most common serpinopathy, results in both emphysema and liver disease. Over 90% of all clinical cases of α1AT deficiency are caused by the Z variant in which Glu342, located at the top of s5A, is replaced by a Lys which results in polymerization both in vivo and in vitro. The Glu342Lys mutation removes a salt bridge and a hydrogen bond but does not effect the thermodynamic stability of Z α1AT compared to the wild type protein, M α1AT, and so it is unclear why Z α1AT has an increased polymerization propensity. We speculated that the loss of these interactions would make the native state of Z α1AT more dynamic than M α1AT and that this change renders the protein more polymerization prone. We have used hydrogen/deuterium exchange combined with mass spectrometry (HXMS to determine the structural and dynamic differences between native Z and M α1AT to reveal the molecular basis of Z α1AT polymerization. Our HXMS data shows that the Z mutation significantly perturbs the region around the site of mutation. Strikingly the Z mutation also alters the dynamics of regions distant to the mutation such as the B, D and I helices and specific regions of each β-sheet. These changes in global dynamics may lead to an increase in the likelihood of Z α1AT sampling a polymerogenic structure thereby causing disease.

  3. α-1-Antitrypsin is an endogenous inhibitor of proinflammatory cytokine production in whole blood

    Science.gov (United States)

    Pott, Gregory B.; Chan, Edward D.; Dinarello, Charles A.; Shapiro, Leland

    2009-01-01

    Several observations suggest endogenous suppressors of inflammatory mediators are present in human blood. α-1-Antitrypsin (AAT) is the most abundant serine protease inhibitor in blood, and AAT possesses anti-inflammatory activity in vitro and in vivo. Here, we show that in vitro stimulation of whole blood from persons with a genetic AAT deficiency resulted in enhanced cytokine production compared with blood from healthy subjects. Using whole blood from healthy subjects, dilution of blood with RPMI tissue-culture medium, followed by incubation for 18 h, increased spontaneous production of IL-8, TNF-α, IL-1β, and IL-1R antagonist (IL-1Ra) significantly, compared with undiluted blood. Dilution-induced cytokine production suggested the presence of one or more circulating inhibitors of cytokine synthesis present in blood. Serially diluting blood with tissue-culture medium in the presence of cytokine stimulation with heat-killed Staphylococcus epidermidis (S. epi) resulted in 1.2- to 55-fold increases in cytokine production compared with S. epi stimulation alone. Diluting blood with autologous plasma did not increase the production of IL-8, TNF-α, IL-1β, or IL-1Ra, suggesting that the endogenous, inhibitory activity of blood resided in plasma. In whole blood, diluted and stimulated with S. epi, exogenous AAT inhibited IL-8, IL-6, TNF-α, and IL-1β significantly but did not suppress induction of the anti-inflammatory cytokines IL-1Ra and IL-10. These ex vivo and in vitro observations suggest that endogenous AAT in blood contributes to the suppression of proinflammatory cytokine synthesis. PMID:19197072

  4. The effects of weekly augmentation therapy in patients with PiZZ α1-antitrypsin deficiency

    Directory of Open Access Journals (Sweden)

    Schmid ST

    2012-09-01

    Full Text Available ST Schmid,1 J Koepke,1 M Dresel,1 A Hattesohl,1 E Frenzel,2 J Perez,3 DA Lomas,4 E Miranda,5 T Greulich,1 S Noeske,1 M Wencker,6 H Teschler,6 C Vogelmeier,1 S Janciauskiene,2,* AR Koczulla1,*1Department of Internal Medicine, Division for Pulmonary Diseases, University Hospital Marburg, Marburg, Germany; 2Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany; 3Department of Cellular Biology, University of Malaga, Malaga, Spain; 4Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; 5Department of Biology and Biotechnology, Istituto Pasteur – Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy; 6Department of Pneumology, West German Lung Clinic, Essen University Hospital, Essen, Germany*These authors contributed equally to this workBackground: The major concept behind augmentation therapy with human α1-antitrypsin (AAT is to raise the levels of AAT in patients with protease inhibitor phenotype ZZ (Glu342Lys-inherited AAT deficiency and to protect lung tissues from proteolysis and progression of emphysema.Objective: To evaluate the short-term effects of augmentation therapy (Prolastin® on plasma levels of AAT, C-reactive protein, and chemokines/cytokines.Materials and methods: Serum and exhaled breath condensate were collected from individuals with protease inhibitor phenotype ZZ AAT deficiency-related emphysema (n = 12 on the first, third, and seventh day after the infusion of intravenous Prolastin. Concentrations of total and polymeric AAT, interleukin-8 (IL-8, monocyte chemotactic protein-1, IL-6, tumor necrosis factor-α, vascular endothelial growth factor, and C-reactive protein were determined. Blood neutrophils and primary epithelial cells were also exposed to Prolastin (1 mg/mL.Results: There were significant fluctuations in serum (but not in exhaled breath condensate levels of AAT polymers, IL-8, monocyte chemotactic protein-1, IL

  5. Plasma α1-antitrypsin: A Neglected Predictor of Angiographic Severity in Patients with Stable Angina Pectoris

    Directory of Open Access Journals (Sweden)

    Hui Zhao

    2015-01-01

    Full Text Available Background: As an acute phase protein, α1-antitrypsin (AAT has been extensively studied in acute coronary syndrome, but it is unclear whether a relationship exists between AAT and stable angina pectoris (SAP. The purpose of the present study was to investigate the association between AAT plasma levels and SAP. Methods: Overall, 103 SAP patients diagnosed by coronary angiography and clinical manifestations and 118 control subjects matched for age and gender were enrolled in this case-control study. Plasma levels of AAT, high-sensitivity C-reactive protein (hsCRP, lipid profiles and other clinical parameters were assayed for all participants. The severity of coronary lesions was evaluated based on the Gensini score (GS assessed by coronary angiography. Results: Positively correlated with the GS (r = 0.564, P < 0.001, the plasma AAT level in the SAP group was significantly higher than that in the control group (142.08 ± 19.61 mg/dl vs. 125.50 ± 19.67 mg/dl, P < 0.001. The plasma AAT level was an independent predictor for both SAP (odds ratio [OR] = 1.037, 95% confidence interval [CI]: 1.020-1.054, P < 0.001 and a high GS (OR = 1.087, 95% CI: 1.051-1.124, P < 0.001 in a multivariate logistic regression model. In the receiver operating characteristic curve analysis, plasma AAT level was found to have a larger area under the curve (AUC for predicting a high GS (AUC = 0.858, 95% CI: 0.788-0.929, P < 0.001 than that of hsCRP (AUC = 0.665, 95% CI: 0.557-0.773, P = 0.006; Z = 2.9363, P < 0.001, with an optimal cut-off value of 137.85 mg/dl (sensitivity: 94.3%, specificity: 68.2%. Conclusions: Plasma AAT levels correlate with both the presence and severity of coronary stenosis in patients with SAP, suggesting that it could be a potential predictive marker of severe stenosis in SAP patients.

  6. [Value of determination of haptoglobin and α1-antitrypsin in predicting response to glucocorticoid therapy in children with primary nephrotic syndrome].

    Science.gov (United States)

    Yang, Juan; Zhang, Bi-Li

    2015-03-01

    To study the value of the determination of serum and urine haptoglobin (HP) and alpha 1-antitrypsin (AAT) in predicting the response to glucocorticoid therapy in children with primary nephrotic syndrome (PNS). A total of 84 children with PNS were classified to steroid-sensitive nephrotic syndrome (SSNS) (n=58) and steroid-resistant nephrotic syndrome (SRNS) groups (n=26). Forty healthy children were randomly selected for the control group. HP and AAT levels in blood and urinary samples were determined using ELISA. The efficiency of HP and AAT in predicting the response to glucocorticoid treatment of PNS was evaluated by the receiver operating characteristic (ROC) curve. Compared with the control group, both the SSNS and SRNS groups had significantly higher serum HP concentrations and urine AAT/Cr ratio before treatment (Pratio before treatment and after one week and four weeks of treatment (Phighest efficiency in predicting the response to glucocorticoid treatment of PNS at the concentration of 37.935 mg/mL, with the sensitivity and specificity being 92.3% and 86.2% respectively. Urine AAT/Cr ratio had the highest prediction efficiency at 0.0696, with the sensitivity and specificity being 100% and 79.3% respectively. ROC curve analysis of serum HP combined with urine AAT/Cr ratio showed a better prediction efficiency, with the sensitivity and specificity being 92.3% and 96.6% respectively. The increase in serum HP level or urine AAT/Cr ratio may indicate glucocorticoid resistance in the early stage of PNS. A combination of the two can achieve better efficiency in the prediction of SRNS.

  7. Reactivity of alpha 1-antitrypsin mutants against proteolytic enzymes of the kallikrein-kinin, complement, and fibrinolytic systems

    NARCIS (Netherlands)

    Patston, P.A.; Roodi, N.; Schifferli, J.A.; Bischoff, Rainer; Courtney, M.; Schapira, M.

    1990-01-01

    Increased extracellular proteolysis because of unregulated activation of blood coagulation, complement, and fibrinolysis is observed in thrombosis, shock, and inflammation. In the present study, we have examined whether the plasma kallikrein-kinin system, the classical pathway of complement, and the

  8. Recombinant AAV Serotype and Capsid Mutant Comparison for Pulmonary Gene Transfer of α-1-Antitrypsin Using Invasive and Noninvasive Delivery

    Science.gov (United States)

    Liqun Wang, Rejean; McLaughlin, Thomas; Cossette, Travis; Tang, Qiushi; Foust, Kevin; Campbell-Thompson, Martha; Martino, Ashley; Cruz, Pedro; Loiler, Scott; Mueller, Christian; Flotte, Terence R

    2008-01-01

    Recombinant adeno-associated viral (rAAV) vectors have been widely used in pulmonary gene therapy research. In this study, we evaluated the transduction and expression efficiencies of several AAV serotypes and AAV2 capsid mutants with specific pulmonary targeting ligands in the mouse lung. The noninvasive intranasal delivery was compared with the traditional intratracheal lung delivery. The rAAV8 was the most efficient serotype at expressing α-1-antitrypsin (AAT) in the lung among all the tested serotypes and mutants. A dose of 1 × 1010 vg of rAAV8-CB-AAT transduced a high percentage of cells in the lung when delivered intratrachealy. The serum and the broncho-alveolar lavage fluid (BALF) levels of human AAT (hAAT) were about 6- and 2.5-fold higher, respectively, than those of rAAV5 group. Among the rAAV2 capsid mutants, the rAAV2 capsid mutants that display a peptide sequence from hAAT (“long serpin”) indicated a twofold increase in transgene expression. For most vectors, the serum hAAT levels achieved after intranasal delivery were 1/2 to 1/3 of those with the intratracheal method. Overall, rAAV8 was the most promising vector for the future application in gene therapy of pulmonary diseases such as AAT deficiency–related emphysema. PMID:18941444

  9. The association between adiponectin, HDL-cholesterol and α1-antitrypsin-LDL in female subjects without metabolic syndrome.

    Science.gov (United States)

    Kotani, Kazuhiko; Yamada, Toshiyuki; Taniguchi, Nobuyuki

    2010-12-30

    Oxidized low-density lipoprotein (LDL) may act as an atheroprotective (anti-atherosclerotic) agent under some conditions. While the α1-antitrypsin (AT)-LDL complex is considered a type of oxidized LDL, its clinical relevance remains unknown. The aim of the present study was to investigate the association between AT-LDL and anti-atherosclerotic variables such as HDL-cholesterol and adiponectin in subjects with and without metabolic syndrome (MetS). In asymptomatic females (n = 194; mean age, 54 years) who were divided into non-MetS (n = 108) and MetS groups (n = 86), the fasting levels of serum AT-LDL, adiponectin and glucose/lipid panels were measured, in addition to body mass index (BMI) and blood pressure. The MetS group showed significantly higher BMI, blood pressure, glucose and triglyceride levels as well as significantly lower levels of HDL-cholesterol and adiponectin than the non-MetS group. A multivariate-adjusted analysis revealed that in the non-MetS group, AT-LDL was significantly, independently and positively correlated with adiponectin (β = 0.297, P cholesterol (β = 0.217, P LDL was significantly, independently and positively correlated with LDL-cholesterol only (β = 0.342, P LDL may exert anti-atherosclerotic effects in female subjects without MetS. More studies are required to clarify the clinical roles of AT-LDL in relation to the pathophysiology of MetS.

  10. Electrochemical sandwich-type biosensors for α-1 antitrypsin with carbon nanotubes and alkaline phosphatase labeled antibody-silver nanoparticles.

    Science.gov (United States)

    Zhu, Gangbing; Lee, Hye Jin

    2017-03-15

    A novel sandwich-type biosensor was developed for the electrochemical detection of α-1 antitrypsin (AAT, a recognized biomarker for Alzheimer's disease). The biosensor was composed of 3, 4, 9, 10-perylene tetracarboxylic acid/carbon nanotubes (PTCA-CNTs) as a sensing platform and alkaline phosphatase-labeled AAT antibody functionalized silver nanoparticles (ALP-AAT Ab-Ag NPs) as a signal enhancer. CNTs offer high surface area and good electrical conductivity. Importantly, Ag NPs could increase the amount of ALP on the sensing surface and the ALP could dephosphorylate 4-amino phenyl phosphate (APP) enzymatically to produce electroactive species 4-aminophenol (AP). For detecting AAT based on the sandwich-type biosensor, the results show that the peak current value of AP using ALP-AAT Ab-Ag NPs as signal enhancer is much higher than that by using ALP-AAT Ab bioconjugate (without Ag NPs), the biosensor exhibited desirable performance for AAT determination with a wide linearity in the range from 0.05 to 20.0pM and a low detection limit of 0.01pM. Finally, the developed sensor was successfully applied to the analysis of AAT concentration in serum samples. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results.

    Science.gov (United States)

    Flotte, Terence R; Trapnell, Bruce C; Humphries, Margaret; Carey, Brenna; Calcedo, Roberto; Rouhani, Farshid; Campbell-Thompson, Martha; Yachnis, Anthony T; Sandhaus, Robert A; McElvaney, Noel G; Mueller, Christian; Messina, Louis M; Wilson, James M; Brantly, Mark; Knop, David R; Ye, Guo-jie; Chulay, Jeffrey D

    2011-10-01

    Recombinant adeno-associated virus (rAAV) vectors offer promise for the gene therapy of α(1)-antitrypsin (AAT) deficiency. In our prior trial, an rAAV vector expressing human AAT (rAAV1-CB-hAAT) provided sustained, vector-derived AAT expression for >1 year. In the current phase 2 clinical trial, this same vector, produced by a herpes simplex virus complementation method, was administered to nine AAT-deficient individuals by intramuscular injection at doses of 6.0×10(11), 1.9×10(12), and 6.0×10(12) vector genomes/kg (n=3 subjects/dose). Vector-derived expression of normal (M-type) AAT in serum was dose dependent, peaked on day 30, and persisted for at least 90 days. Vector administration was well tolerated, with only mild injection site reactions and no serious adverse events. Serum creatine kinase was transiently elevated on day 30 in five of six subjects in the two higher dose groups and normalized by day 45. As expected, all subjects developed anti-AAV antibodies and interferon-γ enzyme-linked immunospot responses to AAV peptides, and no subjects developed antibodies to AAT. One subject in the mid-dose group developed T cell responses to a single AAT peptide unassociated with any clinical effects. Muscle biopsies obtained on day 90 showed strong immunostaining for AAT and moderate to marked inflammatory cell infiltrates composed primarily of CD3-reactive T lymphocytes that were primarily of the CD8(+) subtype. These results support the feasibility and safety of AAV gene therapy for AAT deficiency, and indicate that serum levels of vector-derived normal human AAT >20 μg/ml can be achieved. However, further improvements in the design or delivery of rAAV-AAT vectors will be required to achieve therapeutic target serum AAT concentrations.

  12. Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results.

    LENUS (Irish Health Repository)

    Flotte, Terence R

    2011-10-01

    Recombinant adeno-associated virus (rAAV) vectors offer promise for the gene therapy of α(1)-antitrypsin (AAT) deficiency. In our prior trial, an rAAV vector expressing human AAT (rAAV1-CB-hAAT) provided sustained, vector-derived AAT expression for >1 year. In the current phase 2 clinical trial, this same vector, produced by a herpes simplex virus complementation method, was administered to nine AAT-deficient individuals by intramuscular injection at doses of 6.0×10(11), 1.9×10(12), and 6.0×10(12) vector genomes\\/kg (n=3 subjects\\/dose). Vector-derived expression of normal (M-type) AAT in serum was dose dependent, peaked on day 30, and persisted for at least 90 days. Vector administration was well tolerated, with only mild injection site reactions and no serious adverse events. Serum creatine kinase was transiently elevated on day 30 in five of six subjects in the two higher dose groups and normalized by day 45. As expected, all subjects developed anti-AAV antibodies and interferon-γ enzyme-linked immunospot responses to AAV peptides, and no subjects developed antibodies to AAT. One subject in the mid-dose group developed T cell responses to a single AAT peptide unassociated with any clinical effects. Muscle biopsies obtained on day 90 showed strong immunostaining for AAT and moderate to marked inflammatory cell infiltrates composed primarily of CD3-reactive T lymphocytes that were primarily of the CD8(+) subtype. These results support the feasibility and safety of AAV gene therapy for AAT deficiency, and indicate that serum levels of vector-derived normal human AAT >20 μg\\/ml can be achieved. However, further improvements in the design or delivery of rAAV-AAT vectors will be required to achieve therapeutic target serum AAT concentrations.

  13. Health-Related Quality of Life in Patients With α1 Antitrypsin Deficency: A Cross Sectional Study.

    Science.gov (United States)

    Torres Redondo, Margarida; Campoa, Elsa; Ruano, Luis; Sucena, Maria

    2017-02-01

    Measures of health related quality of life (HRQoL) in patients with α1-antitrypsin deficiency (AATD) can help to determine the impact of the disease and provide an important insight into the intervention outcomes. There is few data regarding this issue in the literature. The aim of this study is to assess the relationship between HRQoL and gender, functional parameters and history of hospitalizations in patients with AATD. This is a cross-sectional study of 26 patients with severe AATD recruited in the pulmonology outpatient clinic at a tertiary care medical center. Social-demographic, clinical and functional parameters were recorded and HRQoL was assessed with the Portuguese version of the medical outcome study short form-36 (SF-36) self-administered questionnaire. Older patients, females and patients with at least one hospitalization in the previous year due to respiratory disease had statistical lower scores in some dimensions of the SF-36 questionnaire. Superior FEV1 and higher distance mark in the 6-min walking test distance influenced positively several dimensions of the questionnaire. Higher scores in the mMRC scale influenced negatively the HRQoL. These data suggests that older and female patients with AATD have worse HRQoL. Hospitalizations and functional markers of respiratory disease progression influenced negatively the HRQoL, suggesting that the SF-36 questionnaire could be useful as an outcome for AATD patients with lung involvement. Copyright © 2016 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.

  14. The Shapes of Z-α1-Antitrypsin Polymers in Solution Support the C-Terminal Domain-Swap Mechanism of Polymerization

    DEFF Research Database (Denmark)

    Behrens, Manja Annette; Sendall, Timothy J.; Pedersen, Jan Skov

    2014-01-01

    Emphysema and liver cirrhosis can be caused by the Z mutation (Glu342Lys) in the serine protease inhibitor α1-antitrypsin (α1AT), which is found in more than 4% of the Northern European population. Homozygotes experience deficiency in the lung concomitantly with a massive accumulation of polymers...... within hepatocytes, causing their destruction. Recently, it was proposed that Z-α1AT polymerizes by a C-terminal domain swap. In this study, small-angle x-ray scattering (SAXS) was used to characterize Z-α1AT polymers in solution. The data show that the Z-α1AT trimer, tetramer, and pentamer all form ring...

  15. Alpha-1, are you in? (C)harlie (O)scar (P)appa (D)elta, over!

    African Journals Online (AJOL)

    The global numbers are expected to continue to increase as risk ... risk factor is alpha-1 antitrypsin (AAT) deficiency. This risk is particularly high if someone deficient in AAT also smokes. AAT inhibits a wide variety of proteases. It protects tissue from .... Perhaps collateral ventilation or interalveolar air drift through the pores ...

  16. Large-scale purification of high purity α1-antitrypsin from Cohn Fraction IV with virus inactivation by solvent/detergent and dry-heat treatment.

    Science.gov (United States)

    Huangfu, Chaoji; Zhang, Jinchao; Ma, Yuyuan; Jia, Junting; Li, Jingxuan; Lv, Maomin; Ma, Xiaowei; Zhao, Xiong; Zhang, Jingang

    2017-10-26

    α1-Antitrypsin (AAT) is widely used to treat patients with congenital AAT deficiency. Cohn Fraction IV (Cohn F IV) is normally discarded during the manufacturing process of albumin but contains approximately 33% of plasma AAT. We established a new process for large-scale purification of AAT from it. liquid chromatography-electrospray ionization-tandem mass spectrometry and high-performance liquid chromatography were applied for qualitative identification and composition analysis, respectively. Stabilizers were optimized for AAT activity protection during lyophilization and dry-heat. Virus inactivation by dry-heat and solvent/detergent (S/D) was validated on a range of viruses. AAT with purity of 95.54%, specific activity of 3,938.5 IU/mg, and yield of 26.79%, was achieved. More than 95% activity was reserved after S/D. More than 96% activity was obtained after lyophilization or dry-heat. After S/D, pseudorabies virus (PRV) and vesicular stomatitis virus (VSV) were inactivated below detectable level within 1 H. Virus titer reductions of more than 5.50 log 10 and 5.38 log 10 were achieved for PRV and VSV, respectively. Porcine parvovirus and encephalomyocarditis virus were inactivated by 3.17 log 10 and 5.88 log 10 reduction after dry-heat. The advantages of this process, including suitability for large-scale production, high purity, better utilization of human plasma, viral safety, commercial and inexpensive chromatography medium, may facilitate its further application. © 2017 International Union of Biochemistry and Molecular Biology, Inc.

  17. Metabolic flux rearrangement in the amino acid metabolism reduces ammonia stress in the α1-antitrypsin producing human AGE1.HN cell line.

    Science.gov (United States)

    Priesnitz, Christian; Niklas, Jens; Rose, Thomas; Sandig, Volker; Heinzle, Elmar

    2012-03-01

    This study focused on metabolic changes in the neuronal human cell line AGE1.HN upon increased ammonia stress. Batch cultivations of α(1)-antitrypsin (A1AT) producing AGE1.HN cells were carried out in media with initial ammonia concentrations ranging from 0mM to 5mM. Growth, A1AT production, metabolite dynamics and finally metabolic fluxes calculated by metabolite balancing were compared. Growth and A1AT production decreased with increasing ammonia concentration. The maximum A1AT concentration decreased from 0.63g/l to 0.51g/l. Central energy metabolism remained relatively unaffected exhibiting only slightly increased glycolytic flux at high initial ammonia concentration in the medium. However, the amino acid metabolism was significantly changed. Fluxes through transaminases involved in amino acid degradation were reduced concurrently with a reduced uptake of amino acids. On the other hand fluxes through transaminases working in the direction of amino acid synthesis, i.e., alanine and phosphoserine, were increased leading to increased storage of excess nitrogen in extracellular alanine and serine. Glutamate dehydrogenase flux was reversed increasingly fixing free ammonia with increasing ammonia concentration. Urea production additionally observed was associated with arginine uptake by the cells and did not increase at high ammonia stress. It was therefore not used as nitrogen sink to remove excess ammonia. The results indicate that the AGE1.HN cell line can adapt to ammonia concentrations usually present during the cultivation process to a large extent by changing metabolism but with slightly reduced A1AT production and growth. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. Low Levels of IgG Recognizing the α-1-Antitrypsin Peptide and Its Association with Taiwanese Women with Primary Sjögren’s Syndrome

    Directory of Open Access Journals (Sweden)

    Yu-Sheng Chang

    2017-12-01

    Full Text Available The aim of this study was to examine oxidative stress and low level of α-1-antitrypsin (A1AT in primary Sjögren’s syndrome (pSS, and evaluate the associated autoreactivity against unmodified and their 4-hydroxy-2-nonenal (HNE-modified peptides with pSS. Two differentially expressed proteins, α-1-acid glycoprotein 1 (A1AG1 and A1AT, exhibited 2-fold differences, and their HNE modifications were identified by depleted-albumin and immunoglobulin G (IgG serum protein, in-solution digestion, in-gel digestion, and nano-liquid chromatography–tandem mass spectrometry (nano-LC-MS/MS from pSS patients and age-matched healthy controls (HCs. Furthermore, levels of proteins, confirmation of HNE modifications, HNE-protein adducts and autoreactivity against unmodified and their HNE-modified peptides were further validated. Levels of the HNE-protein adduct and A1AG1 were significantly higher in pSS patients than HCs, but levels of A1AT were significantly lower in pSS patients compared to HCs. Only the HNE modification of A1AT was confirmed. Our study suggests that elevated HNE-protein adduct, oxidative stress, level (odds ratio (OR 4.877, p = 0.003, lowered A1AT level (OR 3.910, p = 0.010 and a decreased level of anti-A1AT50–63 IgG (OR 3.360, p = 0.010 showed an increased risk in pSS patients compared to HCs, respectively.

  19. Two novel nonradioactive polymerase chain reaction-based assays of dried blood spots, genomic DNA, or whole cells for fast, reliable detection of Z and S mutations in the alpha 1-antitrypsin gene

    DEFF Research Database (Denmark)

    Andresen, B S; Knudsen, I; Jensen, P K

    1992-01-01

    from individuals who are normal, heterozygous, or homozygous for the mutations. We show that the two assays can be performed with purified genomic DNA as well as with boiled blood spots. The new assays were validated by parallel testing with a technique in which PCR is combined with allele......-specific oligonucleotide (ASO) probes. In all cases tested the results obtained by the different techniques were in accordance. The new assays can be used for prenatal diagnostics and can be performed directly with boiled tissue samples. Because the new assays are easy to perform and reliable, we conclude...

  20. Alpha-1 couples: interpersonal and intrapersonal predictors of spousal communication and stress.

    Science.gov (United States)

    Smith, Rachel A; Wienke, Sara; Coffman, Donna L

    2014-04-01

    Couples often discuss genetic test results, and then manage their implications together. This interdependence can lead to common, shared experiences, similar intrapersonal processes to manage shared stressors, or interpersonal influences between spouses, leading to different outcomes. This study sought to reveal the intracouple, intrapersonal, and interpersonal influences of genetic stigma and negative feelings on spousal communication and perceived stress with 50 couples in which one spouse is a member of a genetic disease registry. The results were analyzed with dyadic analysis, including multilevel modeling. The findings showed that registered members and their spouses were not statistically different in their mean levels of perceived genetic stigma, negative feelings about alpha-1 antitrypsin deficiency (AATD), conversations with each other about the AATD test results, and their perceived stress. The findings also showed that their intracouple consistencies were not high, and their intrapersonal and interpersonal influences on communication and stress differed. The social implications of genetic research at the interpersonal level are discussed.

  1. 25 Ways to Love Your Liver

    Science.gov (United States)

    ... Related Liver Disease Alpha 1 Antitrypsin Deficiency Autoimmune Hepatitis Benign Liver Tumors Biliary Atresia Cirrhosis of the Liver Galactosemia ... Related Liver Disease Alpha 1 Antitrypsin Deficiency Autoimmune Hepatitis Benign Liver Tumors Biliary Atresia Cirrhosis of the Liver Galactosemia ...

  2. Buffett's Alpha

    DEFF Research Database (Denmark)

    Frazzini, Andrea; Kabiller, David; Heje Pedersen, Lasse

    Berkshire Hathaway has realized a Sharpe ratio of 0.76, higher than any other stock or mutual fund with a history of more than 30 years, and Berkshire has a significant alpha to traditional risk factors. However, we find that the alpha becomes insignificant when controlling for exposures to Betting-Against-Beta...... in publicly traded stocks versus wholly-owned private companies, we find that the former performs the best, suggesting that Buffett's returns are more due to stock selection than to his effect on management. These results have broad implications for market efficiency and the implementability of academic...

  3. Manglende effekt af substitutionsbehandling ved alfa 1-antitrypsin-mangel

    DEFF Research Database (Denmark)

    Dahl, Ronald; Hilberg, Ole; Ottesen, Anders Løkke

    2011-01-01

    in the decrease of lung density measured by computed tomographies, but found no clinical nor statistical significant difference in respiratory symptoms, quality of life, lung function, use of medication, exacerbations, respiratory infections or survival. Based on the present evidence A1AT substitution therapy...

  4. Coulomb correction to elastic. alpha. -. alpha. scattering

    Energy Technology Data Exchange (ETDEWEB)

    Bera, P.K.; Jana, A.K.; Haque, N.; Talukdar, B. (Department of Physics, Visva-Bharati University, Santiniketan-731235, West Bengal, India (IN))

    1991-02-01

    The elastic {alpha}-{alpha} scattering is treated within the framework of a generalized phase-function method (GPFM). This generalization consists in absorbing the effect of Coulomb interaction in the comparison functions for developing the phase equation. Based on values of scattering phase shifts computed by the present method, it is concluded that the GPFM provides an uncomplicated approach to rigorous Coulomb correction in the {alpha}-{alpha} scattering.

  5. Intrahepatic expression of interferon alpha & interferon alpha ...

    African Journals Online (AJOL)

    kemrilib

    Alpha m-RNA while 30% only expressed Interferon Alpha Receptor m-RNA. Responders and non-responders to Interferon therapy ... expression of IFN Alpha Receptor mRNA. Regardless of the response to interferon, histological .... generation reverse hybridisation, line probe assay. (Inno-LiPA HCV II; Innogenetics, Ghent,.

  6. The determination of $\\alpha_s$ by the ALPHA collaboration

    CERN Document Server

    Bruno, Mattia

    2016-01-01

    We review the ALPHA collaboration strategy for obtaining the QCD coupling at high scale. In the three-flavor effective theory it avoids the use of perturbation theory at $\\alpha > 0.2$ and at the same time has the physical scales small compared to the cutoff $1/a$ in all stages of the computation. The result $\\Lambda_\\overline{MS}^{(3)}=332(14)$~MeV is translated to $\\alpha_\\overline{MS}(m_Z)=0.1179(10)(2)$ by use of (high order) perturbative relations between the effective theory couplings at the charm and beauty quark "thresholds". The error of this perturbative step is discussed and estimated as $0.0002$.

  7. Lyman Alpha Control

    CERN Document Server

    Nielsen, Daniel Stefaniak

    2015-01-01

    This document gives an overview of how to operate the Lyman Alpha Control application written in LabVIEW along with things to watch out for. Overview of the LabVIEW code itself as well as the physical wiring of and connections from/to the NI PCI-6229 DAQ box is also included. The Lyman Alpha Control application is the interface between the ALPHA sequencer and the HighFinesse Wavelength Meter as well as the Lyman Alpha laser setup. The application measures the wavelength of the output light from the Lyman Alpha cavity through the Wavelength Meter. The application can use the Wavelength Meter’s PID capabilities to stabilize the Lyman Alpha laser output as well as switch between up to three frequencies.

  8. New ALPHA-2 magnet

    CERN Multimedia

    Anaïs Schaeffer

    2012-01-01

    On 21 June, members of the ALPHA collaboration celebrated the handover of the first solenoid designed for the ALPHA-2 experiment. The magnet has since been successfully installed and is working well.   Khalid Mansoor, Sumera Yamin and Jeffrey Hangst in front of the new ALPHA-2 solenoid. “This was the first of three identical solenoids that will be installed between now and September, as the rest of the ALPHA-2 device is installed and commissioned,” explains ALPHA spokesperson Jeffrey Hangst. “These magnets are designed to allow us to transfer particles - antiprotons, electrons and positrons - between various parts of the new ALPHA-2 device by controlling the transverse size of the particle bunch that is being transferred.” Sumera Yamin and Khalid Mansoor, two Pakistani scientists from the National Centre for Physics in Islamabad, came to CERN in February specifically to design and manufacture these magnets. “We had the chance to work on act...

  9. Alpha Shapes and Proteins

    DEFF Research Database (Denmark)

    Winter, Pawel; Sterner, Henrik; Sterner, Peter

    2009-01-01

    We provide a unified description of (weighted) alpha shapes, beta shapes and the corresponding simplicialcomplexes. We discuss their applicability to various protein-related problems. We also discuss filtrations of alpha shapes and touch upon related persistence issues.We claim that the full...... potential of alpha-shapes and related geometrical constructs in protein-related problems yet remains to be realized and verified. We suggest parallel algorithms for (weighted) alpha shapes, and we argue that future use of filtrations and kinetic variants for larger proteins will need such implementation....

  10. [Production of human proteins in the blood of transgenic animals

    NARCIS (Netherlands)

    Massoud, M.; Bischoff, Rainer; Dalemans, W.; Pointu, H.; Attal, J.; Schultz, H.; Clesse, D.; Stinnakre, M.G.; Pavirani, A.; Houdebine, L.M.

    1990-01-01

    The human alpha 1-antitrypsin gene has been microinjected into rabbit embryos. A line of transgenic rabbits has thus been established. Human alpha 1-antitrypsin was found in the blood of transgenic animals at the concentration of 1 mg/ml plasma. The human protein was active and separable from its

  11. Novel Therapeutic and Prophylactic Modalities to Protect the United States Armed Forces Against Mayor Biological Threat Agents

    Science.gov (United States)

    2007-08-01

    fact that GSK-3β is a specific substrate of AKT kinase activity, that the downstream activity of GSK-3β regulating glycogenolysis by liver and...Br J Haematol 2000, 109(2):342-348. 102 Janciauskiene S, Nita I, Stevens T: Alpha1-antitrypsin, old dog , new tricks. Alpha1-antitrypsin exerts in

  12. Targeted Alpha Therapy: From Alpha to Omega

    International Nuclear Information System (INIS)

    Allen, Barry J; Clarke, Raymond; Huang Chenyu

    2013-01-01

    This review covers the broad spectrum of Targeted Alpha Therapy (TAT) research in Australia; from in vitro and in vivo studies to clinical trials. The principle of tumour anti-vascular alpha therapy (TAVAT) is discussed in terms of its validation by Monte Carlo calculations of vascular models and the potential role of biological dosimetry is examined. Summmary of this review is as follows: 1. The essence of TAT 2. Therapeutic objectives 3. TAVAT and Monte Carlo microdosimetry 4. Biological dosimetry 5. Preclinical studies 6. Clinical trials 7. What next? 8. Obstacles. (author)

  13. Alpha clustering in nuclei

    International Nuclear Information System (INIS)

    Hodgson, P.E.

    1990-01-01

    The effects of nucleon clustering in nuclei are described, with reference to both nuclear structure and nuclear reactions, and the advantages of using the cluster formalism to describe a range of phenomena are discussed. It is shown that bound and scattering alpha-particle states can be described in a unified way using an energy-dependent alpha-nucleus potential. (author)

  14. Genetics Home Reference: alpha thalassemia

    Science.gov (United States)

    ... Facebook Twitter Home Health Conditions Alpha thalassemia Alpha thalassemia Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Alpha thalassemia is a blood disorder that reduces the production ...

  15. Alpha Thalassemia (For Parents)

    Science.gov (United States)

    ... the body has a problem producing alpha globin Beta thalassemia : when the body has a problem producing beta ... Transfusion Blood Test: Hemoglobin Electrophoresis Sickle Cell Disease Beta Thalassemia Blood All About Genetics Prenatal Genetic Counseling Genetic ...

  16. ALPHA-2: the sequel

    CERN Multimedia

    Katarina Anthony

    2012-01-01

    While many experiments are methodically planning for intense works over the long shutdown, there is one experiment that is already working at full steam: ALPHA-2. Its final components arrived last month and will completely replace the previous ALPHA set-up. Unlike its predecessor, this next generation experiment has been specifically designed to measure the properties of antimatter.   The ALPHA team lower the new superconducting solenoid magnet into place. The ALPHA collaboration is working at full speed to complete the ALPHA-2 set-up for mid-November – this will give them a few weeks of running before the AD shutdown on 17 December. “We really want to get some experience with this device this year so that, if we need to make any changes, we will have time during the long shutdown in which to make them,” says Jeffrey Hangst, ALPHA spokesperson. “Rather than starting the 2014 run in the commissioning stage, we will be up and running from the get go.&...

  17. Expression of triplicated and quadruplicated alpha globin genes in sheep.

    Science.gov (United States)

    Vestri, R; Pieragostini, E; Yang, F; di Gregorio, P; Rando, A; Masina, P

    1991-01-01

    In the sheep alpha alpha alpha globin gene haplotype, the three genes display from the 5' to the 3' end the percentage efficiencies of about 30:14:6, as indicated by the amounts of the three types of alpha chain produced in the alpha alpha alpha/alpha alpha alpha homozygotes. The 3' gene in the alpha alpha alpha alpha haplotype appears to have an efficiency around 1%, as suggested by analysis of one quadruple alpha homozygote. Moreover, the total outputs of the alpha alpha alpha as well as of the alpha alpha alpha alpha haplotypes do not substantially differ from that of the common alpha alpha haplotype.

  18. Monte Carlo alpha calculation

    Energy Technology Data Exchange (ETDEWEB)

    Brockway, D.; Soran, P.; Whalen, P.

    1985-01-01

    A Monte Carlo algorithm to efficiently calculate static alpha eigenvalues, N = ne/sup ..cap alpha..t/, for supercritical systems has been developed and tested. A direct Monte Carlo approach to calculating a static alpha is to simply follow the buildup in time of neutrons in a supercritical system and evaluate the logarithmic derivative of the neutron population with respect to time. This procedure is expensive, and the solution is very noisy and almost useless for a system near critical. The modified approach is to convert the time-dependent problem to a static ..cap alpha../sup -/eigenvalue problem and regress ..cap alpha.. on solutions of a/sup -/ k/sup -/eigenvalue problem. In practice, this procedure is much more efficient than the direct calculation, and produces much more accurate results. Because the Monte Carlo codes are intrinsically three-dimensional and use elaborate continuous-energy cross sections, this technique is now used as a standard for evaluating other calculational techniques in odd geometries or with group cross sections.

  19. Monte Carlo alpha deposition

    International Nuclear Information System (INIS)

    Talley, T.L.; Evans, F.

    1988-01-01

    Prior work demonstrated the importance of nuclear scattering to fusion product energy deposition in hot plasmas. This suggests careful examination of nuclear physics details in burning plasma simulations. An existing Monte Carlo fast ion transport code is being expanded to be a test bed for this examination. An initial extension, the energy deposition of fast alpha particles in a hot deuterium plasma, is reported. The deposition times and deposition ranges are modified by allowing nuclear scattering. Up to 10% of the initial alpha particle energy is carried to greater ranges and times by the more mobile recoil deuterons. 4 refs., 5 figs., 2 tabs

  20. Buffett’s Alpha

    DEFF Research Database (Denmark)

    Frazzini, Andrea; Kabiller, David; Heje Pedersen, Lasse

    Berkshire Hathaway has realized a Sharpe ratio of 0.76, higher than any other stock or mutual fund with a history of more than 30 years, and Berkshire has a significant alpha to traditional risk factors. However, we find that the alpha becomes insignificant when controlling for exposures to Betting......-Against-Beta and Quality-Minus-Junk factors. Further, we estimate that Buffett’s leverage is about 1.6-to-1 on average. Buffett’s returns appear to be neither luck nor magic, but, rather, reward for the use of leverage combined with a focus on cheap, safe, quality stocks. Decomposing Berkshires’ portfolio into ownership...

  1. CK (Creatine Kinase) Test

    Science.gov (United States)

    ... Blood Testing Alpha-1 Antitrypsin Alpha-fetoprotein (AFP) Tumor Marker AMAS Aminoglycoside Antibiotics Ammonia Amniocentesis Amylase ANCA/MPO/ ... Beta-2 Microglobulin Kidney Disease Beta-2 Microglobulin Tumor Marker Bicarbonate (Total CO2) Bilirubin Blood Culture Blood Gases ...

  2. Myasthenia Gravis Tests

    Science.gov (United States)

    ... Blood Testing Alpha-1 Antitrypsin Alpha-fetoprotein (AFP) Tumor Marker AMAS Aminoglycoside Antibiotics Ammonia Amniocentesis Amylase ANCA/MPO/ ... Beta-2 Microglobulin Kidney Disease Beta-2 Microglobulin Tumor Marker Bicarbonate (Total CO2) Bilirubin Blood Culture Blood Gases ...

  3. HIV Genotypic Resistance Testing

    Science.gov (United States)

    ... Blood Testing Alpha-1 Antitrypsin Alpha-fetoprotein (AFP) Tumor Marker AMAS Aminoglycoside Antibiotics Ammonia Amniocentesis Amylase ANCA/MPO/ ... Beta-2 Microglobulin Kidney Disease Beta-2 Microglobulin Tumor Marker Bicarbonate (Total CO2) Bilirubin Blood Culture Blood Gases ...

  4. With Home Testing, Consumers Take Charge of Their Health

    Science.gov (United States)

    ... Blood Testing Alpha-1 Antitrypsin Alpha-fetoprotein (AFP) Tumor Marker AMAS Aminoglycoside Antibiotics Ammonia Amniocentesis Amylase ANCA/MPO/ ... Beta-2 Microglobulin Kidney Disease Beta-2 Microglobulin Tumor Marker Bicarbonate (Total CO2) Bilirubin Blood Culture Blood Gases ...

  5. Liver Panel

    Science.gov (United States)

    ... Blood Testing Alpha-1 Antitrypsin Alpha-fetoprotein (AFP) Tumor Marker AMAS Aminoglycoside Antibiotics Ammonia Amniocentesis Amylase ANCA/MPO/ ... Beta-2 Microglobulin Kidney Disease Beta-2 Microglobulin Tumor Marker Bicarbonate (Total CO2) Bilirubin Blood Culture Blood Gases ...

  6. Mono Test

    Science.gov (United States)

    ... Blood Testing Alpha-1 Antitrypsin Alpha-fetoprotein (AFP) Tumor Marker AMAS Aminoglycoside Antibiotics Ammonia Amniocentesis Amylase ANCA/MPO/ ... Beta-2 Microglobulin Kidney Disease Beta-2 Microglobulin Tumor Marker Bicarbonate (Total CO2) Bilirubin Blood Culture Blood Gases ...

  7. Pleural Fluid Analysis Test

    Science.gov (United States)

    ... Blood Testing Alpha-1 Antitrypsin Alpha-fetoprotein (AFP) Tumor Marker AMAS Aminoglycoside Antibiotics Ammonia Amniocentesis Amylase ANCA/MPO/ ... Beta-2 Microglobulin Kidney Disease Beta-2 Microglobulin Tumor Marker Bicarbonate (Total CO2) Bilirubin Blood Culture Blood Gases ...

  8. Coagulation Factors Test

    Science.gov (United States)

    ... Blood Testing Alpha-1 Antitrypsin Alpha-fetoprotein (AFP) Tumor Marker AMAS Aminoglycoside Antibiotics Ammonia Amniocentesis Amylase ANCA/MPO/ ... Beta-2 Microglobulin Kidney Disease Beta-2 Microglobulin Tumor Marker Bicarbonate (Total CO2) Bilirubin Blood Culture Blood Gases ...

  9. Production of glycosylated physiologically normal human α1-antitrypsin by mouse fibroblasts modified by insertion of a human α1-antitrypsin cDNA using a retroviral vector

    International Nuclear Information System (INIS)

    Garver, R.I. Jr.; Chytil, A.; Karlsson, S.

    1987-01-01

    α 2 -Antitrypsin (α 1 AT) deficiency is a hereditary disorder characterized by reduced serum levels of α 1 AT, resulting in destruction of the lower respiratory tract by neutrophil elastase. As an approach to augment α 1 AT levels in this disorder with physiologically normal human α 1 AT, the authors have integrated a full-length normal human α 1 AT cDNA into the genome of mouse fibroblasts. To accomplish this, the retroviral vector N2 was modified by inserting the simian virus 40 early promoter followed by the α 1 AT cDNA. Southern analysis demonstrated that the intact cDNA was present in the genome of selected clones of the transfected murine fibroblasts psi2 and infected NIH 3T3. The clones produced three mRNA transcripts containing human α 1 AT sequences, secreted an α 1 AT molecule recognized by an anti-human α 1 AT antibody, with the same molecular mass as normal human α 1 AT and that complexed with and inhibited human neutrophil elastase. The psi2 produced α 1 AT was glycosylated, and when infused intravenously into mice, it had a serum half-life similar to normal α 1 AT purified from human plasma and markedly longer than that of nonglycosylated human α 1 AT cDNA-directed yeast-produced α 1 AT. These studies demonstrate the feasibility of using a retroviral vector to insert the normal human α 1 AT cDNA into non-α 1 AT-producing cells, resulting in the synthesis and secretion of physiologically normal α 1 AT

  10. ATZ11 recognizes not only Z-α1-antitrypsin-polymers and complexed forms of non-Z-α1-antitrypsin but also the von Willebrand factor.

    Directory of Open Access Journals (Sweden)

    Diane Goltz

    Full Text Available AIMS: The ATZ11 antibody has been well established for the identification of α1-anti-trypsin (AAT molecule type PiZ (Z-AAT in blood samples and liver tissue. In this study, we systematically analyzed the antibody for additional binding sites in human tissue. METHODS AND RESULTS: Ultrastructural ATZ11 binding was investigated immunoelectron microscopically in human umbilical vein endothelial cells (HUVECs and in platelets of a healthy individual. Human embryonic kidney (HEK293 cells were transiently transfected with Von Willebrand factor (VWF and analyzed immunocytochemically using confocal microscopy and SDS-PAGE electrophoresis followed by western blotting (WB. Platelets and serum samples of VWF-competent and VWF-deficient patients were investigated using native PAGE and SDS-PAGE electrophoresis followed by WB. The specificity of the ATZ11 reaction was tested immunohistochemically by extensive antibody-mediated blocking of AAT- and VWF-antigens. ATZ11-positive epitopes could be detected in Weibel-Palade bodies (WPBs of HUVECs and α-granules of platelets. ATZ11 stains pseudo-WBP containing recombinant wild-type VWF (rVWF-WT in HEK293 cells. In SDS-PAGE electrophoresis followed by WB, anti-VWF and ATZ11 both identified rVWF-WT. However, neither rVWF-WT-multimers, human VWF-multimers, nor serum proteins of VWF-deficient patients were detected using ATZ11 by WB, whereas anti-VWF antibody (anti-VWF detected rVWF-WT-multimers as well as human VWF-multimers. In human tissue specimens, AAT-antigen blockade using anti-AAT antibody abolished ATZ11 staining of Z-AAT in a heterozygous AAT-deficient patient, whereas VWF-antigen blockade using anti-VWF abolished ATZ11 staining of endothelial cells and megakaryocytes. CONCLUSIONS: ATZ11 reacts with cellular bound and denatured rVWF-WT and human VWF as shown using immunocytochemistry and subsequent confocal imaging, immunoelectron microscopy, SDS-PAGE and WB, and immunohistology. These immunoreactions are

  11. Case Study - Alpha

    Directory of Open Access Journals (Sweden)

    Stephen Leybourne

    2016-11-01

    Full Text Available This case study was developed from an actual scenario by Dr. Steve Leybourne of Boston University.  The case documents the historical evolution of an organization, and has been used successfully in courses dealing with organizational and cultural change, and the utilization of ‘soft skills’ in project-based management. This is a short case, ideal for classroom use and discussion.  The issues are easily accessible to students, and there is a single wide ranging question that allows for the inclusion of many issues surrounding strategic decision-making, and behavioural and cultural change. Alpha was one of the earlier companies in the USA to invest in large, edge-of-town superstores, with plentiful free vehicle parking, selling food and related household products. Alpha was created in the 1950s as a subsidiary of a major publicly quoted retail group.  It started business by opening a string of very large discount stores in converted industrial and warehouse premises in the south of the United States. In the early days shoppers were offered a limited range of very competitively priced products. When Alpha went public in 1981 it was the fourth largest food retailer in the US, selling an ever-widening range of food and non-food products.  Its success continued to be based on high volume, low margins and good value for money, under the slogan of ‘Alpha Price.’

  12. Alpha-mannosidosis

    DEFF Research Database (Denmark)

    Borgwardt, Line; Stensland, Hilde Monica Frostad Riise; Olsen, Klaus Juul

    2015-01-01

    of the three subgroups of genotype/subcellular localisation and the clinical and biochemical data were done to investigate the potential relationship between genotype and phenotype in alpha-mannosidosis. Statistical analyses were performed using the SPSS software. Analyses of covariance were performed...

  13. Demystifying AlphaGo Zero as AlphaGo GAN

    OpenAIRE

    Dong, Xiao; Wu, Jiasong; Zhou, Ling

    2017-01-01

    The astonishing success of AlphaGo Zero\\cite{Silver_AlphaGo} invokes a worldwide discussion of the future of our human society with a mixed mood of hope, anxiousness, excitement and fear. We try to dymystify AlphaGo Zero by a qualitative analysis to indicate that AlphaGo Zero can be understood as a specially structured GAN system which is expected to possess an inherent good convergence property. Thus we deduct the success of AlphaGo Zero may not be a sign of a new generation of AI.

  14. $\\alpha$-Representation for QCD

    OpenAIRE

    Tuan, Richard Hong

    1998-01-01

    An $\\alpha$-parameter representation is derived for gauge field theories.It involves, relative to a scalar field theory, only constants and derivatives with respect to the $\\alpha$-parameters. Simple rules are given to obtain the $\\alpha$-representation for a Feynman graph with an arbitrary number of loops in gauge theories in the Feynman gauge.

  15. Alpha Theta Meditation: Phenomenological, neurophysiologic ...

    African Journals Online (AJOL)

    Alpha Theta Meditation: Phenomenological, neurophysiologic, mindfulness, mood, health and sport implications. ... the single alpha theta meditation was associated with elevated alpha and theta activity, as well as decrease in negative mood perceptions, especially with regard to anxiety, sadness and confusion scores.

  16. Alpha scintillation radon counting

    International Nuclear Information System (INIS)

    Lucas, H.F. Jr.

    1977-01-01

    Radon counting chambers which utilize the alpha-scintillation properties of silver activated zinc sulfide are simple to construct, have a high efficiency, and, with proper design, may be relatively insensitive to variations in the pressure or purity of the counter filling. Chambers which were constructed from glass, metal, or plastic in a wide variety of shapes and sizes were evaluated for the accuracy and the precision of the radon counting. The principles affecting the alpha-scintillation radon counting chamber design and an analytic system suitable for a large scale study of the 222 Rn and 226 Ra content of either air or other environmental samples are described. Particular note is taken of those factors which affect the accuracy and the precision of the method for monitoring radioactivity around uranium mines

  17. Combining Alphas via Bounded Regression

    Directory of Open Access Journals (Sweden)

    Zura Kakushadze

    2015-11-01

    Full Text Available We give an explicit algorithm and source code for combining alpha streams via bounded regression. In practical applications, typically, there is insufficient history to compute a sample covariance matrix (SCM for a large number of alphas. To compute alpha allocation weights, one then resorts to (weighted regression over SCM principal components. Regression often produces alpha weights with insufficient diversification and/or skewed distribution against, e.g., turnover. This can be rectified by imposing bounds on alpha weights within the regression procedure. Bounded regression can also be applied to stock and other asset portfolio construction. We discuss illustrative examples.

  18. Treatment of alpha bearing wastes

    International Nuclear Information System (INIS)

    1988-01-01

    This report deals with the current state of the art of alpha waste treatment, which is an integral part of the overall nuclear waste management system. The International Atomic Energy Agency (IAEA) defines alpha bearing waste as 'waste containing one or more alpha emitting radionuclides, usually actinides, in quantities above acceptable limits'. The limits are established by national regulatory bodies. The limits above which wastes are considered as alpha contaminated refer to the concentrations of alpha emitters that need special consideration for occupational exposures and/or potential safety, health, or environmental impact during one or more steps from generation through disposal. Owing to the widespread use of waste segregation by source - that is, based upon the 'suspect origin' of the material - significant volumes of waste are being handled as alpha contaminated which, in fact, do not require such consideration by reason of risk or environmental concern. The quantification of de minimis concepts by national regulatory bodies could largely contribute to the safe reduction of waste volumes and associated costs. Other factors which could significantly contribute to the reduction of alpha waste arisings are an increased application of assaying and sorting, instrumentation and the use of feedback mechanisms to control or modify the processes which generate these wastes. Alpha bearing wastes are generated during fabrication and reprocessing of nuclear fuels, decommissioning of alpha contaminated facilities, and other activities. Most alpha wastes are contact handled, but a small portion may require shielding or remote handling because of high levels of neutron (n), beta (β), or gamma (γ) emissions associated with the waste material. This report describes the sources and characteristics of alpha wastes and strategies for alpha waste management. General descriptions of treatment processes for solid and liquid alpha wastes are included. 71 refs, 14 figs, 9 tabs

  19. The alpha effect

    International Nuclear Information System (INIS)

    Anon.

    1982-01-01

    Much of the recent interest in RAM system reliability stems from concern over alpha particle soft error rates reported for the initial 64 k RAMs. With increasing memory density likely in the next few years the problem of soft errors is rearing its head again. A few years ago ITT carried out experiments on 16k RAMs and found no significant problems. However, recent tests have shown a raise in the number of soft errors with 64k RAMs, and the launch of 256k and 512k memories is likely to make the problem acute

  20. Alpha-mannosidosis

    Directory of Open Access Journals (Sweden)

    Nilssen Øivind

    2008-07-01

    Full Text Available Abstract Alpha-mannosidosis is an inherited lysosomal storage disorder characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and intellectual disability. It occurs in approximately 1 of 500,000 live births. The children are often born apparently normal, and their condition worsens progressively. Some children are born with ankle equinus or develop hydrocephalus in the first year of life. Main features are immune deficiency (manifested by recurrent infections, especially in the first decade of life, skeletal abnormalities (mild-to-moderate dysostosis multiplex, scoliosis and deformation of the sternum, hearing impairment (moderate-to-severe sensorineural hearing loss, gradual impairment of mental functions and speech, and often, periods of psychosis. Associated motor function disturbances include muscular weakness, joint abnormalities and ataxia. The facial trait include large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. Slight strabismus is common. The clinical variability is significant, representing a continuum in severity. The disorder is caused by lysosomal alpha-mannosidase deficiency. Alpha-mannosidosis is inherited in an autosomal recessive fashion and is caused by mutations in the MAN2B1 gene located on chromosome 19 (19 p13.2-q12. Diagnosis is made by measuring acid alpha-mannosidase activity in leukocytes or other nucleated cells and can be confirmed by genetic testing. Elevated urinary secretion of mannose-rich oligosaccharides is suggestive, but not diagnostic. Differential diagnoses are mainly the other lysosomal storage diseases like the mucopolysaccharidoses. Genetic counseling should be given to explain the nature of the disease and to detect carriers. Antenatal diagnosis is possible, based on both biochemical and genetic methods. The management should be pro-active, preventing complications and treating

  1. Alpha activity measurement with lsc

    International Nuclear Information System (INIS)

    Dobrin, R. I.; Dulama, C. N.; Ciocirlan, C. N.; Toma, A.; Stoica, S. M.; Valeca, M.

    2013-01-01

    Recently, we showed that the alpha activity in liquid samples can be measured using a liquid scintillation analyzer without alpha/beta discrimination capability. The purpose of this work was to evaluate the performances of the method and to optimize the procedure of the sample preparation. A series of tests was performed to validate the procedure of alpha emitting radionuclides extraction in aqueous samples with Actinide Resin, especially regarding to the contact time required to extract all alpha nuclides. The main conclusions were that a minimum 18 hours stirring time is needed to achieve a percent recovery of the alpha nuclides grater than 90% and that the counting efficiency of alphas measurements with LSC is nearly 100%. (authors)

  2. Molecular characterization of alpha 1- and alpha 2-adrenoceptors.

    Science.gov (United States)

    Harrison, J K; Pearson, W R; Lynch, K R

    1991-02-01

    Three 'alpha 1-adrenoceptors' and three 'alpha 2-adrenoceptors' have now been cloned. How closely do these receptors match the native receptors that have been identified pharmacologically? What are the properties of these receptors, and how do they relate to other members of the cationic amine receptor family? Kevin Lynch and his colleagues discuss these questions in this review.

  3. Alpha wastes treatment

    International Nuclear Information System (INIS)

    Thouvenot, P.

    2000-01-01

    Alter 2004, the alpha wastes issued from the Commissariat a l'Energie Atomique installations will be sent to the CEDRA plant. The aims of this installation are decontamination and wastes storage. Because of recent environmental regulations concerning ozone layer depletion, the use of CFC 113 in the decontamination unit, as previously planned, is impossible. Two alternatives processes are studied: the AVD process and an aqueous process including surfactants. Best formulations for both processes are defined issuing degreasing kinetics. It is observed that a good degreasing efficiency is linked to a good decontamination efficiency. Best results are obtained with the aqueous process. Furthermore, from the point of view of an existing waste treatment unit, the aqueous process turns out to be more suitable than the AVD process. (author)

  4. Mind Your p's and Alphas.

    Science.gov (United States)

    Stallings, William M.

    In the educational research literature alpha, the a priori level of significance, and p, the a posteriori probability of obtaining a test statistic of at least a certain value when the null hypothesis is true, are often confused. Explanations for this confusion are offered. Paradoxically, alpha retains a prominent place in textbook discussions of…

  5. Summary of Alpha Particle Transport

    Energy Technology Data Exchange (ETDEWEB)

    Medley, S.S.; White, R.B.; Zweben, S.J.

    1998-08-19

    This paper summarizes the talks on alpha particle transport which were presented at the 5th International Atomic Energy Agency's Technical Committee Meeting on "Alpha Particles in Fusion Research" held at the Joint European Torus, England in September 1997.

  6. Proteinaceous alpha-araylase inhibitors

    DEFF Research Database (Denmark)

    Svensson, Birte; Fukuda, Kenji; Nielsen, P.K.

    2004-01-01

    Proteins that inhibit alpha-amylases have been isolated from plants and microorganisms. These inhibitors can have natural roles in the control of endogenous a-amylase activity or in defence against pathogens and pests; certain inhibitors are reported to be antinutritional factors. The alpha-amylase...... inhibitors belong to seven different protein structural families, most of which also contain evolutionary related proteins without inhibitory activity. Two families include bifunctional inhibitors acting both on alpha-amylases and proteases. High-resolution structures are available of target alpha-amylases...... in complex with inhibitors from five families. These structures indicate major diversity but also some similarity in the structural basis of alpha-amylase inhibition. Mutational analysis of the mechanism of inhibition was performed in a few cases and various protein engineering and biotechnological...

  7. Cystic Fibrosis Chest X-Ray Findings: A Teaching Analog

    Science.gov (United States)

    2008-07-01

    Congenital Cystic Fibrosis Kartagener’s Syndrome Alpha-1 Antitrypsin Deficiency Bronchomalacia Yellow- Nail Syndrome Severe Inflammation...Mycobacterium (i.e. Tuberculosis) MRSA TORCHES Fungal Infection Obstructive Foreign Body Aspiration Bronchial Stricture Airway Mass/Tumor

  8. ALPHA freezes antiprotons

    CERN Multimedia

    CERN Bulletin

    2010-01-01

    Laboratories like CERN can routinely produce many different types of antiparticles. In 1995, the PS210 experiment formed the first antihydrogen atoms and a few years later, in 2002, ATRAP and ATHENA were already able to produce several thousand of them. However, no experiment in the world has succeeded in ‘trapping’ these anti-atoms in order to study them. This is the goal of the ALPHA experiment, which has recently managed to cool down the antiprotons to just a few Kelvin. This represents a major step towards trapping the anti-atom, thus opening a new avenue into the investigation of antimatter properties.   Members of the ALPHA collaboration working on the apparatus in the Antiproton Decelerator experimental hall at CERN. Just like the atom, the anti-atom is neutral. Unlike the atom, the anti-atom is made up of antiprotons (as opposed to protons in the atom) and positrons (as opposed to electrons). In order to thoroughly study the properties of the anti-atoms, scien...

  9. Measurement of $\\alpha_{s}$ with Radiative Hadronic Events

    CERN Document Server

    Abbiendi, G; Åkesson, P F; Alexander, G; Anagnostou, G; Anderson, K J; Asai, S; Axen, D; Bailey, I; Barberio, E; Barillari, T; Barlow, R J; Batley, R J; Bechtle, P; Behnke, T; Bell, K W; Bell, P J; Bella, G; Bellerive, A; Benelli, G; Bethke, S; Biebel, O; Boeriu, O; Bock, P; Boutemeur, M; Braibant, S; Brown, R M; Burckhart, H J; Campana, S; Capiluppi, P; Carnegie, R K; Carter, A A; Carter, J R; Chang, C Y; Charlton, D G; Ciocca, C; Csilling, A; Cuffiani, M; Dado, S; Dallavalle, M; de Roeck, A; De Wolf, E A; Desch, K; Dienes, B; Dubbert, J; Duchovni, E; Duckeck, G; Duerdoth, I P; Etzion, E; Fabbri, F; Ferrari, P; Fiedler, F; Fleck, I; Ford, M; Frey, A; Gagnon, P; Gary, J W; Geich-Gimbel, C; Giacomelli, G; Giacomelli, P; Giunta, M; Goldberg, J; Gross, E; Grunhaus, J; Gruwé, M; Sen-Gupta, A; Hajdu, C; Hamann, M; Hanson, G G; Harel, A; Hauschild, M; Hawkes, C M; Hawkings, R; Herten, G; Heuer, R D; Hill, J C; Horváth, D; Igo-Kemenes, P; Ishii, K; Jeremie, H; Jovanovic, P; Junk, T R; Kanzaki, J; Karlen, D; Kawagoe, K; Kawamoto, T; Keeler, R K; Kellogg, R G; Kennedy, B W; Kluth, S; Kobayashi, T; Kobel, M; Komamiya, S; Kramer, T; Krasznahorkays, A Jr; Krieger, P; Von Krogh, J; Kühl, T; Kupper, M; Lafferty, G D; Landsman, H; Lanske, D; Lellouch, D; Letts, J; Levinson, L; Lillich, J; Lloyd, S L; Loebinger, F K; Lü, J; Ludwig, A; Ludwig, J; Mader, W; Marcellini, S; Martin, A J; Mashimo, T; Mättig, P; McKenna, J; McPherson, R A; Meijers, F; Menges, W; Merritt, F S; Mes, H; Meyer, N; Michelini, A; Mihara, S; Mikenberg, G; Miller, D J; Mohr, W; Mori, T; Mutter, A; Nagai, K; Nakamura, I; Nanjo, H; Neal, H A; O'Neale, S W; Oh, A; Oreglia, M J; Orito, S; Pahl, C; Pásztor, G; Pater, J R; Pilcher, J E; Pinfold, J L; Plane, D E; Pooth, O; Przybycien, M; Quadt, A; Rabbertz, K; Rembser, C; Renkel, P; Roney, J M; Rossi, A M; Rozen, Y; Runge, K; Sachs, K; Saeki, T; Sarkisyan-Grinbaum, E; Schaile, A D; Schaile, O; Scharff-Hansen, P; Schiecks, J; Schörner-Sadenius, T; Schröder, M; Schumacher, M; Seuster, R; Shears, T G; Shen, B C; Sherwood, P; Skuja, A; Smith, A M; Sobie, R J; Söldner-Rembold, S; Spanó, F; Stahl, A; Strom, D; Ströhmer, R; Tarem, S; Tasevsky, M; Teuscher, R; Thomson, M A; Torrence, E; Toya, D; Trigger, I; Trócsányi, Z L; Tsur, E; Turner-Watson, M F; Ueda, I; Ujvári, B; Vollmer, C F; Vannerem, P; Vertesi, R; Verzocchi, M; Voss, H; Vossebeld, J; Ward, C P; Ward, D R; Watkins, P M; Watson, A T; Watson, N K; Wells, P S; Wengler, T; Wermes, N; Wilson, G W; Wilson, J A; Wolf, G; Wyatt, T R; Yamashita, S; Zer-Zion, D; Zivkovic, L

    2008-01-01

    Hadronic final states with a hard isolated photon are studied using data taken at centre-of-mass energies around the mass of the Z0 boson with the OPAL detector at LEP. The strong coupling alpha S is extracted by comparing data and QCD predictions for event shape observables at average reduced centre-of-mass energies ranging from 24 GeV to 78 GeV, and the energy dependence of alpha S is studied. Our results are consistent with the running of alpha S as predicted by QCD and show that within the uncertainties of our analysis event shapes in hadronic Z0 decays with hard and isolated photon radiation can be described by QCD at reduced centre-of-mass energies. Combining all values from different event shape observables and energies gives alpha S (Mz)=0.1182 pm 0.0015(stat.) pm 0.0101(syst.).

  10. What Powers Lyman alpha Blobs?

    OpenAIRE

    Ao, Y.; Matsuda, Y.; Beelen, A.; Henkel, C.; Cen, R.; De Breuck, C.; Francis, P.; Kovacs, A.; Lagache, G.; Lehnert, M.; Mao, M.; Menten, K. M.; Norris, R.; Omont, A.; Tatemastu, K.

    2015-01-01

    Lyman alpha blobs (LABs) are spatially extended lyman alpha nebulae seen at high redshift. The origin of Lyman alpha emission in the LABs is still unclear and under debate. To study their heating mechanism(s), we present Australia Telescope Compact Array (ATCA) observations of the 20 cm radio emission and Herschel PACS and SPIRE measurements of the far-infrared (FIR) emission towards the four LABs in the protocluster J2143-4423 at z=2.38. Among the four LABs, B6 and B7 are detected in the rad...

  11. Alpha heating in toroidal devices

    Energy Technology Data Exchange (ETDEWEB)

    Miley, G.H.

    1978-01-01

    Ignition (or near-ignition) by alpha heating is a key objective for the achievement of economic fusion reactors. While good confinement of high-energy alphas appears possible in larger reactors, near-term tokamak-type ignition experiments as well as some concepts for small reactors (e.g., the Field-Reversed Mirror or FRM) potentially face marginal situations. Consequently, there is a strong motivation to develop methods to evaluate alpha losses and heating profiles in some detail. Such studies for a TFTR-size tokamak and for a small FRM are described here.

  12. Classification of alpha 1-adrenoceptor subtypes

    NARCIS (Netherlands)

    Michel, M. C.; Kenny, B.; Schwinn, D. A.

    1995-01-01

    Two alpha 1-adrenoceptor subtypes (alpha 1A and alpha 1B) have been detected in various tissues by pharmacological techniques, and three distinct cDNAs encoding alpha 1-adrenoceptor subtypes have been cloned. The profile of an increasing number of subtype-selective compounds at cloned and endogenous

  13. Triplication of alpha-globin genes is responsible for unusual alpha 113Leu/alpha 113His-globin chain ratios in sheep.

    Science.gov (United States)

    Vestri, R; Masina, P; Rando, A; Testa, A; Di Gregorio, P

    1987-10-01

    By investigations at the DNA and protein level, it has been shown that in sheep a previously detected, presumed quantitative allele of the II alpha 113His gene, displaying a reduced efficiency (called the II alpha 113His decreases gene), is carried by a chromosome bearing three alpha-globin loci. In particular, five sheep having an alpha 113Leu/alpha 113His-chain ratio of about 13:1 (13:1 phenotype) possessed the -I alpha 113Leu-II alpha 113Leu-/-I alpha 113Leu-II alpha 113Leu-III alpha 113His decreases genotype. One sheep showing a alpha 113Leu/alpha 113His-chain ratio of about 3:1 (3:1 phenotype) had the -I alpha 113Leu-II alpha 113His-/-I alpha 113Leu-II alpha 113Leu-III alpha 113His decreases genotype, while one sheep having a chain ratio of about 6:1 (6:1 phenotype) carried the -I alpha 113Leu-II alpha 113Leu-II alpha 113His decreases-/-I alpha 113Leu-II alpha 113Leu-III alpha 113His decreases genotype. Nineteen sheep, displaying the common phenotypes, all possessed the alpha alpha/alpha alpha gene arrangement. Furthermore, the possible location of the gene with reduced efficiency and the expression of the three genes in the triple alpha-globin loci chromosome are discussed.

  14. Contribution to the study of the alpha-alpha interaction

    International Nuclear Information System (INIS)

    Darriulat, Pierre

    1965-01-01

    The new variable energy cyclotron at Berkeley that can accelerate an alpha beam up to an energy of 130 MeV and the mass production of lithium diffused junctions have enabled us to perform 2 series of measurement, in the first one we use alpha beams with an energy ranging between 50 and 120 MeV to study alpha-alpha forces in the second one we use the flexibility of the variable energy cyclotron the resonances around 40 MeV, region that can not yet be reached by tandem accelerators. This work is divided into 6 chapters. The first chapter is dedicated to the formalism of partial wave analysis and the theory of the compound nucleus. In the second chapter the author presents the 88 cyclotron at Berkeley and the diffusion chamber, the alpha detectors are lithium diffused junctions made of silicon. The third chapter deals with the experimental methods used and the issue of the reduction of the volume of data. In the fourth chapter the results obtained in the upper part of the energy range are described in terms of complex shifts that allow the description of the α-α interaction at high energy. The very low impact parameter has enabled us to find 2 new components (l=6 and l=8) of the rotational spectrum and to define a more accurate phenomenological potential. The fifth chapter is dedicated to the narrow resonances we have found between 12 and 27 MeV. We present in the last chapter a calculation of the binding energy of C 12 in which we have considered the 12 C nucleus as formed by 3 alpha particles interacting with each other through the phenomenological potential defined above

  15. Workshop on Precision Measurements of $\\alpha_s$

    Energy Technology Data Exchange (ETDEWEB)

    Bethke, Siegfried; /Munich, Max Planck Inst.; Hoang, Andre H.; /Vienna U.; Kluth, Stefan; /Munich, Max Planck Inst.; Schieck, Jochen; /Munich U.; Stewart, Iain W.; Aoki, S.; Beneke, M.; Bethke, S.; Blumlein, J.; Brambilla, N.; Brodsky, S.; /MIT, LNS

    2011-10-01

    These are the proceedings of the Workshop on Precision Measurements of {alpha}{sub s} held at the Max-Planck-Institute for Physics, Munich, February 9-11, 2011. The workshop explored in depth the determination of {alpha}{sub s}(m{sub Z}) in the {ovr MS} scheme from the key categories where high precision measurements are currently being made, including DIS and global PDF fits, {tau}-decays, electro-weak precision observables and Z-decays, event-shapes, and lattice QCD. These proceedings contain a short summary contribution from the speakers, as well as the lists of authors, conveners, participants, and talks.

  16. Conditioning of alpha bearing wastes

    International Nuclear Information System (INIS)

    1991-01-01

    Alpha bearing wastes are generated during the reprocessing of spent fuel, mixed oxide fuel fabrication, decommissioning and other activities. The safe and effective management of these wastes is of particular importance owing to the radiotoxicity and long lived characteristics of certain transuranic (TRU) elements. The management of alpha bearing wastes involves a number of stages which include collection, characterization, segregation, treatment, conditioning, transport, storage and disposal. This report describes the currently available matrices and technologies for the conditioning of alpha wastes and relates them to their compatibility with the other stages of the waste management process. The selection of a specific immobilization process is dependent on the waste treatment state and the subsequent handling, transport, storage and disposal requirements. The overall objectives of immobilization are similar for all waste producers and processors, which are to produce: (a) Waste forms with sufficient mechanical, physical and chemical stability to satisfy all stages of handling, transport and storage (referred to as the short term requirements), and (b) Waste forms which will satisfy disposal requirements and inhibit the release of radionuclides to the biosphere (referred to as the long term requirements). Cement and bitumen processes have already been successfully applied to alpha waste conditioning on the industrial scale in many of the IAEA Member States. Cement systems based on BFS and pozzolanic cements have emerged as the principal encapsulation matrices for the full range of alpha bearing wastes. Alternative technologies, such as polymers and ceramics, are being developed for specific waste streams but are unlikely to meet widespread application owing to cost and process complexity. The merits of alpha waste conditioning are improved performance in transport, storage and disposal combined with enhanced public perception of waste management operations. These

  17. Improved Alpha Testing Using Hashed Sampling.

    Science.gov (United States)

    Wyman, Chris; McGuire, Morgan

    2017-08-14

    We further describe and analyze the idea of hashed alpha testing from Wyman and McGuire [1], which builds on stochastic alpha testing and simplifies stochastic transparency. Typically, alpha testing provides a simple mechanism to mask out complex silhouettes using simple proxy geometry with applied alpha textures. While widely used, alpha testing has a long-standing problem: geometry can disappear entirely as alpha mapped polygons recede with distance. As foveated rendering for virtual reality spreads, this problem worsens as peripheral minification and prefiltering introduce this problem on nearby objects.

  18. ALPHA,·ANTITRYPSIN DEFICIENCY*

    African Journals Online (AJOL)

    1971-02-06

    Feb 6, 1971 ... Lieberman," in fact, found that 15·2% of 66 patients hospitalized with pulmonary emphysema had heterozygous alpha,-antitrypsin deficiency. The over-all incidence of the deficiency was 25'8% in this group. Of patients under the age of 50 years, 47·8% had deficient levels. If such observations are confirmed ...

  19. Alpha sources deposit by sublimation

    International Nuclear Information System (INIS)

    Amoudry, F.; Eloy, J.F.

    1983-09-01

    We studied and realized a device able to perform some very thin substracts used for alpha spectrometry measurements. Sources are prepared by sublimation of the sample in a vacuum container. The energy required for this sublimation is furnished by a laser beam [fr

  20. The effect of a metalloproteinase inhibitor (GI5402) on tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha receptors during human endotoxemia

    NARCIS (Netherlands)

    Dekkers, P. E.; Lauw, F. N.; ten Hove, T.; te Velde, A. A.; Lumley, P.; Becherer, D.; van Deventer, S. J.; van der Poll, T.

    1999-01-01

    Tumor necrosis factor-alpha (TNF-alpha) is released from the cell surface by cleavage of pro-TNF-alpha by metalloproteinases (MPs). In cell cultures, inhibition of MPs has been found not only to reduce the release of TNF-alpha, but also to enhance the surface expression of TNF-alpha and TNF-alpha

  1. Calibration of sources for alpha spectroscopy systems

    International Nuclear Information System (INIS)

    Freitas, I.S.M.; Goncalez, O.L.

    1992-01-01

    This paper describes the calibration methodology for measuring the total alpha activity of plane and thin sources with the Alpha Spectrometer for Silicon Detector in the Nuclear Measures and Dosimetry laboratory at IEAv/CTA. (author)

  2. 42 CFR 493.927 - General immunology.

    Science.gov (United States)

    2010-10-01

    ... evaluated include: Analyte or Test Procedure Alpha-l antitrypsin Alpha-fetoprotein (tumor marker... Criteria for acceptable performance Alpha-1 antitrypsin Target value ±3 SD. Alpha-fetoprotein (tumor marker... Hepatitis markers (HBsAg, anti-HBc, HBeAg) IgA IgG IgE IgM Infectious mononucleosis Rheumatoid factor...

  3. Enzyme replacement therapy for alpha-mannosidosis

    DEFF Research Database (Denmark)

    Borgwardt, Line Gutte; Dali, Christine I.; Fogh, J

    2013-01-01

    Alpha-mannosidosis (OMIM 248500) is a rare lysosomal storage disease (LSD) caused by alpha-mannosidase deficiency. Manifestations include intellectual disabilities, facial characteristics and hearing impairment. A recombinant human alpha-mannosidase (rhLAMAN) has been developed for weekly intrave...... intravenous enzyme replacement therapy (ERT). We present the preliminary data after 12 months of treatment....

  4. THE ALPHA/BETA-HYDROLASE FOLD

    NARCIS (Netherlands)

    OLLIS, DL; CHEAH, E; CYGLER, M; FROLOW, F; FRANKEN, SM; HAREL, M; REMINGTON, SJ; SILMAN, [No Value; SCHRAG, J; SUSSMAN, JL; VERSCHUEREN, KHG; GOLDMAN, A

    We have identified a new protein fold-the alpha/beta-hydrolase fold-that is common to several hydrolytic enzymes of widely differing phylogenetic origin and catalytic function. The core of each enzyme is similar: an alpha/beta-sheet, not barrel, of eight beta-sheets connected by alpha-helices. These

  5. Nature of the pygmy dipole resonance in Ce-140 studied in (alpha, alpha 'gamma) experiments

    NARCIS (Netherlands)

    Savran, D.; Babilon, M.; van den Berg, A.M.; Harakeh, M.N.; Hasper, J.; Matic, A.; Wörtche, H.J.; Zilges, A.

    2006-01-01

    A concentration of electric-dipole excitations below the particle threshold, which is frequently denoted as the pygmy dipole resonance, has been studied in the semimagic nucleus Ce-140 in (alpha, alpha(')gamma) experiments at E-alpha=136 MeV. The technique of alpha-gamma coincidence experiments

  6. Alternative splicing of T cell receptor (TCR) alpha chain transcripts containing V alpha 1 or V alpha 14 elements.

    Science.gov (United States)

    Mahotka, C; Hansen-Hagge, T E; Bartram, C R

    1995-10-01

    Human acute lymphoblastic leukemia cell lines represent valuable tools to investigate distinct steps of the complex regulatory pathways underlying T cell receptor recombination and expression. A case in point are V delta 2D delta 3 and subsequent V delta 2D delta 3J alpha rearrangements observed in human leukemic pre-B cells as well as in normal lymphopoiesis. The functional expression of these unusual (VD) delta (JC) alpha hybrids is almost exclusively prevented by alternative splicing events. In this report we show that alternative splicing at cryptic splice donor sites within V elements is not a unique feature of hybrid TCR delta/alpha transcripts. Among seven V alpha families analyzed by RT-PCR, alternatively spliced products were observed in TCR alpha recombinations containing V alpha 1 or V alpha 14 elements. In contrast to normal peripheral blood cells and thymocytes, the leukemia cell line JM expressing functional V alpha 1J alpha 3C alpha transcripts lacked evidence of aberrant TCR alpha RNA species.

  7. Alpha particles detection in nitrocellulose

    International Nuclear Information System (INIS)

    Romero C, M.

    1976-01-01

    The method for the manufacturing of the detection films follows these steps: preparation of the mass which includes nitrocellulose in the form of cotton as raw material ethyl acetate, cellosolve acetate, isopropyl and butyl alcohols as solvents and dioctyl phtalate as plasticiser; dilution of the paste; pouring of the diluted mass; and drying of the detection films. The results obtained experimentally are: The determination of the development times of the different thicknesses of the manufactured films. Response linearity of the detectors, variation of the number of tracks according to the distance of the source to the detector. Sizes of the diameter of the tracks depending of the distance detector-alpha emmission source. As a conclusion we can say the the nitrocellulose detectors are specific for alpha radiation; the more effective thicknesses in uranium prospecting works were those of 60 microns, since for the laboratory works the thicknesses of 30 to 40 microns were the ideal; the development technique of the detection films is simple and cheap and can be realized even in another place than the laboratory; this way of the manufacturing of nitrocellulose detection film sensitive to alpha nuclear radiation is open to future research. (author)

  8. Measurement and analysis of $\\alpha$ particle induced reactions on yttrium

    CERN Document Server

    Singh, N L; Chintalapudi, S N

    2000-01-01

    Excitation functions for /sup 89/Y[( alpha ,3n); ( alpha ,4n); ( alpha , p3n); ( alpha , alpha n); ( alpha , alpha 2n)] reactions were measured up to 50 MeV using stacked foil activation technique and HPGe gamma ray spectroscopy method. The experimental data were compared with calculations considering equilibrium as well as preequilibrium reactions according to the hybrid model of Blann (ALICE/90). For ( alpha , xnyp) type of reactions, the precompound contributions are described by the model. There seems to be indications of direct inelastic scattering effects in ( alpha , alpha xn) type of reactions. To the best of our knowledge, the excitation functions for ( alpha ,4n), ( alpha , p3n), ( alpha , alpha n) and ( alpha , alpha 2n) reactions were measured for the first time. (23 refs).

  9. Measurement and analysis of alpha particle induced reactions on yttrium

    Energy Technology Data Exchange (ETDEWEB)

    Singh, N.L.; Gadkari, M.S. [Baroda Univ. (India). Dept. of Physics; Chintalapudi, S.N. [IUC-DAEF Calcutta Centre, Calcutta (India)

    2000-05-01

    Excitation functions for {sup 89}Y[({alpha},3n);({alpha},4n);({alpha},p3n);({alpha},{alpha}n);({alpha},{alpha}2n)] reactions were measured up to 50 MeV using stacked foil activation technique and HPGe gamma ray spectroscopy method. The experimental data were compared with calculations considering equilibrium as well as preequilibrium reactions according to the hybrid model of Blann (ALICE/90). For ({alpha},xnyp) type of reactions, the precompound contributions are described by the model. There seems to be indications of direct inelastic scattering effects in ({alpha},{alpha}xn) type of reactions. To the best of our knowledge, the excitation functions for ({alpha},4n), ({alpha},p3n), ({alpha},{alpha}n) and ({alpha},{alpha}2n) reactions were measured for the first time. (orig.)

  10. Interferon Alpha in Systemic Lupus Erythematosus

    Directory of Open Access Journals (Sweden)

    Timothy B. Niewold

    2010-01-01

    Full Text Available The pleiotropic cytokine interferon alpha is involved in multiple aspects of lupus etiology and pathogenesis. Interferon alpha is important under normal circumstances for antiviral responses and immune activation. However, heightened levels of serum interferon alpha and expression of interferon response genes are common in lupus patients. Lupus-associated autoantibodies can drive the production of interferon alpha and heightened levels of interferon interfere with immune regulation. Several genes in the pathways leading to interferon production or signaling are associated with risk for lupus. Clinical and cellular manifestations of excess interferon alpha in lupus combined with the genetic risk factors associated with interferon make this cytokine a rare bridge between genetic risk and phenotypic effects. Interferon alpha influences the clinical picture of lupus and may represent a therapeutic target. This paper provides an overview of the cellular, genetic, and clinical aspects of interferon alpha in lupus.

  11. Novel alpha-mannosidase inhibitors; Nye alfa-mannosidaseinhibitorer

    Energy Technology Data Exchange (ETDEWEB)

    Farr, R.A.; Kang, M.S.; Peet, N.P.; Sunkara, S.P.

    1997-05-20

    [4S-(4{alpha}, 4a{beta}, 6{alpha}, 7{alpha}, 7a{alpha})]-Octahydro-1H-1-pyridine-4,5,6,7-tetrols and [4R-(4{alpha}, 4a{alpha}, 5{alpha}, 6{beta}, 7{beta}, 7a{beta})]-octahydro-1H-1-pyridine-4,5,6,7-tetrols are useful inhibitors of alpha-mannosidase and are useful immunostimulants, chemoprotective and radioprotective agents and antimetastatic agents.

  12. Activator protein 2alpha mediates parathyroid TGF-alpha self-induction in secondary hyperparathyroidism.

    Science.gov (United States)

    Arcidiacono, Maria Vittoria; Cozzolino, Mario; Spiegel, Noah; Tokumoto, Masanori; Yang, Jing; Lu, Yan; Sato, Tetsuhiko; Lomonte, Carlo; Basile, Carlo; Slatopolsky, Eduardo; Dusso, Adriana S

    2008-10-01

    In secondary hyperparathyroidism, enhanced expression of TGF-alpha in the parathyroid leads to its own upregulation, generating a feed-forward loop for TGF-alpha activation of its receptor, EGFR receptor (EGFR), which promotes parathyroid hyperplasia. These studies examined the role of activator protein 2alpha (AP2), an inducer of TGF-alpha gene transcription, in the upregulation of parathyroid TGF-alpha in secondary hyperparathyroidism. In rat and human secondary hyperparathyroidism, parathyroid AP2 expression strongly correlated with TGF-alpha levels and with the rate of parathyroid growth, as expected. Furthermore, the increases in rat parathyroid content of AP2 and its binding to a consensus AP2 DNA sequence preceded the increase in TGF-alpha induced by high dietary phosphate. More significant, in A431 cells, which provide a model of enhanced TGF-alpha and TGF-alpha self-induction, mutating the core AP2 site of the human TGF-alpha promoter markedly impaired promoter activity induced by endogenous or exogenous TGF-alpha. Important for therapy, in five-sixths nephrectomized rats fed high-phosphate diets, inhibition of parathyroid TGF-alpha self-induction using erlotinib, a highly specific inhibitor of TGF-alpha/EGFR-driven signals, reduced AP2 expression dosage dependently. This suggests that the increases in parathyroid AP2 occur downstream of EGFR activation by TGF-alpha and are required for TGF-alpha self-induction. Indeed, in A431 cells, erlotinib inhibition of TGF-alpha self-induction caused parallel reductions in AP2 expression and nuclear localization, as well as TGF-alpha mRNA and protein levels. In summary, increased AP2 expression and transcriptional activity at the TGF-alpha promoter determine the severity of the hyperplasia driven by parathyroid TGF-alpha self-upregulation in secondary hyperparathyroidism.

  13. Alpha particle studies during JET DT experiments

    International Nuclear Information System (INIS)

    1999-01-01

    The 1997 DT experiment (DTE1) at the Joint European Torus included studies of the behaviour of alpha particles in high temperature plasmas. Clear alpha particle heating was observed in a series of otherwise similar 10MW hot-ion H-modes by scanning the DT mixture from 0%T to 93%T. Maxima in central temperature and energy content were obtained which corresponded with the maximum in fusion yield. Alfven Eigenmodes (AEs) have been detected in JET, driven by NBI or ICRH fast ions. However, in agreement with theory, no AE activity was observed in DT plasmas which could be attributed to alpha particle drive, except in the afterglow of some Optimised Shear pulses. Ion Cyclotron Emission (ICE) was detected at harmonics of the alpha particle cyclotron frequency at the outer edge of the plasma. The ICE is interpreted as being close to magnetoacoustic cyclotron instability, driven by inverted alpha distributions at the plasma edge. The high-energy neutral particle spectra showed features, which are ascribed to a mixture of alphas, neutralised by helium-like impurities, and deuterons, born from elastic collisions with alpha particles and neutralised by hydrogen-like impurities. The results of all these studies are consistent with classical alpha particle trapping and slowing-down. Future DT experiments will aim to increase alpha particle pressure, so interactions with plasma instabilities can be studied. The measurement of knock-on neutral triton spectra offers a clean way to determine confined alpha densities in these future experiments. (author)

  14. Alpha particle studies during JET DT experiments

    International Nuclear Information System (INIS)

    2001-01-01

    The 1997 DT experiment (DTE1) at the Joint European Torus included studies of the behaviour of alpha particles in high temperature plasmas. Clear alpha particle heating was observed in a series of otherwise similar 10MW hot-ion H-modes by scanning the DT mixture from 0%T to 93%T. Maxima in central temperature and energy content were obtained which corresponded with the maximum in fusion yield. Alfven Eigenmodes (AEs) have been detected in JET, driven by NBI or ICRH fast ions. However, in agreement with theory, no AE activity was observed in DT plasmas which could be attributed to alpha particle drive, except in the afterglow of some Optimised Shear pulses. Ion Cyclotron Emission (ICE) was detected at harmonics of the alpha particle cyclotron frequency at the outer edge of the plasma. The ICE is interpreted as being close to magnetoacoustic cyclotron instability, driven by inverted alpha distributions at the plasma edge. The high-energy neutral particle spectra showed features, which are ascribed to a mixture of alphas, neutralised by helium-like impurities, and deuterons, born from elastic collisions with alpha particles and neutralised by hydrogen-like impurities. The results of all these studies are consistent with classical alpha particle trapping and slowing-down. Future DT experiments will aim to increase alpha particle pressure, so interactions with plasma instabilities can be studied. The measurement of knock-on neutral triton spectra offers a clean way to determine confined alpha densities in these future experiments. (author)

  15. The Alpha Magnetic Spectrometer (AMS)

    CERN Document Server

    Alcaraz, J; Ambrosi, G; Anderhub, H; Ao, L; Arefev, A; Azzarello, P; Babucci, E; Baldini, L; Basile, M; Barancourt, D; Barão, F; Barbier, G; Barreira, G; Battiston, R; Becker, R; Becker, U; Bellagamba, L; Bene, P; Berdugo, J; Berges, P; Bertucci, B; Biland, A; Bizzaglia, S; Blasko, S; Bölla, G; Boschini, M; Bourquin, Maurice; Brocco, L; Bruni, G; Buénerd, M; Burger, J D; Burger, W J; Cai, X D; Camps, C; Cannarsa, P; Capell, M; Casadei, D; Casaus, J; Castellini, G; Cecchi, C; Chang, Y H; Chen, H F; Chen, H S; Chen, Z G; Chernoplekov, N A; Tzi Hong Chiueh; Chuang, Y L; Cindolo, F; Commichau, V; Contin, A; Crespo, P; Cristinziani, M; Cunha, J P D; Dai, T S; Deus, J D; Dinu, N; Djambazov, L; Dantone, I; Dong, Z R; Emonet, P; Engelberg, J; Eppling, F J; Eronen, T; Esposito, G; Extermann, P; Favier, Jean; Fiandrini, E; Fisher, P H; Flügge, G; Fouque, N; Galaktionov, Yu; Gervasi, M; Giusti, P; Grandi, D; Grimm, O; Gu, W Q; Hangarter, K; Hasan, A; Hermel, V; Hofer, H; Huang, M A; Hungerford, W; Ionica, M; Ionica, R; Jongmanns, M; Karlamaa, K; Karpinski, W; Kenney, G; Kenny, J; Kim, W; Klimentov, A; Kossakowski, R; Koutsenko, V F; Kraeber, M; Laborie, G; Laitinen, T; Lamanna, G; Laurenti, G; Lebedev, A; Lee, S C; Levi, G; Levchenko, P M; Liu, C L; Liu, H T; Lopes, I; Lu, G; Lü, Y S; Lübelsmeyer, K; Luckey, D; Lustermann, W; Maña, C; Margotti, A; Mayet, F; McNeil, R R; Meillon, B; Menichelli, M; Mihul, A; Mourao, A; Mujunen, A; Palmonari, F; Papi, A; Park, I H; Pauluzzi, M; Pauss, Felicitas; Perrin, E; Pesci, A; Pevsner, A; Pimenta, M; Plyaskin, V; Pozhidaev, V; Postolache, V; Produit, N; Rancoita, P G; Rapin, D; Raupach, F; Ren, D; Ren, Z; Ribordy, M; Richeux, J P; Riihonen, E; Ritakari, J; Röser, U; Roissin, C; Sagdeev, R; Sartorelli, G; Schwering, G; Scolieri, G; Seo, E S; Shoutko, V; Shoumilov, E; Siedling, R; Son, D; Song, T; Steuer, M; Sun, G S; Suter, H; Tang, X W; Ting, Samuel C C; Ting, S M; Tornikoski, M; Torsti, J; Ulbricht, J; Urpo, S; Usoskin, I; Valtonen, E; Vandenhirtz, J; Velcea, F; Velikhov, E P; Verlaat, B; Vetlitskii, I; Vezzu, F; Vialle, J P; Viertel, Gert M; Vitè, Davide F; Gunten, H V; Wallraff, W; Wang, B C; Wang, J Z; Wang, Y H; Wiik, K; Williams, C; Wu, S X; Xia, P C; Yan, J L; Yan, L G; Yang, C G; Yang, M; Ye, S W; Yeh, P; Xu, Z Z; Zhang, H Y; Zhang, Z P; Zhao, D X; Zhu, G Y; Zhu, W Z; Zhuang, H L; Zichichi, A; Zimmermann, B

    2002-01-01

    The Alpha Magnetic Spectrometer (AMS) is a large acceptance (0.65 sr m sup 2) detector designed to operate in the International Space Station (ISS) for three years. The purposes of the experiment are to search for cosmic antimatter and dark matter and to study the composition and energy spectrum of the primary cosmic rays. A 'scaled-down' version has been flown on the Space Shuttle Discovery for 10 days in June 1998. The complete AMS is programmed for installation on the ISS in October 2003 for an operational period of 3 yr. This contribution reports on the experimental configuration that will be installed on the ISS.

  16. Targeted alpha therapy for cancer

    Energy Technology Data Exchange (ETDEWEB)

    Allen, Barry J [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Raja, Chand [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Rizvi, Syed [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Li Yong [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Tsui, Wendy [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Zhang, David [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Song, Emma [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Qu, C F [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Kearsley, John [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Graham, Peter [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Thompson, John [Sydney Melanoma Unit, Royal Prince Alfred Hospital, Camperdown 2050 NSW (Australia)

    2004-08-21

    Targeted alpha therapy (TAT) offers the potential to inhibit the growth of micrometastases by selectively killing isolated and preangiogenic clusters of cancer cells. The practicality and efficacy of TAT is tested by in vitro and in vivo studies in melanoma, leukaemia, colorectal, breast and prostate cancers, and by a phase 1 trial of intralesional TAT for melanoma. The alpha-emitting radioisotope used is Bi-213, which is eluted from the Ac-225 generator and chelated to a cancer specific monoclonal antibody (mab) or protein (e.g. plasminogen activator inhibitor-2 PAI2) to form the alpha-conjugate (AC). Stable alpha-ACs have been produced which have been tested for specificity and cytotoxicity in vitro against melanoma (9.2.27 mab), leukaemia (WM60), colorectal (C30.6), breast (PAI2, herceptin), ovarian (PAI2, herceptin, C595), prostate (PAI2, J591) and pancreatic (PAI2, C595) cancers. Subcutaneous inoculation of 1-1.5 million human cancer cells into the flanks of nude mice causes tumours to grow in all mice. Tumour growth is compared for untreated controls, nonspecific AC and specific AC, for local (subcutaneous) and systemic (tail vein or intraperitoneal) injection models. The {sup 213}Bi-9.2.27 AC is injected into secondary skin melanomas in stage 4 patients in a dose escalation study to determine the effective tolerance dose, and to measure kinematics to obtain the equivalent dose to organs. In vitro studies show that TAT is one to two orders of magnitude more cytotoxic to targeted cells than non-specific ACs, specific beta emitting conjugates or free isotopes. In vivo local TAT at 2 days post-inoculation completely prevents tumour formation for all cancers tested so far. Intra-lesional TAT can completely regress advanced sc melanoma but is less successful for breast and prostate cancers. Systemic TAT inhibits the growth of sc melanoma xenografts and gives almost complete control of breast and prostate cancer tumour growth. Intralesional doses up to 450 {mu

  17. The Alpha Magnetic Spectrometer (ams)

    Science.gov (United States)

    Ionica, Maria

    2004-01-01

    The Alpha Magnetic Spectrometer (AMS), once installed on the International Space Station will provide precise measurements of the cosmic ray spectra up to TeV energy range, and will search for cosmological antimatter and missing matter. A prototype version of the detector was operated successfully on the space shuttle Discovery in June 1998 (STS-91). Here we briefly report on the design of the AMS apparatus and present the results of the measurements of the fluxes of proton, electron, positron and helium from the STS-91 flight.

  18. Crossing symmetry in Alpha space

    CERN Multimedia

    CERN. Geneva

    2017-01-01

    The conformal bootstrap program aims to catalog all conformal field theories (second-order phase transitions) in D dimensions. Despite its ambitious scope much progress has been made over the past decade, e.g. in computing critical exponents for the 3D O(N) models to high precision. At this stage, analytic methods to explore the CFT landscape are not as well developed. In this talk I will describe a new mathematical framework for the bootstrap known as "alpha space", which reduces crossing symmetry to a set of integral equations. Based on arXiv:1702.08471 (with Balt van Rees) and arXiv:1703.08159.

  19. The Alpha Magnetic Spectrometer (AMS)

    International Nuclear Information System (INIS)

    Alcaraz, J.; Alpat, B.; Ambrosi, G.; Anderhub, H.; Ao, L.; Arefiev, A.; Azzarello, P.; Babucci, E.; Baldini, L.; Basile, M.; Barancourt, D.; Barao, F.; Barbier, G.; Barreira, G.; Battiston, R.; Becker, R.; Becker, U.; Bellagamba, L.; Bene, P.; Berdugo, J.; Berges, P.; Bertucci, B.; Biland, A.; Bizzaglia, S.; Blasko, S.; Boella, G.; Boschini, M.; Bourquin, M.; Brocco, L.; Bruni, G.; Buenerd, M.; Burger, J.D.; Burger, W.J.; Cai, X.D.; Camps, C.; Cannarsa, P.; Capell, M.; Casadei, D.; Casaus, J.; Castellini, G.; Cecchi, C.; Chang, Y.H.; Chen, H.F.; Chen, H.S.; Chen, Z.G.; Chernoplekov, N.A.; Chiueh, T.H.; Chuang, Y.L.; Cindolo, F.; Commichau, V.; Contin, A.; Crespo, P.; Cristinziani, M.; Cunha, J.P. da; Dai, T.S.; Deus, J.D.; Dinu, N.; Djambazov, L.; DAntone, I.; Dong, Z.R.; Emonet, P.; Engelberg, J.; Eppling, F.J.; Eronen, T.; Esposito, G.; Extermann, P.; Favier, J.; Fiandrini, E.; Fisher, P.H.; Fluegge, G.; Fouque, N.; Galaktionov, Yu.; Gervasi, M.; Giusti, P.; Grandi, D.; Grimm, O.; Gu, W.Q.; Hangarter, K.; Hasan, A.; Hermel, V.; Hofer, H.; Huang, M.A.; Hungerford, W.; Ionica, M.; Ionica, R.; Jongmanns, M.; Karlamaa, K.; Karpinski, W.; Kenney, G.; Kenny, J.; Kim, W.; Klimentov, A.; Kossakowski, R.; Koutsenko, V.; Kraeber, M.; Laborie, G.; Laitinen, T.; Lamanna, G.; Laurenti, G.; Lebedev, A.; Lee, S.C.; Levi, G.; Levtchenko, P.; Liu, C.L.; Liu, H.T.; Lopes, I.; Lu, G.; Lu, Y.S.; Luebelsmeyer, K.; Luckey, D.; Lustermann, W.; Mana, C.; Margotti, A.; Mayet, F.; McNeil, R.R.; Meillon, B.; Menichelli, M.; Mihul, A.; Mourao, A.; Mujunen, A.; Palmonari, F.; Papi, A.; Park, I.H.; Pauluzzi, M.; Pauss, F.; Perrin, E.; Pesci, A.; Pevsner, A.; Pimenta, M.; Plyaskin, V.; Pojidaev, V.; Postolache, V.; Produit, N.; Rancoita, P.G.; Rapin, D.; Raupach, F.; Ren, D.; Ren, Z.; Ribordy, M.; Richeux, J.P.; Riihonen, E.; Ritakari, J.; Roeser, U.; Roissin, C.; Sagdeev, R.; Sartorelli, G.; Schultz von Dratzig, A.; Schwering, G.; Scolieri, G.; Seo, E.S.; Shoutko, V.; Shoumilov, E.; Siedling, R.; Son, D.; Song, T.; Steuer, M.; Sun, G.S.; Suter, H.; Tang, X.W.; Ting, S.C.C.Samuel C.C.; Ting, S.M.; Tornikoski, M.; Torsti, J.; Tr umper, J.; Ulbricht, J.; Urpo, S.; Usoskin, I.; Valtonen, E.; Vandenhirtz, J.; Velcea, F.; Velikhov, E.; Verlaat, B.; Vetlitsky, I.; Vezzu, F.; Vialle, J.P.; Viertel, G.; Vite, D.; Gunten, H. Von; Wicki, S.W.S. Waldmeier; Wallraff, W.; Wang, B.C.; Wang, J.Z.; Wang, Y.H.; Wiik, K.; Williams, C.; Wu, S.X.; Xia, P.C.; Yan, J.L.; Yan, L.G.; Yang, C.G.; Yang, M.; Ye, S.W.; Yeh, P.; Xu, Z.Z.; Zhang, H.Y.; Zhang, Z.P.; Zhao, D.X.; Zhu, G.Y.; Zhu, W.Z.; Zhuang, H.L.; Zichichi, A.; Zimmermann, B.

    2002-01-01

    The Alpha Magnetic Spectrometer (AMS) is a large acceptance (0.65 sr m 2 ) detector designed to operate in the International Space Station (ISS) for three years. The purposes of the experiment are to search for cosmic antimatter and dark matter and to study the composition and energy spectrum of the primary cosmic rays. A 'scaled-down' version has been flown on the Space Shuttle Discovery for 10 days in June 1998. The complete AMS is programmed for installation on the ISS in October 2003 for an operational period of 3 yr. This contribution reports on the experimental configuration that will be installed on the ISS

  20. Quantum Estimates of Alpha Emitter Life Time

    Directory of Open Access Journals (Sweden)

    B. Santoso

    2006-01-01

    Full Text Available Quantum estimates of several alpha radioactive life time have been made using the probability of quantum tunneling through the nuclear potential barrier. It is assumed that for a given nucleus with mass number A and isotopic number Z, there exists an alpha particle moving freely back and forth in the nucleus with mass and isotopic numbers A -4 and Z-2. If the probability of penetrating the nuclear potential barrier is Τ, then after N times (N=1/Τ hitting the barrier an alpha particle is emitted. To obtain the elapsed time for emitting an alpha particle requires N times τ0, where τ0 is the time travel for alpha across the nuclear diameter, which is dependent on alpha energy. It is assumed here that this kinetic energy is the same as the emitted energy. The emitting alpha kinetic energies here are calculated by the difference of the masses of the parent and daughter nuclei and the alpha particles. They are in closed agreement with the experimental observations. While the alpha radioactive life time are not the same order of magnitudes but give the same linearity on the logarithmic scale as function of the inverse square root of energy.

  1. Sterically hindered C(alpha, alpha)-disubstituted alpha-amino acids: synthesis from alpha-nitroacetate and incorporation into peptides.

    Science.gov (United States)

    Fu, Y; Hammarström, L G; Miller, T J; Fronczek, F R; McLaughlin, M L; Hammer, R P

    2001-10-19

    The preparation of sterically hindered and polyfunctional C(alpha,alpha)-disubstituted alpha-amino acids (alpha alpha AAs) via alkylation of ethyl nitroacetate and transformation into derivatives ready for incorporation into peptides are described. Treatment of ethyl nitroacetate with N,N-diisopropylethylamine (DIEA) in the presence of a catalytic amount of tetraalkylammonium salt, followed by the addition of an activated alkyl halide or Michael acceptor, gives the doubly C-alkylated product in good to excellent yields. Selective nitro reduction with Zn in acetic acid or hydrogen over Raney Ni gives the corresponding amino ester that, upon saponification, can be protected with the fluorenylmethyloxycarbonyl (Fmoc) group. The first synthesis of an orthogonally protected, tetrafunctional C(alpha,alpha)-disubstituted analogue of aspartic acid, 2,2-bis(tert-butylcarboxymethyl)glycine (Bcmg), is described. Also, the sterically demanding C(alpha,alpha)-dibenzylglycine (Dbg) has been incorporated into a peptide using solid-phase synthesis. It was found that once sterically congested Dbg is at the peptide N-terminus, further chain extension becomes very difficult using uronium or phosphonium salts (PyAOP, PyAOP/HOAt, HATU). However, preformed amino acid symmetrical anhydride couples to N-terminal Dbg in almost quantitative yield in nonpolar solvent (dichloroethane-DMF, 9:1).

  2. Hypothalamic PGC-1 alpha Protects Against High-Fat Diet Exposure by Regulating ER alpha

    NARCIS (Netherlands)

    Morselli, Eugenia; Fuente-Martin, Esther; Finan, Brian; Kim, Min; Frank, Aaron; Garcia-Caceres, Cristina; Navas, Carlos Rodriguez; Gordillo, Ruth; Neinast, Michael; Kalainayakan, Sarada P.; Li, Dan L.; Gao, Yuanqing; Yi, Chun-Xia; Hahner, Lisa; Palmer, Biff F.; Tschöp, Matthias H.; Clegg, Deborah J.

    2014-01-01

    High-fat diets (HFDs) lead to obesity and inflammation in the central nervous system (CNS). Estrogens and estrogen receptor alpha (ER alpha) protect premenopausal females from the metabolic complications of inflammation and obesity-related disease. Here, we demonstrate that hypothalamic PGC-1 alpha

  3. Tumor necrosis factor alpha (TNF alpha) in human skin : A comparison of different antibodies for immunohistochemistry

    NARCIS (Netherlands)

    van der Laan, N; de Leij, LFMH; Buurman, W; Timens, W; ten Duis, HJ

    Conflicting results have been reported regarding the localization and presence of TNF alpha in normal human skin, To study TNF alpha expression, we tested a panel of antibodies directed against human TNF alpha, First, antibodies were tested for immunoreactivity on cytospots of isolated

  4. Study of the pygmy dipole resonance in Mo-94 using the (alpha, alpha ' gamma) coincidence technique

    NARCIS (Netherlands)

    Derya, V.; Endres, J.; Elvers, M.; Harakeh, M. N.; Pietralla, N.; Romig, C.; Savran, D.; Scheck, M.; Siebenhuehner, F.; Stoica, V. I.; Wortche, H. J.; Zilges, A.

    2013-01-01

    The (alpha, alpha' gamma) reaction at E-alpha = 136 MeV was used to study the electric dipole response in the open-shell vibrational nucleus Mo-94 below the neutron-separation threshold. The coincidence experiment has been performed at the Kernfysisch Versneller Instituut in Groningen, The

  5. Psychiatric Symptoms in Alpha-Mannosidosis

    Science.gov (United States)

    Malm, D.; Pantel, J.; Linaker, O. M.

    2005-01-01

    Alpha-mannosidosis is characterized by mild to moderate intellectual disability (ID), moderate to severe neurosensory hearing loss, frequent infections, psychomotor disturbances and skeletal dysmorphism. For the first time, a panel of nine alpha-mannosidosis patients with psychiatric symptoms is presented. The clinical picture has several…

  6. Coefficient Alpha Bootstrap Confidence Interval under Nonnormality

    Science.gov (United States)

    Padilla, Miguel A.; Divers, Jasmin; Newton, Matthew

    2012-01-01

    Three different bootstrap methods for estimating confidence intervals (CIs) for coefficient alpha were investigated. In addition, the bootstrap methods were compared with the most promising coefficient alpha CI estimation methods reported in the literature. The CI methods were assessed through a Monte Carlo simulation utilizing conditions…

  7. Alpha Shape Topology of the Cosmic Web

    NARCIS (Netherlands)

    Weygaert, Rien van de; Platen, Erwin; Vegter, Gert; Eldering, Bob; Kruithof, Nico

    2010-01-01

    We study the topology of the Megaparsec Cosmic Web on the basis of the Alpha Shapes of the galaxy distribution. The simplicial complexes of the alpha shapes are used to determine the set of Betti numbers (βk, k = 1, . . . , D), which represent a complete characterization of the topology of a

  8. Central and peripheral alpha-adrenoceptors

    NARCIS (Netherlands)

    van Zwieten, P A; van Meel, J. C. A.; de Jonge, A; Wilffert, B; Timmermans, P B

    1982-01-01

    The recent interest in the characterization and functional, role of alpha-adrenoceptors has prompted us to study the following different, although interdigitated, lines of research: (a) The functional role of calcium ions in the process of vasoconstriction, induced by alpha 2-adrenoceptor

  9. Producing alpha-olefins using polyketide synthases

    Energy Technology Data Exchange (ETDEWEB)

    Fortman, Jeffrey L.; Katz, Leonard; Steen, Eric J.; Keasling, Jay D.

    2018-01-02

    The present invention provides for a polyketide synthase (PKS) capable of synthesizing an .alpha.-olefin, such as 1-hexene or butadiene. The present invention also provides for a host cell comprising the PKS and when cultured produces the .alpha.-olefin.

  10. Bayesian Meta-Analysis of Coefficient Alpha

    Science.gov (United States)

    Brannick, Michael T.; Zhang, Nanhua

    2013-01-01

    The current paper describes and illustrates a Bayesian approach to the meta-analysis of coefficient alpha. Alpha is the most commonly used estimate of the reliability or consistency (freedom from measurement error) for educational and psychological measures. The conventional approach to meta-analysis uses inverse variance weights to combine…

  11. ALPHA experiment facility and Prof. Jeffrey Hangst.

    CERN Multimedia

    Maximilien Brice

    2010-01-01

    Picture 01-07: General views of the ALPHA experiment Picture 5: Andrea Gutierrez, a PhD student from UBC, transfers liquid helium from a storage dewar into the cryostat containing the superconducting magnetic trap used by the ALPHA experiment.Picture 08-11: Jeffery Hangst, spokesperson for ALPHA Picture 12: The ALPHA silicon detector, which surrounds the trapping resion and is used for imaging antiproton annihilations (Credit University of Liverpool) Picture 13: Untrapped antihydrogen atoms annihilating on the inner surface of the ALPHA trap. These are measured by the ALPHA annihilation detector. The events are concentrated at the electrode radius of about 22.3 mm. The coordinates are defined in the Nature article, Figure 1b. Picture 14: The electrodes (gold) for the ALPHA Penning trap being inserted into the vacuum chamber and cryostat assembly. This is the trap used to combine or "mix" positrons and antiprotons to make antihydrogen. (Credit: Niels Madsen ALPHA/Swansea.) Picture 15: Top, a diagram of the...

  12. A stable lipid-induced aggregate of alpha-synuclein

    NARCIS (Netherlands)

    Drescher, Malte; van Rooijen, Bart D; Veldhuis, Gertjan; Subramaniam, Vinod; Huber, Martina

    2010-01-01

    The Parkinson's disease-related protein alpha-Synuclein (alphaS) is a 140 residue intrinsically disordered protein. Its membrane-binding properties are thought to be relevant for its physiological or pathologic activity. Here, the interaction of alphaS with POPG

  13. Improved peak shape fitting in alpha spectra.

    Science.gov (United States)

    Pommé, S; Caro Marroyo, B

    2015-02-01

    Peak overlap is a recurrent issue in alpha-particle spectrometry, not only in routine analyses but also in the high-resolution spectra from which reference values for alpha emission probabilities are derived. In this work, improved peak shape formulae are presented for the deconvolution of alpha-particle spectra. They have been implemented as fit functions in a spreadsheet application and optimum fit parameters were searched with built-in optimisation routines. Deconvolution results are shown for a few challenging spectra with high statistical precision. The algorithm outperforms the best available routines for high-resolution spectrometry, which may facilitate a more reliable determination of alpha emission probabilities in the future. It is also applicable to alpha spectra with inferior energy resolution. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  14. Technical Basis for the Use of Alpha Absorption Corrections on RCF Gross Alpha Data

    International Nuclear Information System (INIS)

    Ceffalo, G.M.

    1999-01-01

    This document provides the supporting data and rationale for making absorption corrections to gross alpha data to correct alpha data for loss due to absorption in the sample matrix. For some time there has been concern that the gross alpha data produced by the Environmental Restoration Contractor Radiological Counting Facility, particularly gross alpha analysis on soils, has been biased toward low results, as no correction for self-absorption was applied to the counting data. The process was investigated, and a new methodology for alpha self-absorption has been developed

  15. Elimination of alpha-gal xenoreactive epitope: alpha-galactosidase treatment of porcine heart valves.

    Science.gov (United States)

    Choi, Sun-Young; Jeong, Hee-Jin; Lim, Hong-Gook; Park, Seong-Sik; Kim, Soo-Hwan; Kim, Yong Jin

    2012-05-01

    Porcine heart valves are among the most widely used tissue valves in clinical heart valve implantation. However, immunologic responses have been implicated as potential causes of the limited durability of xenograft heart valves. The study aim was to determine the effectiveness of alpha-galactosidase treatment used to degrade the major xenoreactive antigens found in xenograft heart valves. Fresh porcine heart valves and pericardium treated with alpha-galactosidase were studied to evaluate the xenoreactive galactose (alpha1,3) galactose (alpha-gal) antigen. Removal of the alpha-gal epitope from the porcine heart valve was monitored via 3,3'-diaminobenzidine staining intensity, while the removal of alpha-gal from N-glycans on porcine heart valves treated with recombinant alpha-galactosidase was determined either qualitatively or quantitatively by mass fingerprinting using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The porcine pericardium was used for monitoring the change in mechanical properties after alpha-galactosidase treatment. In addition, the biomechanical modification property of collagen fiber rearrangement on tissue was assessed using transmission electron microscopy (TEM). Following a 24-h incubation at pH 7.2, 4 degrees C, employing 0.1 U/ml of Bacteroides thetaiotaomicron-derived recombinant alpha-galactosidase, the enzyme effectively removed the alpha-gal epitopes expressed on porcine heart valves. The identification type of alpha-gal N-glycan on fresh aortic valve, aortic wall, pulmonary valve, and pulmonary wall was 7.1%, 10.3%, 6% and 8%, respectively. In the presence of alpha-galactosidase treatment, alpha-gal-containing N-glycans were converted into alpha-gal-negative N-glycans. Likewise, alpha-gal-containing N-glycans were not detected when MALDI-TOF MS quantitative analysis was used. Furthermore, no significant difference was observed in the mechanical properties and findings from TEM in alpha

  16. Determination of alpha_s using jet cross section parameterizations at hadron colliders

    CERN Document Server

    Stenzel, H

    2001-01-01

    Precise measurements of the single inclusive jet cross section have been performed by the TEVATRON experiments and will be provided by the LHC experiments extending to larger values of transverse energy. Theoretical predictions of this observable at NLO in perturbative QCD depend both on the PDF parameterization set and on the value of the strong coupling constant alpha_s. In this paper the dependence of the jet cross section on alpha_s is investigated. A method is presented to extract alpha_s(E_T) from a cross section measurement based on a parameterization of the alpha_s dependence. Systematic uncertainties and the E_T-range of applicability are discussed. A comparative study is performed between the case of ppbar at sqrt{s}=1.8 TeV (TEVATRON) and pp scattering at sqrt{s}=14 TeV (LHC).

  17. Alpha1 and Alpha2 Integrins Mediate Invasive Activity of Mouse Mammary Carcinoma Cells through Regulation of Stromelysin-1 Expression

    Energy Technology Data Exchange (ETDEWEB)

    Lochter, Andre; Navre, Marc; Werb, Zena; Bissell, Mina J

    1998-06-29

    Tumor cell invasion relies on cell migration and extracellular matrix proteolysis. We investigated the contribution of different integrins to the invasive activity of mouse mammary carcinoma cells. Antibodies against integrin subunits {alpha}6 and {beta}1, but not against {alpha}1 and {alpha}2, inhibited cell locomotion on a reconstituted basement membrane in two-dimensional cell migration assays, whereas antibodies against {beta}1, but not against a6 or {alpha}2, interfered with cell adhesion to basement membrane constituents. Blocking antibodies against {alpha}1 integrins impaired only cell adhesion to type IV collagen. Antibodies against {alpha}1, {alpha}2, {alpha}6, and {beta}1, but not {alpha}5, integrin subunits reduced invasion of a reconstituted basement membrane. Integrins {alpha}1 and {alpha}2, which contributed only marginally to motility and adhesion, regulated proteinase production. Antibodies against {alpha}1 and {alpha}2, but not {alpha}6 and {beta}1, integrin subunits inhibited both transcription and protein expression of the matrix metalloproteinase stromelysin-1. Inhibition of tumor cell invasion by antibodies against {alpha}1 and {alpha}2 was reversed by addition of recombinant stromelysin-1. In contrast, stromelysin-1 could not rescue invasion inhibited by anti-{alpha}6 antibodies. Our data indicate that {alpha}1 and {alpha}2 integrins confer invasive behavior by regulating stromelysin-1 expression, whereas {alpha}6 integrins regulate cell motility. These results provide new insights into the specific functions of integrins during tumor cell invasion.

  18. Mapping High-Velocity H-alpha and Lyman-alpha Emission from Supernova 1987A

    Science.gov (United States)

    France, Kevin; McCray, Richard; Fransson, Claes; Larsson, Josefin; Frank, Kari A.; Burrows, David N.; Challis, Peter; Kirshner, Robert P.; Chevalier, Roger A.; Garnavich, Peter; hide

    2015-01-01

    We present new Hubble Space Telescope images of high-velocity H-alpha and Lyman-alpha emission in the outer debris of SN 1987A. The H-alpha images are dominated by emission from hydrogen atoms crossing the reverse shock. For the first time we observe emission from the reverse shock surface well above and below the equatorial ring, suggesting a bipolar or conical structure perpendicular to the ring plane. Using the H-alpha imaging, we measure the mass flux of hydrogen atoms crossing the reverse shock front, in the velocity intervals (-7,500 < V(sub obs) < -2,800 km/s) and (1,000 < V(sub obs) < 7,500 km/s), ?M(sub H) = 1.2 × 10(exp -3) M/ y. We also present the first Lyman-alpha imaging of the whole remnant and new Chandra X-ray observations. Comparing the spatial distribution of the Lyman-alpha and X-ray emission, we observe that the majority of the high-velocity Lyman-alpha emission originates interior to the equatorial ring. The observed Lyman-alpha/H-alpha photon ratio, R(L-alpha/H-alpha) approx. = 17, is significantly higher than the theoretically predicted ratio of approx. = 5 for neutral atoms crossing the reverse shock front. We attribute this excess to Lyman-alpha emission produced by X-ray heating of the outer debris. The spatial orientation of the Lyman-alpha and X-ray emission suggests that X-ray heating of the outer debris is the dominant Lyman-alpha production mechanism in SN 1987A at this phase in its evolution.

  19. Case study on human α1-antitrypsin: Recombinant protein titers obtained by commercial ELISA kits are inaccurate

    DEFF Research Database (Denmark)

    Hansen, Henning Gram; Kildegaard, Helene Faustrup; Min Lee, Gyun

    2016-01-01

    Accurate titer determination of recombinant proteins is crucial for evaluating protein production cell lines and processes. Even though enzyme-linked immunosorbent assay (ELISA) is the most widely used assay for determining protein titer, little is known about the accuracy of commercially availab...

  20. Streptococcal pyogenic exotoxin B (SpeB) boosts the contact system via binding of a-1 antitrypsin

    DEFF Research Database (Denmark)

    Meinert Niclasen, Louise; Olsen, Johan G; Dagil, Robert

    2011-01-01

    The Streptococcus pyogenes cysteine protease SpeB (streptococcal pyrogenic exotoxin B) is important for the invasive potential of the bacteria, but its production is down-regulated following systemic infection. This prompted us to investigate if SpeB potentiated the host immune response after...

  1. Comparison of α1-Antitrypsin, α1-Acid Glycoprotein, Fibrinogen and NOx as Indicator of Subclinical Mastitis in Riverine Buffalo (

    Directory of Open Access Journals (Sweden)

    Anirban Guha

    2013-06-01

    Full Text Available Mastitis set apart as clinical and sub clinical is a disease complex of dairy cattle, with sub clinical being the most important economically. Of late, laboratories showed interest in developing biochemical markers to diagnose sub clinical mastitis (SCM in herds. Many workers reported noteworthy alternation of acute phase proteins (APPs and nitric oxide, (measured as nitrate+nitrite = NOx in milk due to intra-mammary inflammation. But, the literature on validation of these parameters as indicators of SCM, particularly in riverine milch buffalo (Bubalus bubalis milk is inadequate. Hence, the present study focused on comparing several APPs viz. α1- anti trypsin, α1- acid glycoprotein, fibrinogen and NOx as indicators of SCM in buffalo milk. These components in milk were estimated using standardized analytical protocols. Somatic cell count (SCC was done microscopically. Microbial culture was done on 5% ovine blood agar. Of the 776 buffaloes (3,096 quarters sampled, only 347 buffaloes comprising 496 quarters were found positive for SCM i.e. milk culture showed growth in blood agar with SCC≥2×105 cells/ml of milk. The cultural examination revealed Gram positive bacteria as the most prevalent etiological agent. It was observed that α1- anti trypsin and NOx had a highly significant (p<0.01 increase in SCM milk, whereas, the increase of α1- acid glycoprotein in infected milk was significant (p<0.05. Fibrinogen was below detection level in both healthy and SCM milk. The percent sensitivity, specificity and accuracy, predictive values and likelihood ratios were calculated taking bacterial culture examination and SCC≥2×105 cells/ml of milk as the benchmark. Udder profile correlation coefficient was also used. Allowing for statistical and epidemiological analysis, it was concluded that α1- anti trypsin indicates SCM irrespective of etiology, whereas α1- acid glycoprotein better diagnosed SCM caused by gram positive bacteria. NOx did not prove to be a good indicator of SCM. It is recommended measuring both α1- anti trypsin and α1- acid glycoprotein in milk to diagnose SCM in buffalo irrespective of etiology.

  2. Direct binding of syndecan-4 cytoplasmic domain to the catalytic domain of protein kinase C alpha (PKC alpha) increases focal adhesion localization of PKC alpha

    DEFF Research Database (Denmark)

    Lim, Ssang-Taek; Longley, Robert L; Couchman, John R

    2003-01-01

    alpha. Full-length PKC alpha weakly interacted with 4V by yeast two-hybrid assays, but PKC alpha constructs that lack the pseudosubstrate region or constructs of the whole catalytic domain interacted more strongly. A mutated 4V sequence (4V(YF): LGKKPIFKK) did not interact with PKC alpha, indicating...

  3. Increased virulence and competitive advantage of a/alpha over a/a or alpha/alpha offspring conserves the mating system of Candida albicans.

    Science.gov (United States)

    Lockhart, Shawn R; Wu, Wei; Radke, Joshua B; Zhao, Rui; Soll, David R

    2005-04-01

    The majority of Candida albicans strains in nature are a/alpha and must undergo homozygosis to a/a or alpha/alpha to mate. Here we have used a mouse model for systemic infection to test the hypothesis that a/alpha strains predominate in nature because they have a competitive advantage over a/a and alpha/alpha offspring in colonizing hosts. Single-strain injection experiments revealed that a/alpha strains were far more virulent than either their a/a or alpha/alpha offspring. When equal numbers of parent a/alpha and offspring a/a or alpha/alpha cells were co-injected, a/alpha always exhibited a competitive advantage at the time of extreme host morbidity or death. When equal numbers of an engineered a/a/alpha2 strain and its isogenic a/a parent strain were co-injected, the a/a/alpha2 strain exhibited a competitive advantage at the time of host morbidity or death, suggesting that the genotype of the mating-type (MTL) locus, not associated genes on chromosome 5, provides a competitive advantage. We therefore propose that heterozygosity at the MTL locus not only represses white-opaque switching and genes involved in the mating process, but also affects virulence, providing a competitive advantage to the a/alpha genotype that conserves the mating system of C. albicans in nature.

  4. Alpha intrusion on ovenight polysomnogram

    Directory of Open Access Journals (Sweden)

    Nahapetian R

    2014-06-01

    Full Text Available No abstract available. Article truncated after 150 words. A 30 year-old Army veteran with a past medical history significant for chronic lumbar back pain stemming from a fall-from-height injury sustained in 2006 was referred to the sleep laboratory for evaluation of chronic fatigue and excessive daytime hypersomnolence. His Epworth sleepiness scale score was 16. He denied a history of snoring and witnessed apnea. Body Mass Index (BMI was 25.7 kg/m2. His main sleep related complaints were frequent nocturnal arousals, poor sleep quality, un-refreshing sleep, prolonged latency to sleep onset, and nightmares. An In-lab attended diagnostic polysomnogram was performed. Sleep efficiency was reduced (73% and overall arousal index was not significantly elevated (3.2 events/hour. The sleep study showed rapid eye movement (REM related sleep disordered breathing that did not meet diagnostic criteria for sleep apnea. There was no evidence for period limb movement disorder. However, the study was significant for alpha wave intrusion in stage N2 non-REM and stage ...

  5. Diabetes and alpha lipoic acid

    Directory of Open Access Journals (Sweden)

    Issy eLaher

    2011-11-01

    Full Text Available Diabetes mellitus is a multi-faceted metabolic disorder where there is increased oxidative stress that contributes to the pathogenesis of this debilitating disease. This has prompted several investigations into the use of antioxidants as a complementary therapeutic approach. Alpha lipoic acid, a naturally occurring dithiol compound which plays an essential role in mitochondrial bioenergetic reactions, has gained considerable attention as an antioxidant for use in managing diabetic complications. Lipoic acid quenches reactive oxygen species, chelates metal ions, and reduces the oxidized forms of other antioxidants such as vitamin C, vitamin E and glutathione. It also boosts antioxidant defense system through Nrf2-mediated antioxidant gene expression and by modulation of peroxisome proliferator activated receptors-regulated genes. ALA inhibits nuclear factor kappa B and activates AMPK in skeletal muscles, which in turn have a plethora of metabolic consequences. These diverse actions suggest that a lipoic acid acts by multiple mechanisms, many of which have only been uncovered recently. In this review we briefly summarize the known biochemical properties of lipoic acid and then discussed the oxidative mechanisms implicated in diabetic complications and the mechanisms by which lipoic acid may ameliorate these reactions. The findings of some of the clinical trials in which lipoic acid administration has been tested in diabetic patients during the last 10 years are summarized. It appears that the clearest benefit of lipoic acid supplementation is in patients with diabetic neuropathy.

  6. Diagnostics for PLX-alpha

    Science.gov (United States)

    Gilmore, Mark; Hsu, Scott

    2015-11-01

    The goal of the Plasma Liner eXperiment PLX-alpha at Los Alamos National Laboratory is to establish the viability of creating a spherically imploding plasma liner for MIF and HED applications, using a spherical array of supersonic plasma jets launched by innovative contoured-gap coaxial plasma guns. PLX- α experiments will focus in particular on establishing the ram pressure and uniformity scalings of partial and fully spherical plasma liners. In order to characterize these parameters experimentally, a suite of diagnostics is planned, including multi-camera fast imaging, a 16-channel visible interferometer (upgraded from 8 channels) with reconfigurable, fiber-coupled front end, and visible and VUV high-resolution and survey spectroscopy. Tomographic reconstruction and data fusion techniques will be used in conjunction with interferometry, imaging, and synthetic diagnostics from modeling to characterize liner uniformity in 3D. Diagnostic and data analysis design, implementation, and status will be presented. Supported by the Advanced Research Projects Agency - Energy - U.S. Department of Energy.

  7. Effects of alpha particles on zebrafish embryos

    International Nuclear Information System (INIS)

    Yum, E.H.W.; Choi, V.W.Y.; Yu, K.N.; Li, V.W.T.; Cheng, S.H.

    2008-01-01

    Full text: Ionizing radiation such as X-ray and alpha particles can damage cellular macromolecules, which can lead to DNA single- and double-strand breaks. In the present work, we studied the effects of alpha particles on dechorionated zebrafish embryos. Thin polyallyldiglycol carbonate (PADC) films with a thickness of 16 μm were prepared from commercially available PADC films (with thickness of 100 μm) by chemical etching and used as support substrates for holding zebrafish embryos for alpha-particle irradiation. These films recorded alpha-particle hit positions, quantified the number and energy of alpha particles actually incident on the embryo cells, and thus enabled the calculation of the dose absorbed by the embryo cells. Irradiation was made at 1.25 hours post fertilization (hpf) with various absorbed dose. TdT-mediated dUTP Nick-End Labeling (TUNEL) assay was performed on the embryos at different time stages after irradiation. Marked apoptosis was detected only in embryos at earlier time stages. The results showed that DNA double-strand break during zebrafish embryogenesis can be induced by alpha-particle irradiation, which suggests that zebrafish is a potential model for assessing the effects of alpha-particle radiation

  8. Cortical Alpha Activity in Schizoaffective Patients

    Directory of Open Access Journals (Sweden)

    Mahdi Moeini

    2017-02-01

    Full Text Available Objective: Electrophysiological studies have identified abnormal oscillatory activities in the cerebral cortex in schizophrenia and mood disorders. Biological and pathophysiological evidence suggests specific deficits in serotonin (5-HT receptor function in schizoaffective disorder (SA, a clinical syndrome with characteristics of both schizophrenia and bipolar disorder. This study investigated alpha oscillations in patients with SA.Method: Electroencephalography was used to measure ongoing and evoked alpha oscillations in 38 adults meeting Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition (DSM–IV criteria for SA, and in 39 healthy controls.Results: Spontaneous alpha power of the participants with SA was significantly lower than that of healthy participants [F (1, 75 = 8.81, P < 0.01]. Evoked alpha activity was also decreased in SA compared to controls [F (1, 75 = 5.67, P = 0.025].Conclusion: A strong reduction of alpha power in the posterior regions may reflect abnormality in the thalamocortical circuits. It is shown that hypoxia and reduced cerebral blood flow is associated with reduced alpha activity among different regions of the brain. Therefore, it can be concluded that greatly decreased alpha activity, particularly in centro-parietal and occipital regions, is related to SA symptoms such as hallucinations.

  9. Lucid dreaming and alpha activity: a preliminary report.

    Science.gov (United States)

    Ogilvie, R D; Hunt, H T; Tyson, P D; Lucescu, M L; Jeakins, D B

    1982-12-01

    10 good dream recallers spent 2 nights in the sleep lab during which they were awakened 4 times per night from REM sleep, twice during their highest alpha activity in REM, and twice during low REM alpha. 5 were given alpha feedback training prior to sleep onset. Arousals from high alpha REM sleep yielded significantly higher lucidity ratings. Alpha feedback had no effect upon lucidity or REM alpha levels. Similarities between lucid dreams and meditative phenomena are discussed.

  10. Anomalous atomic volume of alpha-Pu

    DEFF Research Database (Denmark)

    Kollar, J.; Vitos, Levente; Skriver, Hans Lomholt

    1997-01-01

    We have performed full charge-density calculations for the equilibrium atomic volumes of the alpha-phase light actinide metals using the local density approximation (LDA) and the generalized gradient approximation (GGA). The average deviation between the experimental and the GGA atomic radii is 1.......3%. The comparison between the LDA and GGA results show that the anomalously large atomic volume of alpha-Pu relative to alpha-Np can be ascribed to exchange-correlation effects connected with the presence of low coordinated sites in the structure where the f electrons are close to the onset of localization...

  11. Alpha spectral analysis via artificial neural networks

    International Nuclear Information System (INIS)

    Kangas, L.J.; Hashem, S.; Keller, P.E.; Kouzes, R.T.; Troyer, G.L.

    1994-10-01

    An artificial neural network system that assigns quality factors to alpha particle energy spectra is discussed. The alpha energy spectra are used to detect plutonium contamination in the work environment. The quality factors represent the levels of spectral degradation caused by miscalibration and foreign matter affecting the instruments. A set of spectra was labeled with a quality factor by an expert and used in training the artificial neural network expert system. The investigation shows that the expert knowledge of alpha spectra quality factors can be transferred to an ANN system

  12. Production of alpha 1-proteinase inhibitor (human).

    Science.gov (United States)

    Hein, R H; Van Beveren, S M; Shearer, M A; Coan, M H; Brockway, W J

    1990-03-01

    A method for large scale isolation of alpha 1-proteinase inhibitor (alpha 1-PI) is described. This method employs waste Cohn Fraction IV-1 as the starting material and involves fractional precipitation with polyethylene glycol followed by ion exchange chromatography on diethylaminoethanol (DEAE)-Sepharose. The process also incorporates a ten hour, at 60 degrees C, heat-treatment step to reduce or eliminate the risk of transmission of viral disease. The final product, having a purity of approximately 60%, is freeze-dried. This preparation behaves almost identically to the alpha 1-PI in plasma and is suitable for replacement therapy in hereditary emphysema.

  13. Measurements of $\\alpha_s$ in $pp$ Collisions at the LHC

    CERN Document Server

    Warburton, Andreas; The ATLAS collaboration

    2015-01-01

    The coupling of the strong force, $\\alpha_s$, is deemed to be a fundamental parameter of Nature, and, beyond the quark masses, constitutes the only free parameter in the QCD Lagrangian. Provided is an overview of CERN Large Hadron Collider (LHC) measurements of $\\alpha_s(M_Z)$ evaluated at the $Z$-boson mass and of the running of $\\alpha_s(Q)$ as a function of energy-momentum transfer $Q$. The measurements were performed by the ATLAS and CMS Collaborations using proton-proton ($pp$) collisions with centre-of-mass energies of 7 TeV and data samples with time-integrated luminosities of up to 5 fb$^{-1}$. Four different categories of observable were used in the described extractions of $\\alpha_s$: inclusive jet cross sections, 3-jet to 2-jet inclusive cross-section ratios, 3-jet mass cross sections, and top-quark pair production cross sections. These results, which include the first NNLO measurement of $\\alpha_s$ at a hadron collider and the first determinations of $\\alpha_s$ at energy scales above 1 TeV, are co...

  14. A Quantitative Electrochemiluminescence Assay for Clostridium perfringens alpha toxin

    National Research Council Canada - National Science Library

    Merrill, Gerald A; Rivera, Victor R; Neal, Dwayne D; Young, Charles; Poli, Mark A

    2006-01-01

    .... Biotinylated antibodies to C. perfringens alpha toxin bound to streptavidin paramagnetic beads specifically immunoadsorbed soluble sample alpha toxin which subsequently selectively immunoadsorbed ruthenium (Ru...

  15. Neutron-induced alpha radiography

    International Nuclear Information System (INIS)

    Pereira, Marco Antonio Stanojev

    2008-01-01

    A new radiography technique to inspect thin samples was developed. Low energy alpha particles, generated by a boron based screen under thermal neutron irradiation, are used as penetrating radiation. The solid state nuclear track detector CR-39 has been used to register the image. The interaction of the α - particles with the CR-39 gives rise to damages which under an adequate chemical etching became tracks the basic units forming the image. A digital system was developed for data acquisition and data analysis as well as for image processing. The irradiation and etching conditions to obtain the best radiography are 1,3 hours and 25 minutes at 70 deg C respectively. For such conditions samples having 10 μm in thickness can be inspected with a spatial resolution of 32 μm. The use of the digital system has reduced the time spent for data acquisition and data analysis and has improved the radiography image visualization. Furthermore, by using the digital system, it was possible to study several new parameters regarding the tracks which are very important to understand and study the image formation theory in solid state nuclear track detectors, the one used in this thesis. Some radiography images are also shown which demonstrate the potential of the proposed radiography technique. When compared with the other radiography techniques already in use to inspect thin samples, the present one developed in the present paper allows a smaller time to obtain the image, it is not necessary to handle liquid radioactive substances, the detector is insensitive to β, γ, X-ray and visible light. (author)

  16. Liquid scintillation alpha particle spectrometry. Progress report

    International Nuclear Information System (INIS)

    Bell, L.L.; Hakooz, S.A.; Johnson, L.O.; Nieschmidt, E.B.; Meikrantz, D.H.

    1979-12-01

    Objective to develop a technique whereby Pu may be put into solution, extracted by solvent extraction into a suitable extractive scintillant and subsequently counted. Presented here are results of attempts to separate beta and alpha activities through pulse shape discrimination. A qualitative discussion is given which yields alpha particle peak widths, resolution and response. The detection efficiency for alpha particles in a liquid scintillant is 100%. Present detection sensitivities of the equipment being used are: 4.5 x 10 -6 μCi (100 s), 1.2 x 10 -6 μCi (1000 s), and 4.0 x 10 -7 μCi (10,000 s) at the 3 sigma level. The detectability of a particular alpha-emitting species is strongly dependent upon the population of other species. The ability to discriminate depends upon the system resolution. 14 figures, 2 tables

  17. NEW APPROACHES TO CONFINED ALPHA DIAGNOSTICS

    Energy Technology Data Exchange (ETDEWEB)

    FISHER,R.K

    2004-04-01

    Three new approaches to obtain information on the confined fast alphas in International Thermonuclear Experimental Reactor (ITER) are proposed. The first technique measures the energetic charge exchange (CX) neutrals that result from the alpha collision-induced knock-on fuel ion tails undergoing electron capture on the MeV D neutral beams planned for heating and current drive. The second technique measures the energetic knock-on neutron tail due to alphas using the lengths of the proton recoil tracks produced by neutron collisions in nuclear emulsions. The range of the 14 to 20 MeV recoil protons increases by {approx}140 microns per MeV. The third approach would measure the CX helium neutrals resulting from confined alphas capturing two electrons in the ablation cloud surrounding a dense gas jet that has been proposed for disruption mitigation in ITER.

  18. NEW APPROACHES TO CONFINED ALPHA DIAGNOSTICS

    International Nuclear Information System (INIS)

    FISHER, R.K.

    2004-01-01

    Three new approaches to obtain information on the confined fast alphas in International Thermonuclear Experimental Reactor (ITER) are proposed. The first technique measures the energetic charge exchange (CX) neutrals that result from the alpha collision-induced knock-on fuel ion tails undergoing electron capture on the MeV D neutral beams planned for heating and current drive. The second technique measures the energetic knock-on neutron tail due to alphas using the lengths of the proton recoil tracks produced by neutron collisions in nuclear emulsions. The range of the 14 to 20 MeV recoil protons increases by ∼140 microns per MeV. The third approach would measure the CX helium neutrals resulting from confined alphas capturing two electrons in the ablation cloud surrounding a dense gas jet that has been proposed for disruption mitigation in ITER

  19. Strichartz estimates on $alpha$-modulation spaces

    Directory of Open Access Journals (Sweden)

    Weichao Guo

    2013-05-01

    Full Text Available In this article, we consider some dispersive equations, including Schrodinger equations, nonelliptic Schrodinger equations, and wave equations. We develop some Strichartz estimates in the frame of alpha-modulation spaces.

  20. Targeted alpha therapy: Applications and current status

    Energy Technology Data Exchange (ETDEWEB)

    Bruchertseifer, Frank, E-mail: frank.bruchertseifer@ec.europa.eu [European Commission, Joint Research Centre, Karlsruhe (Germany)

    2017-07-01

    Full text: The field of targeted alpha therapy has been developed rapidly in the last decade. Besides {sup 223}Ra, {sup 211}At and {sup 212}Pb/{sup 212}Bi the alpha emitters {sup 225}Ac and {sup 213}Bi are promising therapeutic radionuclides for application in targeted alpha therapy of cancer and infectious diseases. The presentation will give a short overview about the current clinical treatments with alpha emitting radionuclides and will place an emphasis on the most promising clinical testing of peptides and antibodies labelled with {sup 225}Ac and {sup 213}Bi for treatment of metastatic castration-resistant prostate cancer patients with glioma and glioblastoma multiform, PSMA-positive tumor phenotype and bladder carcinoma in situ. (author)

  1. Calibration of alpha surface contamination monitor

    International Nuclear Information System (INIS)

    Freitas, I.S.M. de; Goncalez, O.L.

    1990-01-01

    In this work, the results, as well as the methodology, of the calibration of an alpha surface contamination monitor are presented. The calibration factors are obtained by least-squares fitting with effective variance. (author)

  2. Solar Imagery - Chromosphere - H-Alpha

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Collection includes a variety of H-alpha photographic datasets contributed by a number of national and private solar observatories located worldwide. Solar...

  3. Energy dependence of event shapes and of $\\alpha_s$ at LEP 2

    CERN Document Server

    Abreu, P; Adye, T; Adzic, P; Albrecht, Z; Alderweireld, T; Alekseev, G D; Alemany, R; Allmendinger, T; Allport, P P; Almehed, S; Amaldi, Ugo; Amapane, N; Amato, S; Anassontzis, E G; Andersson, P; Andreazza, A; Andringa, S; Antilogus, P; Apel, W D; Arnoud, Y; Åsman, B; Augustin, J E; Augustinus, A; Baillon, Paul; Bambade, P; Barão, F; Barbiellini, Guido; Barbier, R; Bardin, Dimitri Yuri; Barker, G; Baroncelli, A; Battaglia, Marco; Baubillier, M; Becks, K H; Begalli, M; Behrmann, A; Beillière, P; Belokopytov, Yu A; Belous, K S; Benekos, N C; Benvenuti, Alberto C; Bérat, C; Berggren, M; Bertini, D; Bertrand, D; Besançon, M; Bianchi, F; Bigi, M; Bilenky, S M; Bizouard, M A; Bloch, D; Blom, H M; Bonesini, M; Bonivento, W; Boonekamp, M; Booth, P S L; Borgland, A W; Borisov, G; Bosio, C; Botner, O; Boudinov, E; Bouquet, B; Bourdarios, C; Bowcock, T J V; Boyko, I; Bozovic, I; Bozzo, M; Branchini, P; Brenke, T; Brenner, R A; Brückman, P; Brunet, J M; Bugge, L; Buran, T; Burgsmüller, T; Buschbeck, Brigitte; Buschmann, P; Cabrera, S; Caccia, M; Calvi, M; Camporesi, T; Canale, V; Carena, F; Carroll, L; Caso, Carlo; Castillo-Gimenez, M V; Cattai, A; Cavallo, F R; Chabaud, V; Chapkin, M M; Charpentier, P; Chaussard, L; Checchia, P; Chelkov, G A; Chierici, R; Chliapnikov, P V; Chochula, P; Chorowicz, V; Chudoba, J; Cieslik, K; Collins, P; Contri, R; Cortina, E; Cosme, G; Cossutti, F; Cowell, J H; Crawley, H B; Crennell, D J; Crépé, S; Crosetti, G; Cuevas-Maestro, J; Czellar, S; Davenport, Martyn; Da Silva, W; Deghorain, A; Della Ricca, G; Delpierre, P A; Demaria, N; De Angelis, A; de Boer, Wim; De Clercq, C; De Lotto, B; De Min, A; De Paula, L S; Dijkstra, H; Di Ciaccio, Lucia; Dolbeau, J; Doroba, K; Dracos, M; Drees, J; Dris, M; Duperrin, A; Durand, J D; Eigen, G; Ekelöf, T J C; Ekspong, Gösta; Ellert, M; Elsing, M; Engel, J P; Erzen, B; Espirito-Santo, M C; Falk, E; Fanourakis, G K; Fassouliotis, D; Fayot, J; Feindt, Michael; Fenyuk, A; Ferrari, P; Ferrer, A; Ferrer-Ribas, E; Ferro, F; Fichet, S; Firestone, A; Flagmeyer, U; Föth, H; Fokitis, E; Fontanelli, F; Franek, B J; Frodesen, A G; Frühwirth, R; Fulda-Quenzer, F; Fuster, J A; Galloni, A; Gamba, D; Gamblin, S; Gandelman, M; García, C; Gaspar, C; Gaspar, M; Gasparini, U; Gavillet, P; Gazis, E N; Gelé, D; Ghodbane, N; Gil, I; Glege, F; Gokieli, R; Golob, B; Gómez-Ceballos, G; Gonçalves, P; González-Caballero, I; Gopal, Gian P; Gorn, L; Górski, M; Guz, Yu; Gracco, Valerio; Grahl, J; Graziani, E; Green, C; Grimm, H J; Gris, P; Grosdidier, G; Grzelak, K; Günther, M; Guy, J; Hahn, F; Hahn, S; Haider, S; Hallgren, A; Hamacher, K; Hansen, J; Harris, F J; Hedberg, V; Heising, S; Hernández, J J; Herquet, P; Herr, H; Hessing, T L; Heuser, J M; Higón, E; Holmgren, S O; Holt, P J; Hoorelbeke, S; Houlden, M A; Hrubec, Josef; Huet, K; Hughes, G J; Hultqvist, K; Jackson, J N; Jacobsson, R; Jalocha, P; Janik, R; Jarlskog, C; Jarlskog, G; Jarry, P; Jean-Marie, B; Johansson, E K; Jönsson, P E; Joram, C; Juillot, P; Kapusta, F; Karafasoulis, K; Katsanevas, S; Katsoufis, E C; Keränen, R; Kersevan, Borut P; Khomenko, B A; Khovanskii, N N; Kiiskinen, A P; King, B J; Kinvig, A; Kjaer, N J; Klapp, O; Klein, H; Kluit, P M; Kokkinias, P; Koratzinos, M; Kostyukhin, V; Kourkoumelis, C; Kuznetsov, O; Krammer, Manfred; Kriznic, E; Krstic, J; Krumshtein, Z; Kubinec, P; Kurowska, J; Kurvinen, K L; Lamsa, J; Lane, D W; Langefeld, P; Lapin, V; Laugier, J P; Lauhakangas, R; Leder, Gerhard; Ledroit, F; Lefébure, V; Leinonen, L; Leisos, A; Leitner, R; Lemonne, J; Lenzen, Georg; Lepeltier, V; Lesiak, T; Lethuillier, M; Libby, J; Liko, D; Lipniacka, A; Lippi, I; Lörstad, B; Loken, J G; Lopes, J H; López, J M; López-Fernandez, R; Loukas, D; Lutz, P; Lyons, L; MacNaughton, J N; Mahon, J R; Maio, A; Malek, A; Malmgren, T G M; Maltezos, S; Malychev, V; Mandl, F; Marco, J; Marco, R P; Maréchal, B; Margoni, M; Marin, J C; Mariotti, C; Markou, A; Martínez-Rivero, C; Martínez-Vidal, F; Martí i García, S; Mastroyiannopoulos, N; Matorras, F; Matteuzzi, C; Matthiae, Giorgio; Masik, J; Mazzucato, F; Mazzucato, M; McCubbin, M L; McKay, R; McNulty, R; McPherson, G; Meroni, C; Meyer, W T; Migliore, E; Mirabito, L; Mitaroff, Winfried A; Mjörnmark, U; Moa, T; Moch, M; Møller, R; Mönig, K; Monge, M R; Moreau, X; Morettini, P; Morton, G A; Müller, U; Münich, K; Mulders, M; Mulet-Marquis, C; Muresan, R; Murray, W J; Muryn, B; Myatt, Gerald; Myklebust, T; Naraghi, F; Nassiakou, M; Navarria, Francesco Luigi; Navas, S; Nawrocki, K; Negri, P; Némécek, S; Neufeld, N; Neumeister, N; Nicolaidou, R; Nielsen, B S; Nikolenko, M; Nomokonov, V P; Normand, Ainsley; Nygren, A; Obraztsov, V F; Olshevskii, A G; Onofre, A; Orava, Risto; Orazi, G; Österberg, K; Ouraou, A; Paganoni, M; Paiano, S; Pain, R; Paiva, R; Palacios, J; Palka, H; Papadopoulou, T D; Papageorgiou, K; Pape, L; Parkes, C; Parodi, F; Parzefall, U; Passeri, A; Passon, O; Pegoraro, M; Peralta, L; Pernicka, Manfred; Perrotta, A; Petridou, C; Petrolini, A; Phillips, H T; Pierre, F; Pimenta, M; Piotto, E; Podobnik, T; Pol, M E; Polok, G; Poropat, P; Pozdnyakov, V; Privitera, P; Pukhaeva, N; Pullia, Antonio; Radojicic, D; Ragazzi, S; Rahmani, H; Ratoff, P N; Read, A L; Rebecchi, P; Redaelli, N G; Regler, Meinhard; Reid, D; Reinhardt, R; Renton, P B; Resvanis, L K; Richard, F; Rídky, J; Rinaudo, G; Røhne, O M; Romero, A; Ronchese, P; Rosenberg, E I; Rosinsky, P; Roudeau, Patrick; Rovelli, T; Royon, C; Ruhlmann-Kleider, V; Ruiz, A; Saarikko, H; Sacquin, Yu; Sadovskii, A; Sajot, G; Salt, J; Sampsonidis, D; Sannino, M; Schneider, H; Schwemling, P; Schwering, B; Schwickerath, U; Schyns, M A E; Scuri, F; Seager, P; Sedykh, Yu; Segar, A M; Sekulin, R L; Shellard, R C; Sheridan, A; Siebel, M; Simard, L C; Simonetto, F; Sissakian, A N; Smadja, G; Smirnov, N; Smirnova, O G; Smith, G R; Sopczak, André; Sosnowski, R; Spassoff, Tz; Spiriti, E; Sponholz, P; Squarcia, S; Stanescu, C; Stanic, S; Stevenson, K; Stocchi, A; Strub, R; Stugu, B; Szczekowski, M; Szeptycka, M; Tabarelli de Fatis, T; Tegenfeldt, F; Terranova, F; Thomas, J; Timmermans, J; Tinti, N; Tkatchev, L G; Todorova-Nová, S; Tomaradze, A G; Tomé, B; Tonazzo, A; Tortora, L; Tranströmer, G; Treille, D; Tristram, G; Trochimczuk, M; Troncon, C; Tsirou, A L; Turluer, M L; Tyapkin, I A; Tzamarias, S; Ullaland, O; Uvarov, V; Valenti, G; Vallazza, E; Van der Velde, C; van Apeldoorn, G W; van Dam, P; Van Doninck, W K; Van Eldik, J; Van Lysebetten, A; Van Vulpen, I B; Vassilopoulos, N; Vegni, G; Ventura, L; Venus, W A; Verbeure, F; Verlato, M; Vertogradov, L S; Verzi, V; Vilanova, D; Vitale, L; Vlasov, E; Vodopyanov, A S; Vollmer, C F; Voulgaris, G; Vrba, V; Wahlen, H; Walck, C; Weiser, C; Wicke, D; Wickens, J H; Wilkinson, G R; Winter, M; Witek, M; Wolf, G; Yi, J; Yushchenko, O P; Zaitsev, A; Zalewska-Bak, A; Zalewski, Piotr; Zavrtanik, D; Zevgolatakos, E; Zimin, N I; Zucchelli, G C; Zumerle, G

    1999-01-01

    Infrared and collinear safe event shape distributions and their mean values are determined using the data taken at ve di erent centre of mass energies above $M_Z$ with the DELPHI detector at LEP. From the event shapes, the strong coupling $\\alpha_s$ is extracted in $O(\\alpha^2_s)$, NLLA and a combined scheme using hadronisation corrections evaluated with fragmentation model generators as well as using an analytical power ansatz. Comparing these measurements to those obtained at MZ, the energy dependence (running) of $\\alpha_s$ is accessible. The logarithmic energy slope of the inverse strong coupling is measured to be $d\\alpha_{s}^{-1}/d log(E_{cm}) = 1.39 \\pm 0.34(stat) \\pm 0.17(syst)$, in good agreement with the QCD expectation of 1.27.

  4. Influence of fast alpha diffusion and thermal alpha buildup on tokamak reactor performance

    International Nuclear Information System (INIS)

    Uckan, N.A.; Tolliver, J.S.; Houlberg, W.A.; Attenberger, S.E.

    1988-01-01

    The effect of fast alpha diffusion and thermal alpha accumulation on the confinement capability of a candidate Engineering Test Reactor plasma (Tokamak Ignition/Burn Experimental Reactor) in achieving ignition and steady-state driven operation has been assessed using both global and 1-1/2-dimensional transport models. Estimates are made of the threshold for radial diffusion of fast alphas and thermal alpha buildup. It is shown that a relatively low level of radial transport, when combined with large gradients in the fast alpha density, leads to a significant radial flow with a deleterious effect on plasma performance. Similarly, modest levels of thermal alpha concentration significantly influence the ignition and steady-state burn capability

  5. Measurement of the angle alpha at BABAR

    Energy Technology Data Exchange (ETDEWEB)

    Perez, A.; /Orsay, LAL

    2009-06-25

    The authors present recent measurements of the CKM angle {alpha} using data collected by the BABAR detector at the PEP-II asymmetric-energy e{sup +}e{sup -} collider at the SLAC National Accelerator Laboratory, operating at the {Upsilon}(4S) resonance. They present constraints on {alpha} from B {yields} {pi}{pi}, B {yields} {rho}{rho} and B {yields} {rho}{pi} decays.

  6. Improved peak shape fitting in alpha spectra

    OpenAIRE

    POMME Stefaan; CARO MARROYO BELEN

    2014-01-01

    Peak overlap is a recurrent issue ina lpha-particle spectrometry, not only in routine analyses but also in the high-resolution spectra from which reference values for alpha emission probabilities are derived. In this work, improved peak shape formulae are presented for the deconvolution of alpha-particle spectra. They have been implemented as fit functions in a spreadsheet application and optimum fit parameters were searched with built-in optimisation routines. Deconvolution results are shown...

  7. Conceptual design report for alpha waste incinerator

    International Nuclear Information System (INIS)

    1979-04-01

    The Alpha Waste Incinerator, a new facility in the SRP H-Area, will process transuranic or alpha-contaminated combustible solid wastes. It will seal the radioactive ash and scrubbing salt residues in cans for interim storage in drums on site burial ground pads. This report includes objectives, project estimate, schedule, standards and criteria, excluded costs, safety evaluation, energy consumption, environmental assessment, and key drawings

  8. Beteigeuze (Alpha Orionis) und Mintaka (Delta Orionis)

    Science.gov (United States)

    Vollmann, Wolfgang

    2013-02-01

    Magnitude measures transformed to Johnson V of Alpha Orionis (Betelgeuse) and Delta Orionis with a wide-angle lens and DSLR are presented and discussed. Alpha Orionis light changes are shown clearly. The primary and secondary eclipses of Delta Orionis with amplitudes of 0.12 and 0.05 mag respectively are clearly recorded. They occur near phase 0.00 and 0.50 respectively of current elements from VSX (2).

  9. Considering the determination of an alpha value

    International Nuclear Information System (INIS)

    Lorenz, B.

    1987-01-01

    Following an outline of the most important international methods of evaluating an alpha value (the monetary equivalent of one man-sievert) and an approach deemed suitable for use in the GDR, it is recommended that alpha be taken as 30,000 Mark per man-sievert in national cost-benefit analyses. This value should be revisited every five to ten years. (author)

  10. Alpha-root Processes for Derivatives pricing

    OpenAIRE

    Balakrishna, BS

    2010-01-01

    A class of mean reverting positive stochastic processes driven by alpha-stable distributions, referred to here as alpha-root processes in analogy to the square root process (Cox-Ingersoll-Ross process), is a subclass of affine processes, in particular continuous state branching processes with immigration (CBI processes). Being affine, they provide semi-analytical results for the implied term structures as well as for the characteristic exponents for their associated distributions. Their use h...

  11. Self-assembling, dynamic alphaPNAs

    DEFF Research Database (Denmark)

    Nielsen, Peter E

    2009-01-01

    In the recent report published in Science, Ghadiri and coworkers describe dynamic tPNAs, alphaPNA derivatives with a nucleobase attached via a thioester bond that are a step forward toward self-repairing and replicating molecules.......In the recent report published in Science, Ghadiri and coworkers describe dynamic tPNAs, alphaPNA derivatives with a nucleobase attached via a thioester bond that are a step forward toward self-repairing and replicating molecules....

  12. Alpha-emitters for medical therapy workshop

    International Nuclear Information System (INIS)

    Feinendegen, L.E.; McClure, J.J.

    1996-01-01

    A workshop on ''Alpha-Emitters for Medical Therapy'' was held May 30-31, 1996 in Denver Colorado to identify research goals and potential clinical needs for applying alpha-particle emitters and to provide DOE with sufficient information for future planning. The workshop was attended by 36 participants representing radiooncology, nuclear medicine, immunotherapy, radiobiology, molecular biology, biochemistry, radiopharmaceutical chemistry, dosimetry, and physics. This report provides a summary of the key points and recommendations arrived at during the conference

  13. Cytokine vaccination: neutralising IL-1alpha autoantibodies induced by immunisation with homologous IL-1alpha

    DEFF Research Database (Denmark)

    Svenson, M; Hansen, M B; Thomsen, Allan Randrup

    2000-01-01

    High-affinity IgG autoantibodies (aAb) to IL-1alpha are among the most frequently found aAb to cytokines in humans. To establish an animal model with aAb to IL-1alpha, we immunised mice with recombinant murine IL-1alpha. Unprimed and Bacille Calmette-Guérin (BCG)-primed BALB/cA mice were vaccinat...

  14. Liquid-scintillation alpha-detection techniques

    International Nuclear Information System (INIS)

    McKlveen, J.W.; McDowell, W.J.

    1983-01-01

    Accurate, quantitative determinations of alpha-emitting nuclides by conventional plate-counting methods are difficult because of sample self-absorption problems in counting and because of non-reproducible losses in conventional sample separation methods. Liquid scintillation alpha spectrometry offers an attractive with no sample self-absorption or geometry problems and with 100% counting efficiency. Sample preparation may include extraction of the alpha emitter of interest by a specific organic-phase-soluble compound directly into the liquid scintillation counting medium. Detection electronics use energy and pulse-shape discrimination to yield alpha spectra without beta and gamma background interference. Specific procedures have been developed for gross alpha, uranium, plutonium, thorium, and polonium assay. Possibilities for a large number of other applications exist. Accuracy and reproducibility are typically in the 1% range. Backgrounds on the order of 0.01 cpm are readily achievable. The paper will present an overview of liquid scintillation alpha counting techniques and some of the results achieved for specific applications

  15. Structures of G [alpha [superscript i1

    Energy Technology Data Exchange (ETDEWEB)

    Johnston, Christopher A.; Willard, Francis S.; Jezyk, Mark R.; Fredericks, Zoey; Bodor, Erik T.; Jones, Miller B.; Blaesius, Rainer; Watts, Val J.; Harden, T. Kendall; Sondek, John; Ramer, J. Kevin; Siderovski, David P. (Karo Bio); (UNC); (Purdue)

    2010-07-19

    Heterotrimeric G proteins are molecular switches that regulate numerous signaling pathways involved in cellular physiology. This characteristic is achieved by the adoption of two principal states: an inactive, GDP bound state and an active, GTP bound state. Under basal conditions, G proteins exist in the inactive, GDP bound state; thus, nucleotide exchange is crucial to the onset of signaling. Despite our understanding of G protein signaling pathways, the mechanism of nucleotide exchange remains elusive. We employed phage display technology to identify nucleotide state-dependent G{alpha} binding peptides. Herein, we report a GDP-selective G{alpha} binding peptide, KB-752, that enhances spontaneous nucleotide exchange of G{alpha}{sub i} subunits. Structural determination of the G{alpha}{sub i1}/peptide complex reveals unique changes in the G{alpha} switch regions predicted to enhance nucleotide exchange by creating a GDP dissociation route. Our results cast light onto a potential mechanism by which G{alpha} subunits adopt a conformation suitable for nucleotide exchange.

  16. Current status and perspectives in alpha radioimmunotherapy.

    Science.gov (United States)

    Chérel, M; Davodeau, F; Kraeber-Bodéré, F; Chatal, J F

    2006-12-01

    Systemic administration of radiolabeled antibody directed against tumor antigens in radioimmunotherapy (RIT) enables to specifically target the cancer cells and to destroy them. So far, this strategy has proven its efficiency in the treatment of some hematological cancers with antibodies labeled with beta emitting radionuclides. In the last 2 decades, availability of short half life alpha emitters prompted to consider their use in RIT. Contrary to beta particles, alpha particles have a short path length and display a high lineic energy transfer. Those physical characteristics open new fields of clinical applications complementary to beta-RIT. To date, alpha-RIT is still at a preclinical stage of development: the radiolabeling methods need to be optimized to ensure in vivo stability of the radiopharmaceuticals. Some radionuclides have complex decay schemes with daughters emitting further alpha particles whose toxicity needs to be investigated. The modalities of administration of radiolabeled antibodies in animal models require also to be improved for delivering higher doses to tumor targets. A comprehensive analysis of the specific events occurring at cell or tissue level in response to alpha irradiation would be of great interest in order to define the best therapeutic association for residual disease or consolidation treatments. This approach has been proven to be efficient in increasing antitumor response either by using high doses with organ protection (kidney, bone marrow) or by a synergistic effect between alpha-RIT and associated treatments, such as chemotherapy.

  17. Systemic Targeted Alpha Radiotherapy for Cancer

    Directory of Open Access Journals (Sweden)

    Allan B. J.

    2013-09-01

    Full Text Available Background: The fundamental principles of internal targeted alpha therapy for cancer were established many decades ago.The high linear energy transfer (LET of alpha radiation to the targeted cancer cellscauses double strand breaks in DNA. At the same time, the short range radiation spares adjacent normal tissues. This targeted approach complements conventional external beam radiotherapy and chemotherapy. Such therapies fail on several fronts, such as lack of control of some primary cancers (e.g.glioblastoma multiformeand to inhibit the development of lethal metastatic cancer after successful treatment of the primary cancer. Objective: This review charts the developing role of systemic high LET, internal radiation therapy. Method: Targeted alpha therapy is a rapidly advancing experimental therapy that holds promise to deliver high cytotoxicity to targeted cancer cells. Initially thought to be indicated for leukemia and micrometastases, there is now evidence that solid tumors can also be regressed. Results: Alpha therapy may be molecular or physiological in its targeting. Alpha emitting radioisotopes such as Bi-212, Bi-213, At-211 and Ac-225 are used to label monoclonal antibodies or proteins that target specifc cancer cells. Alternatively, Radium-233 is used for palliative therapy of breast and prostate cancers because of its bone seeking properties. Conclusion: Preclinical studies and clinical trials of alpha therapy are discussed for leukemia, lymphoma, melanoma, glioblastoma multiforme, bone metastases, ovarian cancer, pancreatic cancer and other cancers.

  18. Cytokine vaccination: neutralising IL-1alpha autoantibodies induced by immunisation with homologous IL-1alpha

    DEFF Research Database (Denmark)

    Svenson, M; Hansen, M B; Thomsen, Allan Randrup

    2000-01-01

    High-affinity IgG autoantibodies (aAb) to IL-1alpha are among the most frequently found aAb to cytokines in humans. To establish an animal model with aAb to IL-1alpha, we immunised mice with recombinant murine IL-1alpha. Unprimed and Bacille Calmette-Guérin (BCG)-primed BALB/cA mice were vaccinated...... in mice by vaccination with recombinant murine IL-1alpha conjugated to PPD. Studies of the effects of IL-1alpha aAb in such animals may help clarify the importance of naturally occurring IL-1alpha aAb in humans and permit the evaluation of future therapies with cytokine aAb in patients...... with IL-1alpha coupled to purified protein derivative of tuberculin (PPD). Both unprimed and primed animals developed IgG aAb to IL-1alpha. These aAb persisted at high levels more than 100 days after vaccination and did not cross-react with murine IL-1beta. The induced anti-IL-1alpha aAb inhibited binding...

  19. Alpha 1-blockers vs 5 alpha-reductase inhibitors in benign prostatic hyperplasia. A comparative review

    DEFF Research Database (Denmark)

    Andersen, J T

    1995-01-01

    During recent years, pharmacological treatment of symptomatic benign prostatic hyperplasia (BPH) has become the primary treatment choice for an increasing number of patients. The 2 principal drug classes employed are alpha 1-blockers and 5 alpha-reductase inhibitors. Current information from...... of patients who will respond well to alpha 1-blockers have yet to be identified, and data concerning the long term effects of these drugs are not yet available. 5 alpha-Reductase inhibitors have a slow onset of effect, but treatment leads to improvement in symptoms, reduction of the size of the prostate gland...... or unwilling to undergo surgical resection of the prostate will benefit from such therapy....

  20. Selectivity of the imidazoline alpha-adrenoceptor agonists (oxymetazoline and cirazoline) for human cloned alpha 1-adrenoceptor subtypes.

    Science.gov (United States)

    Horie, K.; Obika, K.; Foglar, R.; Tsujimoto, G.

    1995-01-01

    1. To investigate the structure-activity relationships of alpha-adrenoceptor agonists for the alpha 1-adrenoceptor subtypes, we have compared the imidazoline class of compounds, oxymetazoline and cirazoline, with the phenethylamine, noradrenaline, in their affinities and also in their intrinsic activities in Chinese hamster ovary (CHO) cells stably expressing the cloned human alpha 1-adrenoceptor subtypes (alpha 1a-, alpha 1b-, and alpha 1d-subtypes). 2. Radioligand binding studies with [125I]-HEAT showed that cirazoline and oxymetazoline had higher affinities at alpha 1a-subtype than at alpha 1b- and alpha 1d-subtypes, while noradrenaline had higher affinity at the alpha 1d-subtype than at alpha 1a- and alpha 1b-subtypes. 3. In functional studies, cirazoline caused transients of cytosolic Ca2+ concentrations ([Ca2+]i response) in a concentration-dependent manner and developed a maximal response similar to that to noradrenaline in CHO cells expressing the alpha 1a-subtype, while it acted as a partial agonist at alpha 1b- and alpha 1d-adrenoceptors. Oxymetazoline, on the other hand, was a weak agonist at alpha 1a-adrenoceptors, and has no intrinsic activity at the other subtypes. 4. Using the phenoxybenzamine inactivation method, the relationships between receptor occupancy and noradrenaline-induced [Ca2+]i response for alpha 1a- and alpha 1d-subtypes were found to be linear, whereas it was moderately hyperbolic for the alpha 1b-subtype, indicating the absence of receptor reserves in CHO cells expressing alpha 1a- and alpha 1d-subtypes while there exists a small receptor reserve for CHO cells expressing the alpha 1b-subtype.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8564227

  1. Anti-IL-1alpha autoantibodies in early rheumatoid arthritis

    DEFF Research Database (Denmark)

    Forslind, K; Svensson, Birte; Svenson, M

    2001-01-01

    To investigate the potential predictive value of autoantibodies against IL1-alpha (anti-IL-1alpha) in patients with early rheumatoid arthritis (RA).......To investigate the potential predictive value of autoantibodies against IL1-alpha (anti-IL-1alpha) in patients with early rheumatoid arthritis (RA)....

  2. The nitric oxide-donating pravastatin derivative, NCX 6550 [(1S-[1alpha(betaS*, deltaS*), 2alpha, 6alpha, 8beta-(R*), 8a alpha

    Science.gov (United States)

    Dever, G; Spickett, C M; Kennedy, S; Rush, C; Tennant, G; Monopoli, A; Wainwright, C L

    2007-01-01

    Statins possess anti-inflammatory effects that may contribute to their ability to slow atherogenesis, whereas nitric oxide (NO) also influences inflammatory cell adhesion. This study aimed to determine whether a novel NO-donating pravastatin derivative, NCX 6550 [(1S-[1alpha(betaS*,deltaS*),2alpha,6alpha,8beta-(R*),8a alpha

  3. Measurement of radium micro-precipitates using alpha spectrometry and total alpha counting methods

    International Nuclear Information System (INIS)

    Hosseini, T.; Fathivand, A.A.

    2004-01-01

    Background: This study consists of two parts. The first part deals with both qualitative and quantitative analysis of 226 Ra suing alpha spectrometry measurement method. In the second part, the percentage of radioactive equilibrium between 226 Radium and its daughter products were determined by alpha spectrometry and total alpha measurement system after elapsed time of 15 days from precipitation. Materials and methods: Twelve 226 Radium samples as Barium-Radium Sulfate in form of micro-precipitates on millipore and What man 42 filters were prepared. An alpha spectrometer with surface barrier detector and a total alpha measurement system consists of scintillation crystal assembly Zinc Silver were used for counting. Results: The minimum detection limit of alpha spectrometry and total alpha counting for 226 Radium measurements in samples for counting time equal to 10000 seconds, were found to be 3.7 mBq and 15.8 mBq respectively. Results from total alpha counting showed that radioactive equilibrium between 226 Radium and its daughter products reached to about 92%± 3.5, where as, in the case of alpha spectrometry radioactive equilibrium, it was destroyed due to vacuum during counting the sample. Also in case of alpha spectrometry, the optimum sample to detector distance, was found to be 0.5 centimeter. Conclusion: From this study it was concluded that micro-precipitation can be used as a proper method for sample preparation and alpha spectrometry due to its lower detection limit to measure low concentration of 224 Radium and 226 Radium in these precipitates, prepared from different samples. Besides it is not time consuming and sources can be measured immediately after sample preparation

  4. Hyperpolarised 3He MRI versus HRCT in COPD and normal volunteers: PHIL trial

    DEFF Research Database (Denmark)

    van Beek, E J R; Dahmen, A M; Stavngaard, T

    2009-01-01

    The aim of the present study was to apply hyperpolarised (HP) (3)He magnetic resonance imaging (MRI) to identify patients with chronic obstructive pulmonary disease (COPD) and alpha(1)-antitrypsin deficiency (alpha(1)-ATD) from healthy volunteers and compare HP (3)He MRI findings with high-resolu....... We showed the feasibility of a multicentre study using different magnetic resonance systems....

  5. Inactivation of factor Xia in vivo: studies in chimpanzees and in humans

    NARCIS (Netherlands)

    Wuillemin, W. A.; Hack, C. E.; Bleeker, W. K.; Biemond, B. J.; Levi, M. [=Marcel M.; ten Cate, H.

    1996-01-01

    C1-inhibitor (C1Inh), antithrombin III (ATIII), alpha 1-antitrypsin (a1AT), and alpha 2-antiplasmin (a2AP) are known inhibitors of factor XIa (FXIa). However, their precise contribution to FXIa inactivation in vivo is not known. We investigated FXIa inactivation in chimpanzees and assessed the

  6. Human malignant astrocytes express macrophage phenotype

    NARCIS (Netherlands)

    Leenstra, S.; Das, P. K.; Troost, D.; de Boer, O. J.; Bosch, D. A.

    1995-01-01

    Six well-characterized specimens of cultured astrocytoma cells were investigated with a panel of macrophage markers. Our results show that the macrophage markers OKM-1(CD11b), OKM5(CD36), EBM11(CD68), HAM56, Factor 13, alpha-1-antichymotrypsin, alpha-1-antitrypsin, ferritin and lysozyme are clearly

  7. Serum proteinase inhibitors and other serum proteins in protein-energy malnutrition

    NARCIS (Netherlands)

    Schelp, F.P.; Migasena, P.; Pongpaew, P.; SCHREURS W.H.P

    1977-01-01

    1. The concentrations of serum protein albumin, prealbumin and transferrin were determined in twenty-eight cases of protein-energy malnutrition (PEM) with infection, together with the levels of serum proteinase inhibitors (PI), alpha1-antitrypsin (AT), alpha1-antichymotrypsin (Ach),

  8. Alpha-particle fluence in radiobiological experiments.

    Science.gov (United States)

    Nikezic, Dragoslav; Yu, Kwan Ngok

    2017-03-01

    Two methods were proposed for determining alpha-particle fluence for radiobiological experiments. The first involved calculating the probabilities of hitting the target for alpha particles emitted from a source through Monte Carlo simulations, which when multiplied by the activity of the source gave the fluence at the target. The second relied on the number of chemically etched alpha-particle tracks developed on a solid-state nuclear track detector (SSNTD) that was irradiated by an alpha-particle source. The etching efficiencies (defined as percentages of latent tracks created by alpha particles from the source that could develop to become visible tracks upon chemical etching) were computed through Monte Carlo simulations, which when multiplied by the experimentally counted number of visible tracks would also give the fluence at the target. We studied alpha particles with an energy of 5.486 MeV emitted from an 241Am source, and considered the alpha-particle tracks developed on polyallyldiglycol carbonate film, which is a common SSNTD. Our results showed that the etching efficiencies were equal to one for source-film distances of from 0.6 to 3.5 cm for a circular film of radius of 1 cm, and for source-film distances of from 1 to 3 cm for circular film of radius of 2 cm. For circular film with a radius of 3 cm, the etching efficiencies never reached 1. On the other hand, the hit probability decreased monotonically with increase in the source-target distance, and fell to zero when the source-target distance was larger than the particle range in air. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

  9. Cancer radioimmunotherapy with alpha-emitting nuclides

    Energy Technology Data Exchange (ETDEWEB)

    Couturier, Olivier [INSERM U 601, Nantes (France); Place Alexis Ricordeau, Department of Nuclear Medicine, Nantes, Cedex (France); Supiot, Stephane; Degraef-Mougin, Marie; Faivre-Chauvet, Alain; Carlier, Thomas; Chatal, Jean-Francois; Davodeau, Francois; Cherel, Michel [INSERM U 601, Nantes (France)

    2005-04-01

    In lymphoid malignancies and in certain solid cancers such as medullary thyroid carcinoma, somewhat mixed success has been achieved when applying radioimmunotherapy (RIT) with {beta}-emitters for the treatment of refractory cases. The development of novel RIT with {alpha}-emitters has created new opportunities and theoretical advantages due to the high linear energy transfer (LET) and the short path length in biological tissue of {alpha}-particles. These physical properties offer the prospect of achieving selective tumoural cell killing. Thus, RIT with {alpha}-emitters appears particularly suited for the elimination of circulating single cells or cell clusters or for the treatment of micrometastases at an early stage. However, to avoid non-specific irradiation of healthy tissues, it is necessary to identify accessible tumoural targets easily and rapidly. For this purpose, a small number of {alpha}-emitters have been investigated, among which only a few have been used for in vivo preclinical studies. Another problem is the availability and cost of these radionuclides; for instance, the low cost and the development of a reliable actinium-225/bismuth-213 generator were probably determining elements in the choice of bismuth-213 in the only human trial of RIT with an {alpha}-emitter. This article reviews the literature concerning monoclonal antibodies radiolabelled with {alpha}-emitters that have been developed for possible RIT in cancer patients. The principal radio-immunoconjugates are considered, starting with physical and chemical properties of {alpha}-emitters, their mode of production, the possibilities and difficulties of labelling, in vitro studies and finally, when available, in vivo preclinical and clinical studies. (orig.)

  10. Cancer radioimmunotherapy with alpha-emitting nuclides.

    Science.gov (United States)

    Couturier, Olivier; Supiot, Stéphane; Degraef-Mougin, Marie; Faivre-Chauvet, Alain; Carlier, Thomas; Chatal, Jean-François; Davodeau, François; Cherel, Michel

    2005-05-01

    In lymphoid malignancies and in certain solid cancers such as medullary thyroid carcinoma, somewhat mixed success has been achieved when applying radioimmunotherapy (RIT) with beta-emitters for the treatment of refractory cases. The development of novel RIT with alpha-emitters has created new opportunities and theoretical advantages due to the high linear energy transfer (LET) and the short path length in biological tissue of alpha-particles. These physical properties offer the prospect of achieving selective tumoural cell killing. Thus, RIT with alpha-emitters appears particularly suited for the elimination of circulating single cells or cell clusters or for the treatment of micrometastases at an early stage. However, to avoid non-specific irradiation of healthy tissues, it is necessary to identify accessible tumoural targets easily and rapidly. For this purpose, a small number of alpha-emitters have been investigated, among which only a few have been used for in vivo preclinical studies. Another problem is the availability and cost of these radionuclides; for instance, the low cost and the development of a reliable actinium-225/bismuth-213 generator were probably determining elements in the choice of bismuth-213 in the only human trial of RIT with an alpha-emitter. This article reviews the literature concerning monoclonal antibodies radiolabelled with alpha-emitters that have been developed for possible RIT in cancer patients. The principal radio-immunoconjugates are considered, starting with physical and chemical properties of alpha-emitters, their mode of production, the possibilities and difficulties of labelling, in vitro studies and finally, when available, in vivo preclinical and clinical studies.

  11. Pharmacologic specificity of alpha-2 adrenergic receptor subtypes

    Energy Technology Data Exchange (ETDEWEB)

    Petrash, A.; Bylund, D.

    1986-03-01

    The authors have defined alpha-2 adrenergic receptor subtypes in human and rat tissues using prazosin as a subtype selective drug. Prazosin has a lower affinity (250 nM) at alpha-2A receptor and a higher affinity (5 nM) at alpha-2B receptors. In order to determine if other adrenergic drugs are selective for one or the other subtypes, the authors performed (/sup 3/H)yohimbine inhibition experiments with various adrenergic drugs in tissues containing alpha-2A, alpha-2B or both subtypes. Oxymetazoline, WB4101 and yohimbine were found to be 80-, 20- and 10-fold more potent at alpha-2A receptors than at alpha-2B receptors. Phentolamine, adazoxan, (+)- and (-)-mianserin, clonidine, (+)-butaclamol, (-)- and (+)-norepinephrine, epinephrine, dopamine and thioridazine were found to have equal affinities for the two subtypes. These results further validate the subdivision of alpha-2 adrenergic receptors into alpha-2A and alpha-2B subtypes.

  12. Alpha 1 B- but not alpha 1 A-adrenoceptors mediate inositol phosphate generation

    NARCIS (Netherlands)

    Michel, M. C.; Hanft, G.; Gross, G.

    1990-01-01

    We used novel highly subtype-selective antagonists to study whether alpha 1A- and/or alpha 1B-adrenoceptors mediate the stimulation of inositol phosphate generation by noradrenaline in rat cerebral cortex. Phentolamine (10 microM) and prazosin (100 nM) completely abolished the stimulated inositol

  13. Role of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in acute lung injury in rats

    DEFF Research Database (Denmark)

    Shanley, T P; Schmal, H; Friedl, H P

    1995-01-01

    The role of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in the pathogenesis of acute lung injury in rats after intrapulmonary deposition of IgG immune complexes or intratracheal administration of LPS has been assessed. Critical to these studies was the cloning and functional expression...

  14. Alpha-in-air monitor for continuous monitoring based on alpha to beta ratio

    International Nuclear Information System (INIS)

    Somayaji, K.S.; Venkataramani, R.; Swaminathan, N.; Pushparaja

    1997-01-01

    Measurement of long-lived alpha activity collected on a filter paper in continuous air monitoring of ambient working environment is difficult due to interference from much larger concentrations of short-lived alpha emitting daughter products of 222 Rn and 220 Rn. However, the ratio between the natural alpha and beta activity is approximately constant and this constancy of the ratio is used to discriminate against short-lived natural radioactivity in continuous air monitoring. Detection system was specially designed for the purpose of simultaneous counting of alpha and beta activity deposited on the filter paper during continuous monitoring. The activity ratios were calculated and plotted against the monitoring duration up to about six hours. Monitoring was carried out in three facilities with different ventilation conditions. Presence of any long-lived alpha contamination on the filter paper results in increase in the alpha to beta ratio. Long-lived 239 Pu contamination of about 16 DAC.h could be detected after about 45 minutes of commencement of the sampling. The experimental results using prototype units have shown that the approach of using alpha to beta activity ratio method to detect long-lived alpha activity in the presence of short-lived natural activity is satisfactory. (author)

  15. PLE CATALYZED HYDROLYZES OF ALPHA-SUBSTITUTED ALPHA-HYDROXY ESTERS - THE INFLUENCE OF THE SUBSTITUENTS

    NARCIS (Netherlands)

    MOORLAG, H; KELLOGG, RM

    1991-01-01

    The enzymatic hydrolyses of a variety of alpha-substituted mandelic and lactic esters using pig liver esterase (PLE) have been investigated. High to moderate enantioselectivity was found for various alpha-substituted mandelic esters, whereas PLE showed low to no enantioselectivity for

  16. Increased voluntary exercise in mice deficient for tumour necrosis factor-alpha and lymphotoxin-alpha.

    NARCIS (Netherlands)

    Netea, M.G.; Kullberg, B.J.; Vonk, A.G.; Verschueren, I.; Joosten, L.A.B.; Meer, J.W.M. van der

    2007-01-01

    BACKGROUND: The endogenous mediators playing a role in the sensing of fatigue and cessation of exercise are yet to be characterized. We hypothesized that proinflammatory cytokines, in particular tumour necrosis factor-alpha (TNFalpha) and lymphotoxin-alpha (LT) transmit signals leading to fatigue.

  17. Alpha-particle elastic scattering on [sup 16]O in the four [alpha]-particle model

    Energy Technology Data Exchange (ETDEWEB)

    Li Qingrun (CCAST (World Lab.), Beijing (China) Inst. of High Energy Physics, Academia Sinica, Beijing (China)); Yang Yongxu (Dept. of Physics, Guangxi Normal Univ., Guilin (China))

    1993-08-23

    A folding potential describing the alpha-particle scattering on [sup 16]O is constructed based on the four [alpha]-particle model of the nucleus [sup 16]O. This folding potential provides a good description of the experimental data covering a broad energy range. (orig.)

  18. Consistent Measurements of $\\alpha_{s}$ from Precise Oriented Event Shape Distributions

    CERN Document Server

    Abreu, P.; Adye, T.; Adzic, P.; Albrecht, Z.; Alderweireld, T.; Alekseev, G.D.; Alemany, R.; Allmendinger, T.; Allport, P.P.; Almehed, S.; Amaldi, U.; Amapane, N.; Amato, S.; Anassontzis, E.G.; Andersson, P.; Andreazza, A.; Andringa, S.; Antilogus, P.; Apel, W.D.; Arnoud, Y.; Asman, B.; Augustin, J.E.; Augustinus, A.; Baillon, P.; Bambade, P.; Barao, F.; Barbiellini, G.; Barbier, R.; Bardin, D.Yu.; Barker, G.J.; Baroncelli, A.; Battaglia, M.; Baubillier, M.; Becks, K.H.; Begalli, M.; Behrmann, A.; Beilliere, P.; Belokopytov, Yu.; Benekos, N.C.; Benvenuti, A.C.; Berat, C.; Berggren, M.; Bertini, D.; Bertrand, D.; Besancon, M.; Bigi, M.; Bilenky, Mikhail S.; Bizouard, M.A.; Bloch, D.; Blom, H.M.; Bonesini, M.; Bonivento, W.; Boonekamp, M.; Booth, P.S.L.; Borgland, A.W.; Borisov, G.; Bosio, C.; Botner, O.; Boudinov, E.; Bouquet, B.; Bourdarios, C.; Bowcock, T.J.V.; Boyko, I.; Bozovic, I.; Bozzo, M.; Branchini, P.; Brenke, T.; Brenner, R.A.; Bruckman, P.; Brunet, J.M.; Bugge, L.; Buran, T.; Burgsmuller, T.; Buschbeck, B.; Buschmann, P.; Cabrera, S.; Caccia, M.; Calvi, M.; Camporesi, T.; Canale, V.; Carena, F.; Carroll, L.; Caso, C.; Castillo Gimenez, M.V.; Cattai, A.; Cavallo, F.R.; Chabaud, V.; Charpentier, P.; Chaussard, L.; Checchia, P.; Chelkov, G.A.; Chierici, R.; Chochula, P.; Chorowicz, V.; Chudoba, J.; Cieslik, K.; Collins, P.; Contri, R.; Cortina, E.; Cosme, G.; Cossutti, F.; Cowell, J.H.; Crawley, H.B.; Crennell, D.; Crepe-Renaudin, Sabine; Crosetti, G.; Cuevas Maestro, J.; Czellar, S.; Davenport, M.; Da Silva, W.; Deghorain, A.; Della Ricca, G.; Delpierre, P.; Demaria, N.; De Angelis, A.; De Boer, W.; De Clercq, C.; De Lotto, B.; De Min, A.; De Paula, L.; Dijkstra, H.; Di Ciaccio, L.; Dolbeau, J.; Doroba, K.; Dracos, M.; Drees, J.; Dris, M.; Duperrin, A.; Durand, J.D.; Eigen, G.; Ekelof, T.; Ekspong, G.; Ellert, M.; Elsing, M.; Engel, J.P.; Erzen, B.; Espirito Santo, M.C.; Fanourakis, G.; Fassouliotis, D.; Fayot, J.; Feindt, M.; Ferrari, P.; Ferrer, A.; Ferrer-Ribas, E.; Ferro, F.; Fichet, S.; Firestone, A.; Flagmeyer, U.; Foeth, H.; Fokitis, E.; Fontanelli, F.; Franek, B.; Frodesen, A.G.; Fruhwirth, R.; Fulda-Quenzer, F.; Fuster, J.; Galloni, A.; Gamba, D.; Gamblin, S.; Gandelman, M.; Garcia, C.; Gaspar, C.; Gaspar, M.; Gasparini, U.; Gavillet, P.; Gazis, Evangelos; Gele, D.; Ghodbane, N.; Gil Botella, Ines; Glege, F.; Gokieli, R.; Golob, B.; Gomez-Ceballos, G.; Goncalves, P.; Gonzalez Caballero, I.; Gopal, G.; Gorn, L.; Gracco, V.; Grahl, J.; Graziani, E.; Green, C.; Grimm, H.J.; Gris, P.; Grosdidier, G.; Grzelak, K.; Gunther, M.; Guy, J.; Hahn, F.; Hahn, S.; Haider, S.; Hallgren, A.; Hamacher, K.; Hansen, J.; Harris, F.J.; Hedberg, V.; Heising, S.; Hernandez, J.J.; Herquet, P.; Herr, H.; Hessing, T.L.; Heuser, J.M.; Higon, E.; Holmgren, S.O.; Holt, P.J.; Hoorelbeke, S.; Houlden, M.; Hrubec, J.; Huet, K.; Hughes, G.J.; Hultqvist, K.; Jackson, John Neil; Jacobsson, R.; Jalocha, P.; Janik, R.; Jarlskog, C.; Jarlskog, G.; Jarry, P.; Jean-Marie, B.; Johansson, Erik Karl; Jonsson, P.; Joram, C.; Juillot, P.; Kapusta, Frederic; Karafasoulis, K.; Katsanevas, S.; Katsoufis, E.C.; Keranen, R.; Kersevan, B.P.; Khomenko, B.A.; Khovansky, N.N.; Kiiskinen, A.; King, B.; Kinvig, A.; Kjaer, N.J.; Klapp, O.; Klein, Hansjorg; Kluit, P.; Kokkinias, P.; Koratzinos, M.; Kourkoumelis, C.; Kuznetsov, O.; Krammer, M.; Kriznic, E.; Krumshtein, Z.; Kubinec, P.; Kurowska, J.; Kurvinen, K.; Lamsa, J.W.; Lane, D.W.; Langefeld, P.; Laugier, J.P.; Lauhakangas, R.; Leder, G.; Ledroit, Fabienne; Lefebure, V.; Leinonen, L.; Leisos, A.; Leitner, R.; Lemonne, J.; Lenzen, G.; Lepeltier, V.; Lesiak, T.; Lethuillier, M.; Libby, J.; Liko, D.; Lipniacka, A.; Lippi, I.; Lorstad, B.; Loken, J.G.; Lopes, J.H.; Lopez, J.M.; Lopez-Fernandez, R.; Loukas, D.; Lutz, P.; Lyons, L.; MacNaughton, J.; Mahon, J.R.; Maio, A.; Malek, A.; Malmgren, T.G.M.; Maltezos, S.; Malychev, V.; Mandl, F.; Marco, J.; Marco, R.; Marechal, B.; Margoni, M.; Marin, J.C.; Mariotti, C.; Markou, A.; Martinez-Rivero, C.; Martinez-Vidal, F.; Marti i Garcia, S.; Masik, J.; Mastroyiannopoulos, N.; Matorras, F.; Matteuzzi, C.; Matthiae, G.; Mazzucato, F.; Mazzucato, M.; McCubbin, M.; McKay, R.; McNulty, R.; McPherson, G.; Meroni, C.; Meyer, W.T.; Migliore, E.; Mirabito, L.; Mitaroff, W.A.; Mjornmark, U.; Moa, T.; Moch, M.; Moller, Rasmus; Monig, Klaus; Monge, M.R.; Moreau, X.; Morettini, P.; Morton, G.; Muller, U.; Munich, K.; Mulders, M.; Mulet-Marquis, C.; Muresan, R.; Murray, W.J.; Muryn, B.; Myatt, G.; Myklebust, T.; Naraghi, F.; Nassiakou, M.; Navarria, F.L.; Navas, Sergio; Nawrocki, K.; Negri, P.; Nemecek, S.; Neufeld, N.; Nicolaidou, R.; Nielsen, B.S.; Niezurawski, P.; Nikolenko, M.; Nomokonov, V.; Normand, A.; Nygren, A.; Olshevsky, A.G.; Onofre, A.; Orava, R.; Orazi, G.; Osterberg, K.; Ouraou, A.; Paganoni, M.; Paiano, S.; Pain, R.; Paiva, R.; Palacios, J.; Palka, H.; Papadopoulou, T.D.; Papageorgiou, K.; Pape, L.; Parkes, C.; Parodi, F.; Parzefall, U.; Passeri, A.; Passon, O.; Pegoraro, M.; Peralta, L.; Pernicka, M.; Perrotta, A.; Petridou, C.; Petrolini, A.; Phillips, H.T.; Pierre, F.; Pimenta, M.; Piotto, E.; Podobnik, T.; Pol, M.E.; Polok, G.; Poropat, P.; Pozdnyakov, V.; Privitera, P.; Pukhaeva, N.; Pullia, A.; Radojicic, D.; Ragazzi, S.; Rahmani, H.; Ratoff, P.N.; Read, Alexander L.; Rebecchi, P.; Redaelli, Nicola Giuseppe; Regler, M.; Reid, D.; Reinhardt, R.; Renton, P.B.; Resvanis, L.K.; Richard, F.; Ridky, J.; Rinaudo, G.; Rodrigo, German; Rohne, O.; Romero, A.; Ronchese, P.; Rosenberg, E.I.; Rosinsky, P.; Roudeau, P.; Rovelli, T.; Royon, C.; Ruhlmann-Kleider, V.; Ruiz, A.; Saarikko, H.; Sacquin, Y.; Sadovsky, A.; Sajot, G.; Salt, J.; Sampsonidis, D.; Sannino, M.; Schneider, H.; Schwemling, P.; Schwering, B.; Schwickerath, U.; Schyns, M.A.E.; Scuri, Fabrizio; Seager, P.; Sedykh, Yu.; Segar, A.M.; Sekulin, R.; Shellard, R.C.; Sheridan, A.; Siebel, M.; Simard, L.; Simonetto, F.; Sisakian, A.N.; Smadja, G.; Smirnova, O.; Smith, G.R.; Sopczak, A.; Sosnowski, R.; Spassoff, T.; Spiriti, E.; Sponholz, P.; Squarcia, S.; Stanescu, C.; Stanic, S.; Stevenson, K.; Stocchi, A.; Strauss, J.; Strub, R.; Stugu, B.; Szczekowski, M.; Szeptycka, M.; Tabarelli, T.; Tegenfeldt, F.; Terranova, F.; Thomas, J.; Timmermans, Jan; Tinti, N.; Tkachev, L.G.; Todorova, S.; Tomaradze, A.; Tome, B.; Tonazzo, A.; Tortora, L.; Transtromer, G.; Treille, D.; Tristram, G.; Trochimczuk, M.; Troncon, C.; Tsirou, A.; Turluer, M.L.; Tyapkin, I.A.; Tzamarias, S.; Ullaland, O.; Valenti, G.; Vallazza, E.; Vander Velde, C.; Van Apeldoorn, G.W.; Van Dam, Piet; Van Doninck, Walter; Van Eldik, J.; Van Lysebetten, A.; Van Remortel, N.; Van Vulpen, I.; Vassilopoulos, N.; Vegni, G.; Ventura, L.; Venus, W.; Verbeure, F.; Verlato, M.; Vertogradov, L.S.; Verzi, V.; Vilanova, D.; Vitale, L.; Vodopianov, A.S.; Vollmer, C.; Voulgaris, G.; Vrba, V.; Wahlen, H.; Walck, C.; Weiser, C.; Wicke, D.; Wickens, J.H.; Wilkinson, G.R.; Winter, M.; Witek, M.; Wolf, G.; Yi, J.; Zalewska, A.; Zalewski, P.; Zavrtanik, D.; Zevgolatakos, E.; Zimine, N.I.; Zucchelli, G.C.; Zumerle, G.

    2000-01-01

    An updated analysis using about 1.5 million events recorded at $\\sqrt{s} =M_Z$ with the DELPHI detector in 1994 is presented. Eighteen infrared and collinear safe event shape observables are measured as a function of the polar angle of the thrust axis. The data are compared to theoretical calculations in${\\cal O} (\\alpha_s^2)$ including the event orientation. A combined fit of $\\alpha_s$ and of the renormalization scale $x_{\\mu}$ in $\\cal O(\\alpha_s^2$)yields an excellent description of the high statistics data. The weighted average from 18 observables including quark mass effects and correlations is $\\alpha_s(M_Z^2) = 0.1174 \\pm 0.0026$. The final result, derived from the jet cone energy fraction, the observable with the smallest theoretical and experimental uncertainty, is $\\alpha_s(M_Z^2) = =0:1180 0:0006(exp:) 0:0013(hadr:) 0:0008(scale) 0:0007(mass). Further studies include an s determination using theoretical predictions in the next-to-leading log approximation (NLLA), matched NLLA and O(\\alpha^{2}_{s})...

  19. Activity monitoring of alpha-bearing wastes

    International Nuclear Information System (INIS)

    Birkhoff, G.; Bondar, L.

    1980-01-01

    The paper aims at the survey on the actual situation in activity monitoring of alpha-bearing wastes. Homogeneous materials such as liquid-, gaseous- and homogeneous solid wastes are amenable to destructive analyses of representative samples. Available destructive analyses methods are sensitive and precise enough to cope with all requirements in alpha-waste monitoring. The more difficult problems are encountered with alpha-contaminated solids, when representative sampling is not practicable. Non-destructive analysis techniques are applied for monitoring this category of solid wastes. The techniques for nondestructive analysis of alpha-bearing wastes are based on the detection of gamma and/or neutron-emission of actinides. Principles and a theory of non-destructive radiometric assay of plutonium contaminated solid waste streams are explained. Guidelines for the calibration of instruments and interpretation of experimental data are given. Current theoretical and experimental development work in this problem area is reviewed. Evaluations concerning capabilities and limitations of monitoring systems for alpha-bearing solid wastes are very complex and out of the scope of this paper

  20. Role of Frontal Alpha Oscillations in Creativity

    Science.gov (United States)

    Lustenberger, Caroline; Boyle, Michael R.; Foulser, A. Alban; Mellin, Juliann M.; Fröhlich, Flavio

    2015-01-01

    Creativity, the ability to produce innovative ideas, is a key higher-order cognitive function that is poorly understood. At the level of macroscopic cortical network dynamics, recent EEG data suggests that cortical oscillations in the alpha frequency band (8 – 12 Hz) are correlated with creative thinking. However, whether alpha oscillations play a fundamental role in creativity has remained unknown. Here we show that creativity is increased by enhancing alpha power using 10 Hz transcranial alternating current stimulation (10Hz-tACS) of the frontal cortex. In a study of 20 healthy participants with a randomized, balanced cross-over design, we found a significant improvement of 7.4% in the Creativity Index measured by the Torrance Test of Creative Thinking, a comprehensive and most frequently used assay of creative potential and strengths. In a second similar study with 20 subjects, 40Hz-tACS was used in instead of 10Hz-tACS to rule out a general “electrical stimulation” effect. No significant change in the Creativity Index was found for such frontal gamma stimulation. Our results suggest that alpha activity in frontal brain areas is selectively involved in creativity; this enhancement represents the first demonstration of specific neuronal dynamics that drive creativity and can be modulated by non-invasive brain stimulation. Our findings agree with the model that alpha recruitment increases with internal processing demands and is involved in inhibitory top-down control, which is an important requirement for creative ideation. PMID:25913062

  1. Evaluation of Acute Phase Reactants As Indicators of Activity in Leprosy

    Directory of Open Access Journals (Sweden)

    A P Jain

    1985-01-01

    Full Text Available Acute phase reactants i. e. ESR, C-reactive proteins, alpha 1 antitrypsin, complement (C3 and circulation immune complexes were evaluated in relation with the activity of the disease in leprosy. Levels of all the acute phase reactants were significantly raised during the active plase (LL and ENL, while these were normal during the arrested phase of the disease. Appearance of, circulating immune complexes also followed the same pattern. It is concluded that raised levels of ESR (C-reactive proteins, alpha-1 antitrypsin, complement (C3 and circulating immune complexes suggest active phase (LL ENL of the disease in leprosy.

  2. Feasibility of commercial space manufacturing, production of pharmaceuticals. Volume 2: Technical analysis

    Science.gov (United States)

    1978-01-01

    A technical analysis on the feasibility of commercial manufacturing of pharmaceuticals in space is presented. The method of obtaining pharmaceutical company involvement, laboratory results of the separation of serum proteins by the continuous flow electrophoresis process, the selection and study of candidate products, and their production requirements is described. The candidate products are antihemophilic factor, beta cells, erythropoietin, epidermal growth factor, alpha-1-antitrypsin and interferon. Production mass balances for antihemophelic factor, beta cells, and erythropoietin were compared for space versus ground operation. A conceptual description of a multiproduct processing system for space operation is discussed. Production requirements for epidermal growth factor of alpha-1-antitrypsin and interferon are presented.

  3. Purification and characterization of alpha-amylase from rat pancreatic acinar carcinoma. Comparison with pancreatic alpha-amylase.

    OpenAIRE

    Reddy, M K; Heda, G D; Reddy, J K

    1987-01-01

    alpha-Amylase was purified to apparent homogeneity from normal pancreas and a transplantable pancreatic acinar carcinoma of the rat by affinity chromatography on alpha-glucohydrolase inhibitor (alpha-GHI) bound to aminohexyl-Sepharose 4B. Recovery was 95-100% for both pancreas and tumour alpha-amylases. They were monomeric proteins, with Mr approx. 54000 on SDS/polyacrylamide-gel electrophoresis. Isoelectric focusing of both normal and tumour alpha-amylases resolved each into two major isoenz...

  4. Opposing actions of the progesterone metabolites, 5alpha-dihydroprogesterone (5alphaP) and 3alpha-dihydroprogesterone (3alphaHP) on mitosis, apoptosis, and expression of Bcl-2, Bax and p21 in human breast cell lines.

    Science.gov (United States)

    Wiebe, John P; Beausoleil, Michel; Zhang, Guihua; Cialacu, Valentin

    2010-01-01

    Previous studies have shown that breast tissues and breast cell lines convert progesterone (P) to 5alpha-dihydroprogesterone (5alphaP) and 3alpha-dihydroprogesterone (3alphaHP) and that 3alphaHP suppresses, whereas 5alphaP promotes, cell proliferation and detachment. The objectives of the current studies were to determine if the 5alphaP- and 3alphaHP-induced changes in cell numbers are due to altered rates of mitosis and/or apoptosis, and if 3alphaHP and 5alphaP act on tumorigenic and non-tumorigenic cells, regardless of estrogen (E) and P receptor status. The studies were conducted on tumorigenic (MCF-7, MDA-MB-231, T47D) and non-tumorigenic (MCF-10A) human breast cell lines, employing several methods to assess the effects of the hormones on cell proliferation, mitosis, apoptosis and expression of Bcl-2, Bax and p21. In all four cell lines, 5alphaP increased, whereas 3alphaHP decreased cell numbers, [(3)H]thymidine uptake and mitotic index. Apoptosis was stimulated by 3alphaHP and suppressed by 5alphaP. 5alphaP resulted in increases in Bcl-2/Bax ratio, indicating decreased apoptosis; 3alphaHP resulted in decreases in Bcl-2/Bax ratio, indicating increased apoptosis. The effects of either 3alphaHP or 5alphaP on cell numbers, [(3)H]thymidine uptake, mitosis, apoptosis, and Bcl-2/Bax ratio, were abrogated when cells were treated simultaneously with both hormones. The expression of p21 was increased by 3alphaHP, and was unaffected by 5alphaP. The results provide the first evidence that 5alphaP stimulates mitosis and suppresses apoptosis, whereas 3alphaHP inhibits mitosis and stimulates apoptosis. The opposing effects of 5alphaP and 3alphaHP were observed in all four breast cell lines examined and the data suggest that all breast cancers (estrogen-responsive and unresponsive) might be suppressed by blocking 5alphaP formation and/or increasing 3alphaHP. The findings further support the hypothesis that progesterone metabolites are key regulatory hormones and that changes

  5. Low energy alphas in the drift detector

    International Nuclear Information System (INIS)

    Snowden-Ifft, D.P.; Lawson, T.; Spooner, N.J.C.; Villaume, N.

    2004-01-01

    The Directional Recoil Identification From Tracks project is a US-UK endeavor to build and operate a low pressure negative ion TPC (NITPC) to search for weakly interacting massive particles (WIMPs) thought to make up the dark matter in our Galaxy. Low energy (∼10 keV) alpha events from U and Th decays within the walls and wires of the detector can enter the active volume of the detector and be confused for WIMP interactions. This paper presents data on and a model of low energy alphas in a NITPC operated at 40 Torr CS 2 with the aim of understanding and removing this potentially serious background. A comparison of the data to this model reveals good agreement with range predictions of SRIM2000 and allows us to calculate the energy dissipation per ion pair, W=19.0±0.5 eV for low energy alphas in CS 2

  6. Advances in alpha air monitoring instrumentation

    International Nuclear Information System (INIS)

    Valentine, A.M.

    1979-01-01

    Early detection of airborne radioactive material is important for effective protection of workers, particularly at facilities handling high toxicity alpha-emitting radionuclides such as 238 Pu and 239 Pu. Variable levels of ever present and naturally occurring alpha-emitting radon daughters made gross alpha air monitoring systems unreliable for live-time monitoring of airborne plutonium. Hence, good live-time monitoring was not possible until an improved alpha air monitoring instrument capable of monitoring select plutonium radionuclides of concern was developed and marketed by nuclear instrumentation companies in the USA during the late 1960s and early 1970s. This monitoring instrument utilized a solid-state silicon-diffused junction type of detector and pulse-height analyser system to achieve a radon-daughter rejection capability. This rejection capability has resulted in an improved sensitivity for specific alpha-emitting radionuclides such as 238 Pu, 239 Pu and 241 Am. Current models of this instrument are capable of detecting 40 dis/min (0.65 Bq) of plutonium alpha activity. This activity is about equal to the integrated activity workers would be exposed to if they worked for eight hours in an airborne concentration equal to the maximum permissible concentration for transportable 239 Pu. The Los Alamos Scientific Laboratory began using these instruments in its plutonium research laboratories when they became available in the early 1970s. Approximately 300 are currently in service, and their use has resulted in much improved protection of plutonium workers because accidental airborne releases can now be detected soon after they occur. General design features of these instruments are discussed together with actual operational experience and field calibration procedures. (author)

  7. Parallel Genetic Algorithm for Alpha Spectra Fitting

    Science.gov (United States)

    García-Orellana, Carlos J.; Rubio-Montero, Pilar; González-Velasco, Horacio

    2005-01-01

    We present a performance study of alpha-particle spectra fitting using parallel Genetic Algorithm (GA). The method uses a two-step approach. In the first step we run parallel GA to find an initial solution for the second step, in which we use Levenberg-Marquardt (LM) method for a precise final fit. GA is a high resources-demanding method, so we use a Beowulf cluster for parallel simulation. The relationship between simulation time (and parallel efficiency) and processors number is studied using several alpha spectra, with the aim of obtaining a method to estimate the optimal processors number that must be used in a simulation.

  8. Enteric alpha defensins in norm and pathology

    Directory of Open Access Journals (Sweden)

    Lisitsyn Nikolai A

    2012-01-01

    Full Text Available Abstract Microbes living in the mammalian gut exist in constant contact with immunity system that prevents infection and maintains homeostasis. Enteric alpha defensins play an important role in regulation of bacterial colonization of the gut, as well as in activation of pro- and anti-inflammatory responses of the adaptive immune system cells in lamina propria. This review summarizes currently available data on functions of mammalian enteric alpha defensins in the immune defense and changes in their secretion in intestinal inflammatory diseases and cancer.

  9. Clustering of Lyman-Alpha Emitters galaxies

    Science.gov (United States)

    Francke, Harold

    2009-06-01

    Galaxy clustering properties have been studied for decades to constrain cosmological parameters and have today, with large datasets of high-redshift sources piling up, become a powerful tool to discriminate and characterize primeval galaxies. In the last years, several Lyman-Alpha Emitter (LAE) galaxy samples have been gathered, which are big, uniform and compact enough to allow clustering analysis. Here we present a summary of the discussion session on the clustering properties of LAEs at the "Understanding Lyman-Alpha Emitters" conference.

  10. Diffusion of cobalt in alpha zirconium

    International Nuclear Information System (INIS)

    Ghosh, U.; Pruthi, D.D.; Anand, M.S.

    1979-01-01

    The diffusion of 60 Co in alpha zirconium has been studied in the temperature range of 873-1123 K using the sectioning technique. The diffusion parameters obey the following Arrhenius equation:- D = (1.132 +- 0.22)10 -4 exp((-136.43 +- 3.50 KJ)/RT)m 2 s -1 . The diffusivity in this phase is as high as that observed in β-phase. It is also about five orders of magnitude higher when compared to the self diffusion values. The high diffusivity of cobalt in alpha zirconium has been explained on the basis of an interstitial mechanism. (auth.)

  11. Radiological hazards of alpha-contaminated waste

    International Nuclear Information System (INIS)

    Rodgers, J.C.

    1982-01-01

    The radiological hazards of alpha-contaminated wastes are discussed in this overview in terms of two components of hazard: radiobiological hazard, and radioecological hazard. Radiobiological hazard refers to human uptake of alpha-emitters by inhalation and ingestion, and the resultant dose to critical organs of the body. Radioecological hazard refers to the processes of release from buried wastes, transport in the environment, and translocation to man through the food chain. Besides detailing the sources and magnitude of hazards, this brief review identifies the uncertainties in their estimation, and implications for the regulatory process

  12. The murine alpha B-crystallin/small heat shock protein enhancer: identification of alpha BE-1, alpha BE-2, alpha BE-3, and MRF control elements.

    OpenAIRE

    Gopal-Srivastava, R; Piatigorsky, J

    1993-01-01

    The murine alpha B-crystallin gene (a member of the small heat shock protein family) is expressed constitutively at high levels in the lens and at lower levels in many other tissues, including skeletal muscle. We have previously used the herpes simplex virus thymidine kinase promoter fused to the human growth hormone gene to identify an alpha B-crystallin enhancer at positions -427 to -259 that has high activity in muscle and low activity in lens cell lines. In the study reported here, we per...

  13. Fan-less long range alpha detector

    Science.gov (United States)

    MacArthur, Duncan W.; Bounds, John A.

    1994-01-01

    A fan-less long range alpha detector which operates by using an electrical field between a signal plane and the surface or substance to be monitored for air ions created by collisions with alpha radiation. Without a fan, the detector can operate without the possibility of spreading dust and potential contamination into the atmosphere. A guard plane between the signal plane and the electrically conductive enclosure and maintained at the same voltage as the signal plane, reduces leakage currents. The detector can easily monitor soil, or other solid or liquid surfaces.

  14. Recoil-alpha-fission and recoil-alpha-alpha-fission events observed in the reaction Ca-48 + Am-243

    NARCIS (Netherlands)

    Forsberg, U.; Rudolph, D.; Andersson, L. -L.; Nitto, A. Di; Düllmann, Ch E.; Gates, J. M.; Golubev, P.; Gregorich, K. E.; Gross, C. J.; Herzberg, R. -D.; Hessberger, F. P.; Khuyagbaatar, J.; Kratz, J. V.; Rykaczewski, K.; Sarmiento, L. G.; Schädel, M.; Yakushev, A.; Åberg, S.; Ackermann, D.; Block, M.; Brand, H.; Carlsson, B. G.; Cox, D.; Derkx, X.; Dobaczewski, J.; Eberhardt, K.; Even, J.; Fahlander, C.; Gerl, J.; Jäger, E.; Kindler, B.; Krier, J.; Kojouharov, I.; Kurz, N.; Lommel, B.; Mistry, A.; Mokry, C.; Nazarewicz, W.; Nitsche, H.; Omtvedt, J. P.; Papadakis, P.; Ragnarsson, I.; Runke, J.; Schaffner, H.; Schausten, B.; Shi, Y.; Thörle-Pospiech, P.; Torres, T.; Traut, T.; Trautmann, N.; Türler, A.; Ward, A.; Ward, D. E.; Wiehl, N.

    2016-01-01

    Products of the fusion-evaporation reaction Ca-48 + Am-243 were studied with the TASISpec set-up at the gas-filled separator TASCA at the GSI Helmholtzzentrum f\\"ur Schwerionenforschung. Amongst the detected thirty correlated alpha-decay chains associated with the production of element Z=115, two

  15. Alpha 1-adrenoceptor subtypes in the rat ventricular muscle.

    Science.gov (United States)

    Kinami, J; Tsuchihashi, H; Baba, S; Mano, F; Maruyama, K; Nagatomo, T

    1992-02-01

    Scatchard analyses of [3H]prazosin binding in rat ventricular muscle membranes showed biphasic curves, which identified alpha 1High- and alpha 1Low-affinity sites. The alpha 1High-affinity site was completely inhibited by 1 microM phenoxybenzamine. The displacement potencies of alpha 1-adrenergic antagonists were characterized by [3H]prazosin binding to alpha 1High- and alpha 1Low-affinity sites in the absence and presence of 1 microM phenoxybenzamine. The affinities of most chemicals for alpha 1Low-affinity sites were significantly lower than those for alpha 1High-affinity sites, but WB-4101 (2-(2,6-dimethoxy-phenoxyethyl)aminomethyl-1,4-benzodioxane), arotinolol, cinanserin, nifedipine, and p-aminoclonidine had the same affinities for both alpha 1Low- and alpha 1High-affinity sites. These results show that two alpha 1-adrenoceptor subtypes, alpha 1High- and alpha 1Low-affinity, are present in the rat heart, and that there are physical variations in alpha 1-adrenoceptor binding sites, based on their selectivity to antagonists.

  16. Six HLA-D region alpha-chain genes on human chromosome 6: polymorphisms and associations of DC alpha-related sequences with DR types.

    OpenAIRE

    Spielman, R S; Lee, J; Bodmer, W F; Bodmer, J G; Trowsdale, J

    1984-01-01

    Analysis of cosmid clones containing genes related to the HLA-DR alpha chain calls for at least six HLA-D region alpha-chain coding sequences in man; namely, DR alpha, DC alpha, DX alpha (very closely related to DC alpha), SB alpha 1, SB alpha 2 (two closely linked genes on the same cosmid clones), and DZ alpha. The first four genes have been described previously. SB alpha 2 and DZ alpha are recently identified genes, characterized by their unique and, from a limited study, nonpolymorphic ban...

  17. Phenomenological Alpha-Alpha Interactions and its Application on 16O Nucleus

    International Nuclear Information System (INIS)

    Qandil, O.S.A.A.

    2013-01-01

    The thesis includes the study of alpha-alpha interactions and apply them to the nucleus of the 16 O by using Hartree-Fock method for bosons. The used potentials are Ali-Bodmer potential, Modified Woods- Saxon potential, Fish-Bone I (FB-I) and Fish-Bone II (FB-II) potential. Also, the properties of nuclear structure of 16 O nucleus are calculated such as binding energy, form factor and root mean square radius. The results we have obtained were compared with previous results in the same field of research topic. This work requires knowledge of different kinds of potentials and the difference between the phenomenological and microscopic interactions and research in Hartree-Fock method and nuclear models, especially shell model. The content of the present thesis can be summarized as the following: The first Chapter, (Introduction), presents detailed informations about the nuclear structure, clustering, alpha clustering and nuclear models especially the shell model. Also, a review of previous researches in the research topic ( phenomenological alpha- alpha interactions). The second chapter, (Alpha-Alpha interactions), many types of phenomenological alpha-alpha interactions and its various forms are displayed, including what has been used in the thesis.The third chapter, (Derivation of Hartree-Fock Method for Bosons), illustrates the theoretical calculations which have been used in the thesis, the derivation of the Hartree-Fock method for bosons, the variational method and the derivation of binding energy, form factor and root mean square radius equations. the fourth chapter, (Numerical Results and Discussion), includes the present theoretical results of the nuclear structure of 16 O nucleus using the previous four potentials, and comparing our present results with the experimental and previous theoretical ones.

  18. Thermochemical Stability of alpha-Amino-alpha-carbonylmethyl Radicals and Their Resonance As Measured by ESR.

    Science.gov (United States)

    Welle, Frank M.; Beckhaus, Hans-Dieter; Rüchardt, Christoph

    1997-02-07

    ESR spectra of the captodative alpha-amino-alpha-carbonylmethyl radicals 8 have been recorded. No coalescence temperature for the rotation of the two NMe groups was found at temperatures below the decomposition temperature of the radicals. From known coalescence temperatures and rotational barriers of substituted methyl radicals the rotational barrier of >/=17 kcal mol(-)(1) was estimated for the (*)C-N bond in the radicals 8. Enthalpies DeltaH(diss) and entropies DeltaS(diss) of the homolytic dissociation of 7a,c,d into 8a,c,d have been obtained from equilibrium measurements by ESR. By correcting for substituent interaction enthalpies in 7 (steric and geminal), a radical stabilization enthalpy RSE = -20.7 +/- 1.0 kcal mol(-)(1) was obtained for 8. By addition of the known RSEs of dialkylamino- and carbonyl groups, a RSE = -9.9 kcal mol(-)(1) is predicted for 8. The difference between the experimental and predicted values of 10.8 kcal mol(-)(1) is attributed to a synergistic captodative substituent effect. A linear correlation between the radical stabilization enthalpies of the radicals 8 and of other mono- and disubstituted alkyl radicals and their ESR aH(alpha) coupling constants was found. According to this correlation the reduction of aH(alpha) by 1 G corresponds to an increase in RSE of 1.57 kcal mol(-)(1). The large resonance of the captodative alpha-amino-alpha-carbonylmethyl radicals 3, expressed by their high RSE, their small aH(alpha) coupling constant, and their high rotational barrier, can be rationalized by a strong interaction between the alpha-amino and the alpha-carbonyl groups similar to that in amides and expressed in the resonance structures 6.

  19. Production of pi /sup 0/ at large transverse momentum in alpha alpha and alpha p collisions at the CERN Intersecting Storage Rings

    CERN Document Server

    Karabarbounis, A; Fields, T; Filippas-Tassos, A; Fokitis, E; Goldberg, M; Kourkoumelis, C; Lissauer, D; Mannelli, I; Molzon, W; Mouzourakis, P; Palmer, R B; Rahm, David Charles; Rehak, P; Resvanis, L K; Stumer, I; Trakkas, C; Willis, W

    1981-01-01

    Inclusive pi /sup 0/ production has been measured at the CERN Intersecting Storage Rings in alpha alpha and alpha p collisions near 90 degrees , for p/sub T/ between 2 and 5 GeV/c. The differential cross sections show a slower exponential fall-off with p/sub T/ than has been observed in pp collisions at the corresponding nucleon- nucleon centre-of-mass energies at large p/sub T/. The ratio of the pi /sup 0/ production cross sections for alpha alpha collisions to those for pp collisions is observed to be larger than 16. (8 refs).

  20. A survey of the alpha-nucleon interaction

    International Nuclear Information System (INIS)

    Ali, S.; Ahmad, A.A.Z.; Ferdous, N.

    1984-10-01

    A survey of the alpha-nucleon interaction is made. The experimental work on angular distributions of differential scattering cross-sections and polarizations in proton-alpha and neutron-alpha scattering is described. The phenomenological approach which includes the study of both local and non-local potentials reproducing the experimental alpha-nucleon scattering data, is discussed. Basic studies of the alpha-nucleon interaction attempting to build an interaction between an alpha particle and a nucleon from first principles are then described. A critical discussion of the results with some concluding remarks suggesting the direction for further investigation is made. (author)

  1. Production of {alpha}-glucosidases by Bacillus sp. strains

    Energy Technology Data Exchange (ETDEWEB)

    Castro, G.R. [Univ. Nacional de Tucuman, Facultad de Bioquimica, Quimica y Farmacia, Catedra de Microbiologia Superior, PROIMI-MIRCEN, Tucuman (Argentina); Baigori, M.D. [Univ. Nacional de Tucuman, Facultad de Bioquimica, Quimica y Farmacia, Catedra de Microbiologia Superior, PROIMI-MIRCEN, Tucuman (Argentina); Sineriz, F. [Univ. Nacional de Tucuman, Facultad de Bioquimica, Quimica y Farmacia, Catedra de Microbiologia Superior, PROIMI-MIRCEN, Tucuman (Argentina)

    1995-12-31

    {alpha}-Glucosidase was detected in four wild-type amylolytic production strains belonging to the Bacillus genus. The strains showed {alpha}-glucosidase activity in extracellular and membrane-bound fractions. Kinetic studies of the {alpha}-glucosidase synthesis in the batch cultures of four strains of the Bacillus genus showed two profiles: partially and totally growth-linked synthesis. The presence of different activities and production profiles of {alpha}-glucosidase in the strains at high or low glucose concentrations in the medium would indicate that {alpha}-glucosidase may have a role in the regulation of the metabolism of {alpha}-polysaccharides. (orig.)

  2. Remarks on tilde g_{alpha}-irresolute maps

    Directory of Open Access Journals (Sweden)

    Nirmala Rebecca Paul

    2011-12-01

    Full Text Available Only a few of the class of generalized closed sets form a topology. The class of tilde g_{alpha}-closed sets is one among them. The aim of this paper is to introduce the different notions of irresolute function using tilde g_{alpha}-closed sets and study some of their basic properties.We also study the relation between strongly tilde g_{alpha}- continuous and perfectly eg-continuous functions. We also introduce tilde g_{alpha}-compact and ilde g_{alpha}-connectedspaces and study their properties using tilde g_{alpha}-continuous and eg-irresolute functions.

  3. Neuropsychiatric Complications Associated with Interferon - Alpha ...

    African Journals Online (AJOL)

    Several adverse effects have been associated with interferon alpha 2b treatment and neuropsychiatric effects have also been commonly reported. Psychosis and mood disorders have been described in the literature. This case report is of a 30 year old man with malignant melanoma stage 3a who was receiving adjuvant ...

  4. Alpha -2b treatment of Malignant Melanoma

    African Journals Online (AJOL)

    Introduction. Interferon preparations such as interferon alpha are widely used in the treatment of a number of non malignant and malignant conditions including malignant melanoma where it used. Mania has been observed in patients undergoing interferon treatment especially after significant dose- reduction or treatment ...

  5. Laboratory system for alpha particle spectroscopy

    International Nuclear Information System (INIS)

    Dean, J.R.; Chiu, N.W.

    1987-03-01

    An automated alpha particle spectroscopy system has beeen designed and fabricated. It consists of two major components, the automatic sample changer and the controller/data acquisition unit. It is capable of unattended analysis of ten samples for up to 65,000 seconds per sample

  6. Biomarkers of Alpha Particle Radiation Exposure

    Science.gov (United States)

    2014-04-01

    work towards the identification of gene-based biomarkers of alpha-particle radiation exposure. Peripheral blood mononuclear cells (PBMN) isolated from...manipulation et l’exposition au rayonnement ionisant chez les humains . CSSP-2012-CD-1117 and CSSP-2012-CD-1114 iii Table of contents...19 Acknowledgements This work was supported by the Centre for

  7. Superparamagnetic relaxation in alpha-Fe particles

    DEFF Research Database (Denmark)

    Bødker, Franz; Mørup, Steen; Pedersen, Michael Stanley

    1998-01-01

    The superparamagnetic relaxation time of carbon-supported alpha-Fe particles with an average size of 3.0 Mm has been studied over a large temperature range by the use of Mossbauer spectroscopy combined with AC and DC magnetization measurements. It is found that the relaxation time varies with tem...

  8. Extraction of molybdenum VI by alpha benzoinoxime

    International Nuclear Information System (INIS)

    Achache, M.; Meklati, M.

    1990-06-01

    The concentration of molybdenum, was studied using alpha benzoinoxime dissolved in chloroform. Several acids and salt at different levels of concentration were investigated as well as other parameters such as (mixing time, extractant to metal ratio, temperature etc.) The molybdenum stippling was also studied in alkaline medium with the subsequent recovery of the extractant and solvent

  9. Syndecan-4 associates with alpha-actinin

    DEFF Research Database (Denmark)

    Greene, Daniel K; Tumova, Sarka; Couchman, John R

    2002-01-01

    during the formation of focal adhesions. To date, a direct link between syndecan-4 and the cytoskeleton has remained elusive. We now demonstrate by Triton X-100 extraction immunoprecipitation and in vitro binding assays that the focal adhesion component alpha-actinin interacts with syndecan-4 in a beta...

  10. Diagnosis of foetal membrane ruptures: Placental alpha ...

    African Journals Online (AJOL)

    AbstRACt. Context: Pre‑labour rupture of membranes (PROM) is a common obstetric complication which presents a diagnostic challenge, especially in equivocal cases. Standard methods of diagnosis are limited by high false positives and negatives. This study compared the accuracy of a biomarker placental alpha ...

  11. Evaluation of microcrystalline cellulose modifed from alpha ...

    African Journals Online (AJOL)

    Alpha cellulose was obtained from Costus afer and part of it was modified to microcrystalline cellulose (CAMCC). The physicochemical properties of the microcrystalline cellulose were determined and compared with those of commercial microcrystalline cellulose (Avicel 101). The swelling capacity, hydration capacity, loss ...

  12. Physicochemical and powder properties of alpha- and ...

    African Journals Online (AJOL)

    Cob alpha-celluloses (CAC) was extracted from maize cobs by defibering, delignification and bleaching; then subjected to acid hydrolysis to obtain Cob- microcrystalline-cellulose (CMCC). Their physicochemical properties were evaluated and compared with those of Avicel®, a commercial variety of microcrystalline ...

  13. Comparison of alpha decay and alpha transfer reactions in the lead region. [R matrix theory, absolute alpha widths, cross sections, 93 MeV

    Energy Technology Data Exchange (ETDEWEB)

    DeVries, R.M.

    1978-01-01

    Data were taken for five transitions in the lead region allowing a quantitative comparison with corresponding alpha-decay data via R-matrix theory using the same target + alpha nuclear potential. Good agreement between the absolute reduced widths determined from the two sets of data suggests that in transfer reactions, as in alpha decay, an alpha particle in its ground state is transferred in a one-step process. In a separate analysis, elastic and total reaction cross sections for the systems ..cap alpha.. + /sup 208/Pb, /sup 209/Bi were analyzed to obtain a limited set of potentials which, in turn, were used to calculate absolute alpha widths. Existing shell model calculations give ..gamma../sub ..cap alpha..//sup 2/ values three orders of magnitude smaller.

  14. Involvement of the clock gene Rev-erb alpha in the regulation of glucagon secretion in pancreatic alpha-cells.

    Directory of Open Access Journals (Sweden)

    Elaine Vieira

    Full Text Available Disruption of pancreatic clock genes impairs pancreatic beta-cell function, leading to the onset of diabetes. Despite the importance of pancreatic alpha-cells in the regulation of glucose homeostasis and in diabetes pathophysiology, nothing is known about the role of clock genes in these cells. Here, we identify the clock gene Rev-erb alpha as a new intracellular regulator of glucagon secretion. Rev-erb alpha down-regulation by siRNA (60-70% inhibition in alphaTC1-9 cells inhibited low-glucose induced glucagon secretion (p<0.05 and led to a decrease in key genes of the exocytotic machinery. The Rev-erb alpha agonist GSK4112 increased glucagon secretion (1.6 fold and intracellular calcium signals in alphaTC1-9 cells and mouse primary alpha-cells, whereas the Rev-erb alpha antagonist SR8278 produced the opposite effect. At 0.5 mM glucose, alphaTC1-9 cells exhibited intrinsic circadian Rev-erb alpha expression oscillations that were inhibited by 11 mM glucose. In mouse primary alpha-cells, glucose induced similar effects (p<0.001. High glucose inhibited key genes controlled by AMPK such as Nampt, Sirt1 and PGC-1 alpha in alphaTC1-9 cells (p<0.05. AMPK activation by metformin completely reversed the inhibitory effect of glucose on Nampt-Sirt1-PGC-1 alpha and Rev-erb alpha. Nampt inhibition decreased Sirt1, PGC-1 alpha and Rev-erb alpha mRNA expression (p<0.01 and glucagon release (p<0.05. These findings identify Rev-erb alpha as a new intracellular regulator of glucagon secretion via AMPK/Nampt/Sirt1 pathway.

  15. Nicotine enhances expression of the alpha 3, alpha 4, alpha 5, and alpha 7 nicotinic receptors modulating calcium metabolism and regulating adhesion and motility of respiratory epithelial cells.

    Science.gov (United States)

    Zia, S; Ndoye, A; Nguyen, V T; Grando, S A

    1997-09-01

    The purpose of this study was to investigate the possibility of direct toxic effects of nicotine (Nic) on human bronchial epithelial cells (BEC) suggested by our previous findings of functional nicotinic acetylcholine receptors (nAChRs) in the epithelial cells lining mucocutaneous membranes. We now demonstrate for the first time that human and murine BEC both in vivo and in vitro express functional nAChRs, and that classic alpha 3, alpha 4, alpha 5 and alpha 7 subunits can contribute to formation of these acetylcholine-gated ion channels. In human bronchial and mouse lung tissues, and in cultures of human BEC, the nAChRs were visualized by subunit-specific antibodies on the cell membranes, particularly at the sites of cell-to-cell contacts. The epithelial cells of submucosal glands abundantly expressed alpha 7 nAChRs. Smoking significantly (p epithelial nAChRs apparently involve regulation of cell-to-cell communications, adhesion and motility, because Mec caused rapid and profound changes in these cell functions which were reversible by Nic. An over exposure of BEC to Nic, however, produced an antagonist-like effect, suggesting that the pathobiological effects of Nic toxicity might result from both activation of nAChR channels and nAChR desensitization. We conclude that medical consequences of smoking can be mediated by direct toxic effects of inhaled Nic on the respiratory tissues wherein Nic specifically binds to and activates the nicotinic ion channels present on the cell surfaces of BEC. We believe that outside the neural system Nic interferes with functioning of non-neuronal cholinergic networks by displacing from nAChR its natural ligand acetylcholine which acts as a local hormone or cytokine in a variety of non-neuronal locations.

  16. Chromaticity separation and the alpha response.

    Science.gov (United States)

    Haigh, S M; Cooper, N R; Wilkins, A J

    2018-01-08

    Chromatic gratings can be uncomfortable to view and can evoke a large haemodynamic response. Both the discomfort and the amplitude of the haemodynamic response increase monotonically with the perceptual difference in the colour of the component bars of the grating, as registered by the separation in their chromaticity in the CIE 1976 UCS diagram. Individuals with photosensitive epilepsy exhibit epileptiform EEG activity in response to flickering light of alternate colours. The probability of the epileptiform response again increases monotonically with the separation of the colours in the CIE UCS diagram. We investigated whether alpha power, which is known to reflect the excitation of large populations of neurons, is similarly affected by the separation in chromaticity. Chromatic square-wave gratings with bars that differed in CIE UCS chromaticity were presented, together with a central fixation cross. In 18 non-clinical participants, alpha responses were recorded over the visual cortex (O1, Oz, O2, PO3, POz, PO4, P1, P2) and compared to responses in prefrontal cortex (F1, F2). Gratings comprised bars of two alternate colours that either had a small difference in chromaticity (mean CIE UCS separation of 0.03), a medium difference (mean separation of 0.19), or a large difference (mean separation of 0.43). The colour pairs had chromaticities that lay on the red-green, red-blue, or blue-green borders of the screen gamut. Regardless of the hue, the larger the separation in chromaticity, the greater the alpha desynchronization and the lower the alpha power (p = 0.004), but only in posterior electrodes (p < 0.001). Together this indicates that differences in colour evoke a cortical excitation that increases monotonically with the colour difference. In this respect the alpha response resembles the haemodynamic response. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. The measurement of $\\alpha_s$ from event shapes with the DELPHI detector at the highest LEP energies

    CERN Document Server

    Abdallah, J; Adam, W; Adzic, P; Albrecht, T; Alderweireld, T; Alemany-Fernandez, R; Allmendinger, T; Allport, P P; Amaldi, Ugo; Amapane, N; Amato, S; Anashkin, E; Andreazza, A; Andringa, S; Anjos, N; Antilogus, P; Apel, W D; Arnoud, Y; Ask, S; Åsman, B; Augustin, J E; Augustinus, A; Baillon, Paul; Ballestrero, A; Bambade, P; Barbier, R; Bardin, Dimitri Yuri; Barker, G; Baroncelli, A; Battaglia, Marco; Baubillier, M; Becks, K H; Begalli, M; Behrmann, A; Ben-Haim, E; Benekos, N C; Benvenuti, Alberto C; Bérat, C; Berggren, M; Berntzon, L; Bertrand, D; Besançon, M; Besson, N; Bloch, D; Blom, M; Bluj, M; Bonesini, M; Boonekamp, M; Booth, P S L; Borisov, G; Botner, O; Bouquet, B; Bowcock, T J V; Boyko, I; Bracko, M; Brenner, R; Brodet, E; Brückman, P; Brunet, J M; Bugge, L; Buschmann, P; Calvi, M; Camporesi, T; Canale, V; Carena, F; Castro, N; Cavallo, F R; Chapkin, M M; Charpentier, P; Checchia, P; Chierici, R; Shlyapnikov, P; Chudoba, J; Chung, S U; Cieslik, K; Collins, P; Contri, R; Cosme, G; Cossutti, F; Costa, M J; Crennell, D J; Cuevas-Maestro, J; D'Hondt, J; Dalmau, J; Da Silva, T; Da Silva, W; Della Ricca, G; De Angelis, A; de Boer, Wim; De Clercq, C; De Lotto, B; De Maria, N; De Min, A; De Paula, L S; Di Ciaccio, Lucia; Di Simone, A; Doroba, K; Drees, J; Dris, M; Eigen, G; Ekelöf, T J C; Ellert, M; Elsing, M; Espirito-Santo, M C; Fanourakis, G K; Fassouliotis, D; Feindt, M; Fernández, J; Ferrer, A; Ferro, F; Flagmeyer, U; Föth, H; Fokitis, E; Fulda-Quenzer, F; Fuster, J A; Gandelman, M; García, C; Gavillet, P; Gazis, E N; Gokieli, R; Golob, B; Gómez-Ceballos, G; Gonçalves, P; Graziani, E; Grosdidier, G; Grzelak, K; Guy, J; Haag, C; Hallgren, A; Hamacher, K; Hamilton, K; Haug, S; Hauler, F; Hedberg, V; Hennecke, M; Herr, H; Hoffman, J; Holmgren, S O; Holt, P J; Houlden, M A; Hultqvist, K; Jackson, J N; Jarlskog, G; Jarry, P; Jeans, D; Johansson, E K; Johansson, P D; Jonsson, P; Joram, C; Jungermann, L; Kapusta, F; Katsanevas, S; Katsoufis, E C; Kernel, G; Kersevan, Borut P; Kerzel, U; Kiiskinen, A P; King, B T; Kjaer, N J; Kluit, P; Kokkinias, P; Kourkoumelis, C; Kuznetsov, O; Krumshtein, Z; Kucharczyk, M; Lamsa, J; Leder, G; Ledroit, F; Leinonen, L; Leitner, R; Lemonne, J; Lepeltier, V; Lesiak, T; Liebig, W; Liko, D; Lipniacka, A; Lopes, J H; López, J M; Loukas, D; Lutz, P; Lyons, L; MacNaughton, J; Malek, A; Maltezos, S; Mandl, F; Marco, J; Marco, R; Maréchal, B; Margoni, M; Marin, J C; Mariotti, C; Markou, A; Martínez-Rivero, C; Masik, J; Mastroyiannopoulos, N; Matorras, F; Matteuzzi, C; Mazzucato, F; Mazzucato, M; McNulty, R; Meroni, C; Migliore, E; Mitaroff, W A; Mjörnmark, U; Moa, T; Moch, M; Mönig, K; Monge, R; Montenegro, J; Moraes, D; Moreno, S; Morettini, P; Müller, U; Münich, K; Mulders, M; Mundim, L M; Murray, W; Muryn, B; Myatt, Gerald; Myklebust, T; Nassiakou, M; Navarria, Francesco Luigi; Nawrocki, K; Nicolaidou, R; Nikolenko, M; Oblakowska-Mucha, A; Obraztsov, V F; Olshevskii, A G; Onofre, A; Orava, Risto; Österberg, K; Ouraou, A; Oyanguren, A; Paganoni, M; Paiano, S; Palacios, J P; Palka, H; Papadopoulou, T D; Pape, L; Parkes, C; Parodi, F; Parzefall, U; Passeri, A; Passon, O; Peralta, L; Perepelitsa, V F; Perrotta, A; Petrolini, A; Piedra, J; Pieri, L; Pierre, F; Pimenta, M; Piotto, E; Podobnik, T; Poireau, V; Pol, M E; Polok, G; Poropat, P; Pozdnyakov, V; Pukhaeva, N; Pullia, Antonio; Rames, J; Ramler, L; Read, A; Rebecchi, P; Rehn, J; Reid, D; Reinhardt, R; Renton, P B; Richard, F; Rídky, J; Rivero, M; Rodríguez, D; Romero, A; Ronchese, P; Roudeau, Patrick; Rovelli, T; Ruhlmann-Kleider, V; Ryabtchikov, D; Sadovskii, A; Salmi, L; Salt, J; Savoy-Navarro, A; Schwickerath, U; Segar, A; Sekulin, R L; Siebel, M; Sissakian, A N; Smadja, G; Smirnova, O G; Sokolov, A; Sopczak, A; Sosnowski, R; Spassoff, Tz; Stanitzki, M; Stocchi, A; Strauss, J; Stugu, B; Szczekowski, M; Szeptycka, M; Szumlak, T; Tabarelli de Fatis, T; Taffard, A C; Tegenfeldt, F; Timmermans, J; Tkatchev, L G; Tobin, M; Todorovova, S; Tomé, B; Tonazzo, A; Tortosa, P; Travnicek, P; Treille, D; Tristram, G; Trochimczuk, M; Troncon, C; Turluer, M L; Tyapkin, I A; Tyapkin, P; Tzamarias, S; Uvarov, V; Valenti, G; van Dam, P; Van Eldik, J; Van Lysebetten, A; Van Remortel, N; Van Vulpen, I B; Vegni, G; Veloso, F; Venus, W A; Verdier, P; Verzi, V; Vilanova, D; Vitale, L; Vrba, V; Wahlen, H; Washbrook, A J; Weiser, C; Wicke, D; Wickens, J H; Wilkinson, G; Winter, M; Witek, M; Yushchenko, O P; Zalewska-Bak, A; Zalewski, Piotr; Zavrtanik, D; Zhuravlov, V; Zimin, N I; Zinchenko, A I; Zupan, M

    2004-01-01

    Hadronic event shape distributions are determined from data in e+e- collisions between 183 and 207 GeV. From these the strong coupling alpha_s is extracted in O(alpha_s^2), NLLA and matched O(alpha_s^2)+NLLA theory. Hadronisation corrections evaluated with fragmentation model generators as well as an analytical power ansatz are applied. Comparing these measurements to those obtained at and around M_Z allows a combined measurement of alpha_s from all DELPHI data and a test of the energy dependence of the strong coupling.

  18. Measurement of total alpha activity in water; Messung der Gesamt-Alpha-Aktivitaet in Wasser

    Energy Technology Data Exchange (ETDEWEB)

    Eikenberg, Jost [Paul Scherrer Institut (PSI), Villigen (Switzerland). Abt. fuer Strahlenschutz und Sicherheit; Florschuetz, Bernd [Hessisches Landesamt fuer Umwelt und Geologie, Kassel (Germany). Dezernat 15 - Strahlenschutz; Salvamoser, Josef [Institut fuer Angewandte Isotopen-, Gas- und Umweltuntersuchungen, Woerthsee (Germany); Steinkopff, Thomas [Deutscher Wetterdienst, Offenbach am Main (Germany); Wilhelm, Christoph [Karlsruher Institut fuer Technologie (KIT), Eggenstein-Leopoldshafen (Germany). Sicherheitsmanagement - Analytische Labore; Wisser, Sascha [FCI, Mainz (Germany)

    2014-04-01

    The article describes the measurement of the total alpha activity in an (evaporated) liquid sample, and the various sample preparation methods for measurements with proportional counters or LSC. (orig.)

  19. Synthesis and coupling reactions of alpha,alpha-dialkylated amino acids with nucleobase side chains.

    OpenAIRE

    Azumaya, I; Aebi, R; Kubik, S; Rebek, J

    1995-01-01

    Several di- and tripeptides containing protected purine (adenine) and pyrimidine (thymine) residues on their side chains were synthesized. The parent amino acids alpha, alpha-dialkylated in a symmetrical manner. An effective coupling procedure was developed for these sterically hindered amino acids: the fluoren-9-ylmethyloxycarbonyl-protected amino acid was dehydrated to its oxazolinone form, which was coupled in good yields with amino esters in hot tetrachloroethane.

  20. Catalytic enantioselective Michael addition reactions of alpha-nitroesters to alpha,beta-unsaturated ketones

    NARCIS (Netherlands)

    Keller, E; Veldman, N; Spek, AL; Feringa, BL

    1997-01-01

    Enantioselective Michael additions of alpha-nitroesters 2a-d with alpha,beta-unsaturated ketones were carried out in the presence of a catalytic amount of chiral Al-Li-(R,R')-2,2'-dihydroxy-1,1'-binaphthyl ('AlLiBINOL') complex prepared in situ from LiAlH4 and 2.45 equiv. of (R,R')-BINOL. The

  1. CAMEX-4 NOAA LYMAN-ALPHA HYGROMETER V1

    Data.gov (United States)

    National Aeronautics and Space Administration — The CAMEX-4 NOAA Lyman-Alpha Hygrometer dataset was collected by the NOAA Lyman-alpha Total Water Hygrometer, which was flown during the fourth field campaign in the...

  2. Alpha-(trifluoromethyl)amine derivatives via nucleophilic trifluoromethylation of nitrones.

    Science.gov (United States)

    Nelson, D W; Owens, J; Hiraldo, D

    2001-04-20

    (Trifluoromethyl)trimethylsilane (TMSCF(3)) reacts with nitrones to afford alpha-(trifluoromethyl)hydroxylamines protected as O-trimethylsilyl ethers. Potassium t-butoxide initiates the nucleophilic trifluoromethylation. The reaction works best with alpha,N-diaryl nitrones, and the conditions are compatible with a range of substituents on the aryl groups. Acidic deprotection of the nitrone/TMSCF(3) adducts generates alpha-(trifluoromethyl)hydroxylamines. Catalytic hydrogenation of the adducts produces alpha-(trifluoromethyl)amines. Nitrone/TMSCF(3) adducts with strong electron-withdrawing groups on the alpha-aryl ring or heterocyclic alpha-aryl groups undergo an elimination/addition sequence to generate alpha,alpha-bis(trifluoromethyl)amines. Nitrones with alkyl groups bound directly to the 1,3-dipolar moiety fail to react with TMSCF(3), but trifluoromethylation of beta,gamma-unsaturated nitrones followed by reduction of the double bond can circumvent this limitation.

  3. Plasma Ubiquinone, Alpha-Tocopherol and Cholesterol in Man

    DEFF Research Database (Denmark)

    Karlsson, Jan; Diamant, Bertil; Edlund, Per Olof

    1992-01-01

    Farmakologi, Coenzyme Q10, free cholesterol, vitamin E, antioxidants, Alpha-Tocopherol, vitamin Q, plasma, LDL-particle......Farmakologi, Coenzyme Q10, free cholesterol, vitamin E, antioxidants, Alpha-Tocopherol, vitamin Q, plasma, LDL-particle...

  4. Estimation of Time-Varying Autoregressive Symmetric Alpha Stable

    Data.gov (United States)

    National Aeronautics and Space Administration — In the last decade alpha-stable distributions have become a standard model for impulsive data. Especially the linear symmetric alpha-stable processes have found...

  5. Interferon alpha for chronic hepatitis D.

    Science.gov (United States)

    Abbas, Zaigham; Khan, Muhammad Arsalan; Salih, Mohammad; Jafri, Wasim

    2011-12-07

    Hepatitis D virus is a small defective RNA virus that requires the presence of hepatitis B virus infection to infect a person. Hepatitis D is a difficult-to-treat infection. Several clinical trials have been published on the efficacy of interferon alpha for hepatitis D virus (HDV) infection. However, there are few randomised trials evaluating the effects of interferon alpha, and it is difficult to judge any benefit of this intervention from the individual trials. To evaluate the beneficial and harmful effects of interferon alpha for patients with chronic hepatitis D. We identified relevant for the review randomised clinical trials by electronic searches in the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until May 2011. We also checked the bibliographic references of identified randomised trials, textbooks, and review articles in order to find randomised trials not identified by the electronic searches. Randomised clinical trials evaluating interferon alpha versus placebo or no intervention for patients with chronic hepatitis D infection. Two authors assessed the trials and extracted data on mortality, virologic, biochemical, and histological response as well as adverse events at end of treatment and six months or more after completing treatment. The analyses were performed using the intention-to-treat principle including all randomised participants irrespective of follow-up. Drop-outs, withdrawals, and non-compliance were considered as treatment failures. Data were analysed with fixed- and random-effects models. Reported results were based on fixed-effect model except in cases where statistical significance varied between the two models. Six randomised trials fulfilled the inclusion criteria. Two hundred and one randomised participants (male = 174) were included. The risk of bias in all the included trials was high

  6. Silicon vertex detector upgrade in the ALPHA experiment

    CERN Document Server

    Amole, C; Ashkezari, M.D; Baquero-Ruiz, M; Bertsche, W; Burrows, C; Butler, E; Capra, A; Cesar, C.L; Chapman, S; Charlton, M; Deller, A; Eriksson, S; Fajans, J; Friesen, T; Fujiwara, M.C; Gill, D.R; Gutierrez, A; Hangst, J.S; Hardy, W.N; Hayden, M.E; Humphries, A.J; Isaac, C.A; Jonsell, S; Kurchaninov, L; Little, A; Madsen, N; McKenna, J.T.K; Menary, S; Napoli, S.C; Nolan, P; Olchanski, K; Olin, A; Povilus, A; Pusa, P; Rasmussen, C.Ø; Robicheaux, F; Sacramento, R.L; Sampson, J.A; Sarid, E; Seddon, D; Silveira, D.M; So, C; Stracka, S; Tharp, T; Thompson, R.I; Thornhill, J; Tooley, M.P; Van Der Werf, D.P; Wells, D

    2013-01-01

    The Silicon Vertex Detector (SVD) is the main diagnostic tool in the ALPHA-experiment. It provides precise spatial and timing information of antiproton (antihydrogen) annihilation events (vertices), and most importantly, the SVD is capable of directly identifying and analysing single annihilation events, thereby forming the basis of ALPHA ' s analysis. This paper describes the ALPHA SVD and its upgrade, installed in the ALPHA ' s new neutral atom trap.

  7. Expression of alpha-amylase in Bacillus licheniformis.

    OpenAIRE

    Rothstein, D M; Devlin, P E; Cate, R L

    1986-01-01

    In Bacillus licheniformis, alpha-amylase production varied more than 100-fold depending on the presence or absence of a catabolite-repressing carbon source in the growth medium. alpha-Amylase was produced during the growth phase and not at the onset of the stationary phase. Induction of alpha-amylase correlated with synthesis of mRNA initiating at the promoter of the alpha-amylase gene.

  8. Covariation of spectral and nonlinear EEG measures with alpha biofeedback.

    NARCIS (Netherlands)

    Fell, J.; Elfadil, H.; Klaver, P.; Roschke, J.; Elger, C.E.; Fernandez, G.S.E.

    2002-01-01

    This study investigated how different spectral and nonlinear EEG measures covaried with alpha power during auditory alpha biofeedback training, performed by 13 healthy subjects. We found a significant positive correlation of alpha power with the largest Lyapunov-exponent, pointing to an increased

  9. Particularization of alpha contamination using CR-39 track detectors

    Indian Academy of Sciences (India)

    Solid-state nuclear track detectors have found wide use in various domains of science and technology, e.g. in environmental experiments. The measurement of alpha activity on sources in an environment, such as air is not easy because of short penetration range of alpha particles. Furthermore, measurement of alpha ...

  10. Determination of plutonium-238 in plutonium by alpha spectrometry

    International Nuclear Information System (INIS)

    Aggarwal, S.K.; Jain, H.C.; Mathews, C.K.; Ramaniah, M.V.

    1975-01-01

    A method is presented for the determination of 238 Pu in plutonium samples by alpha spectrometry. Various factors attributing towards the energy degradation, a problem usually encountered in alpha spectrometry, are discussed. A computer programme is given for the evaluation of peak areas when the alpha spectrum is degraded. The results are compared with those obtained by mass spectrometry. (author)

  11. Alpha blockers: A relook at phenoxybenzamine

    Directory of Open Access Journals (Sweden)

    Sambhunath Das

    2017-01-01

    Full Text Available Phenoxybenzamine (PBZ is an alpha adrenergic antagonist, used for the management of hypertension. PBZ acts by blocking alpha-adrenergic receptors, leading to vasodilatation and low systemic vascular resistance. This helps in control of blood pressure in pheochromocytoma, improvement of systemic oxygen delivery, and optimization of the Qp/Qs in pediatric cardiac surgery such as hypoplastic left heart syndrome and improving perfusion parameters during open heart surgery. The uses have further extended to causalgia, Raynaud's phenomenon, autonomic hyperreflexia, and even for patency of radial artery conduit in coronary artery bypass grafting surgery. However, its prolonged hypotensive effect limits the regular use. In this review, we discussed the mechanism of action, pharmaco-physiology of PBZ, perioperative uses in different clinical setting and controversies for its uses; publications in different scientific journals from the previous years.

  12. The Alpha Magnetic Spectrometer Silicon Tracker

    CERN Document Server

    Burger, W J

    1999-01-01

    The Alpha Magnetic Spectrometer (AMS) is designed as a independent module for installation on the International Space Station Alpha (ISSA) in the year 2002 for an operational period of three years. The principal scientific objectives are the searches for antimatter and dark matter in cosmic rays. The AMS uses 5.5 m sup 2 of silicon microstrip sensors to reconstruct charged particle trajectories in the field of a permanent magnet. The detector design and construction covered a 3 yr period which terminated with a test flight on the NASA space shuttle Discovery during June 2-12, 1988. In this contribution, we describe the shuttle version of the AMS silicon tracker, including preliminary results of the tracker performance during the flight. (author)

  13. Alpha-contaminated waste management workshop

    International Nuclear Information System (INIS)

    1982-12-01

    These proceedings are published to provide a record of the oral presentations made at the DOE Alpha-Contaminated Workshop held in Gaithersburg, Maryland, on August 10-13, 1982. The papers are transcriptions of these oral presentations and, as such, do not contain as significant detail as will be found in the reviewed papers to be published in the periodical Nuclear and Chemical Waste Management in the first issue for 1983. These transcriptions have been reviewed by the speakers and some illustrations have been provided, but these contain only the preliminary information that will be provided in the technical papers to be published in the periodical. These papers have been grouped under the following headings: source terms; disposal technology and practices for alpha-contaminated waste; risk analyses and safety assessments. These papers in addition to those dealing with legislative and regulatory aspects have been abstracted and indexed for the Energy Data Base

  14. Sneutrino Inflation with $\\alpha$-attractors

    CERN Document Server

    Kallosh, Renata; Roest, Diederik; Wrase, Timm

    2016-11-22

    Sneutrino inflation employs the fermionic partners of the inflaton and stabilizer field as right-handed neutrinos to realize the seesaw mechanism for light neutrino masses. A crucial ingredient in existing constructions for sneutrino (multi-)natural inflation is an unbroken discrete shift symmetry. We demonstrate that a similar construction applies to $\\alpha$-attractor models. In this case the hyperbolic geometry protects the neutrino Yukawa couplings to the inflaton field, and the masses of leptons and Higgs fields, from blowing up when the inflaton is super-Planckian. We find that the predictions for $n_s$ and $r$ for $\\alpha$-attractor cosmological models, compatible with the current cosmological data, are preserved in the presence of the neutrino sector.

  15. The ALPHA project: a progress report

    International Nuclear Information System (INIS)

    Yadigaroglu, G.; Cachard, F. de; Coddington, P.; Dreier, J.; Smith, B.; Guentay, S.; Varadi, G.

    1995-01-01

    A review of the ALPHA project is presented, including a summary of progress and current status. The project comprises the experimental and analytical investigation of the long-term decay heat removal phenomena from the containment of the next generation of 'passive' Advanced Light Water Reactors. The effects of aerosols that may result from hypothetical severe accidents are also considered. The construction of the major ALPHA experimental facilities, PANDA, LINX-2 and AIDA, has been completed and all facilities are now in their commissioning phases. Scaling studies have guided the design of the experimental facilities. Several small-scale experiments and studies have already produced valuable results which can be used to direct the experimental work, as well as the design of the passive ALWRs. (author) 7 figs., 23 refs

  16. Alpha Resonant States in 13C

    International Nuclear Information System (INIS)

    Rodrigues, M. R. D.; Borello-Lewin, T.; Horodynski-Matsushigue, L. B.; Duarte, J. L. M.; Rodrigues, C. L.; Souza, M. A.; Miyake, H.; Cunsolo, A.; Cappuzzello, F.; Ukita, G. M.

    2011-01-01

    The 9 Be( 6 Li,d) 13 C reaction was used to investigate alpha resonant states in 13 C up to 15 MeV of excitation. The reaction was measured at a bombarding energy of 25.5 MeV employing the Sao Paulo Pelletron-Enge-Spectrograph facility and the nuclear emulsion detection technique. An energy resolution of 50 keV was obtained. Several narrow alpha resonant states not previously measured were detected, in particular the one at the (3α+n) threshold populated by an L = 2 transfer, revealing a 9 Be+α component for the 1/2 - cluster state candidate at this threshold. Experimental angular distributions are presented in comparison with DWBA predictions.

  17. Ripple loss of alpha particles in ITER

    International Nuclear Information System (INIS)

    Tani, Keiji; Takizuka, Tomonori; Azumi, Masafumi

    1989-07-01

    Part I: A benchmark test for the ripple loss of alpha particles in ITER has been executed by using an orbit-following Monte-Carlo (OFMC) code. In ITER with a plasma current of the order of 10 MA and an edge ripple of the order of 3%, the total power-loss fraction derived by JAERI's OFMC code is 6.6%. Part II: Two dimensional heat load on the first wall due to ripple loss of alpha particles in ITER has been estimated by using an OFMC code. The peak heat load due to ripple-trapped loss is of the order of 0.1 MW/m 2 . The peak heat load by ripple-untrapped loss averaged over the toroidal angle is about 0.07 MW/m 2 . (author)

  18. Determination of alpha radionuclides in fish

    International Nuclear Information System (INIS)

    Pernicka, L.; Matel, L.; Rosskopfova, O.

    2001-01-01

    In atmospheric water, external water and undercurrent the occurrence of radionuclides is usual. It is an important factor of quality of the environment. Plants ingest radionuclides from water and with they everyone. And it arises radioactivity infest food-chain. Radiotoxicity of this radionuclides is very deer sometimes. The sensitive radiochemical procedures for their determination are necessarily important. The poster presents the combined procedure used at our laboratory for determination of alpha radionuclides in biological samples. (authors)

  19. Alpha autoradiography by cellulose nitrate layer

    International Nuclear Information System (INIS)

    Simonovic, J.; Vukovic, J.; Antanasijevic, R.

    1977-01-01

    From domestic cellulose nitrate bulk material thin layers for α-particle autoradiography were prepared. An artificial test specimen of a uniformly alpha labelled grid source was used. The efficiency of autoradiography by cellulose nitrate was calculated comparing with data from an Ilford K2 nuclear emulsion exposed under the same conditions as the cellulose nitrate film. The resolution was determined as the distance from grid pitch edge at which the track density fell considerably. (Auth.)

  20. Alpha autoradiography by cellulose nitrate layer

    International Nuclear Information System (INIS)

    Simonovic, J.; Vukovic, J.; Antanasijevic, R.

    1976-01-01

    From domestic cellulose nitrate bulk material thin layers for α-particle autoradiography were prepared. An artifical test specimen of a uniformly alpha labelled grid source was used. The efficiency of autoradiographs by cellulose nitrate was calculated comparing with data from an Ilford K2 nuclear emulsion exposed under the same conditions as the cellulose nitrate film. The resolution was determined as the distance from grid pitch edge at which the track density fell considerably. (orig.) [de

  1. Effects of internally deposited alpha emitters

    International Nuclear Information System (INIS)

    Rundo, J.; Schlenker, R.A.; Stebbings, J.H.

    1985-01-01

    This study seeks to identify and quantify the human health effects of occupational exposures to radium, use the health effects data from the radium study to predict responses to other alpha-emitting and/or bone-seeking radionuclides at occupational exposure levels and above, and predict the effects of these radionuclides, specifically environmental radium and its daughters, at nonoccupational exposure levels. 14 refs

  2. Alpha Emitting Radionuclides and Radiopharmaceuticals for Therapy

    International Nuclear Information System (INIS)

    Chérel, Michel; Barbet, Jacques

    2013-01-01

    Today, cancer treatments mainly rely on surgery or external beam radiation to remove or destroy bulky tumors. Chemotherapy is given when tumours cannot be removed or when dissemination is suspected. However, these approaches cannot permanently treat all cancers and relapse occurs in up to 50% of the patients’ population. Radioimmunotherapy (RIT) and peptide receptor radionuclide therapy (PRRT) are effective against some disseminated and metastatic diseases, although they are rarely curative. Most preclinical and clinical developments in this field have involved electron-emitting radionuclides, particularly iodine-131, yttrium-90 and lutetium-177. The large range of the electrons emitted by these radionuclides reduces their efficacy against very small tumour cell clusters or isolated tumour cells present in residual disease and in many haematological tumours (leukaemia, myeloma). The range of alpha particles in biological tissues is very short, less than 0.1 mm, which makes alpha emitters theoretically ideal for treatment of such isolated tumour cells or micro-clusters of malignant cells. Thus, over the last decade, a growing interest for the use of alpha-emitting radionuclides has emerged. Research on targeted alpha therapy (TAT) began years ago in Nantes through cooperation between Subatech, a nuclear physics laboratory, CRCNA, a cancer research centre with a nuclear oncology team and ITU (Karlsruhe, Germany). CD138 was demonstrated as a potential target antigen for Multiple Myeloma, which is a target of huge clinical interest particularly suited for TAT because of the disseminated nature of the disease consisting primarily of isolated cells and small clusters of tumour cells mainly localized in the bone marrow. Thus anti-CD138 antibodies were labelled with bismuth-213 from actinium-225/bismuth-213 generators provided by ITU and used to target multiple myeloma cells. In vitro studies showed cell cycle arrest, synergism with chemotherapy and very little induction

  3. Alpha-particle Gas Pressure Gauge

    Science.gov (United States)

    Buehler, M. G.; Bell, L. D.; Hecht, M. H.

    1995-01-01

    Described are preliminary results obtained on a novel gas pressure gauge that operates between 0.1 and 1000 mb. This gauge uses a 1- micron Ci alpha particle source to ionize the gas in a small chamber with an electric field imposed between anode and cathode electrodes that drives positive ions to the cathode where they are collected electronically. This gauge could make Martian pressure measurements.

  4. Proceedings, High-Precision $\\alpha_s$ Measurements from LHC to FCC-ee

    Energy Technology Data Exchange (ETDEWEB)

    d' Enterria, David [CERN; Skands, Peter Z. [Monash U.

    2015-01-01

    This document provides a writeup of all contributions to the workshop on "High precision measurements of $\\alpha_s$: From LHC to FCC-ee" held at CERN, Oct. 12--13, 2015. The workshop explored in depth the latest developments on the determination of the QCD coupling $\\alpha_s$ from 15 methods where high precision measurements are (or will be) available. Those include low-energy observables: (i) lattice QCD, (ii) pion decay factor, (iii) quarkonia and (iv) $\\tau$ decays, (v) soft parton-to-hadron fragmentation functions, as well as high-energy observables: (vi) global fits of parton distribution functions, (vii) hard parton-to-hadron fragmentation functions, (viii) jets in $e^\\pm$p DIS and $\\gamma$-p photoproduction, (ix) photon structure function in $\\gamma$-$\\gamma$, (x) event shapes and (xi) jet cross sections in $e^+e^-$ collisions, (xii) W boson and (xiii) Z boson decays, and (xiv) jets and (xv) top-quark cross sections in proton-(anti)proton collisions. The current status of the theoretical and experimental uncertainties associated to each extraction method, the improvements expected from LHC data in the coming years, and future perspectives achievable in $e^+e^-$ collisions at the Future Circular Collider (FCC-ee) with $\\cal{O}$(1--100 ab$^{-1}$) integrated luminosities yielding 10$^{12}$ Z bosons and jets, and 10$^{8}$ W bosons and $\\tau$ leptons, are thoroughly reviewed. The current uncertainty of the (preliminary) 2015 strong coupling world-average value, $\\alpha_s(m_Z)$ = 0.1177 $\\pm$ 0.0013, is about 1\\%. Some participants believed this may be reduced by a factor of three in the near future by including novel high-precision observables, although this opinion was not universally shared. At the FCC-ee facility, a factor of ten reduction in the $\\alpha_s$ uncertainty should be possible, mostly thanks to the huge Z and W data samples available.

  5. Convulxin binds to native, human glycoprotein Ib alpha.

    Science.gov (United States)

    Kanaji, Sachiko; Kanaji, Taisuke; Furihata, Kenichi; Kato, Kazunobu; Ware, Jerry L; Kunicki, Thomas J

    2003-10-10

    Convulxin (CVX), a C-type snake protein from Crotalus durissus terrificus venom, is the quintessential agonist for studies of the collagen receptor, glycoprotein VI (GPVI) and its role in platelet adhesion to collagens. In this study, CVX, purified from venom, behaves as expected, i.e. it binds to platelet GPVI and recombinant human GPVI, induces platelet aggregation and platelet prothrombinase activity, and binds uniquely to GPVI in ligand blots of SDS-denatured proteins. Nonetheless, we find that CVX has a dual specificity for both GPVI and native but not denatured human GPIb alpha. First, CVX binds to human GPIb alpha expressed on the surface of CHO cells. Second, CVX binds weakly to murine platelet GPIb alpha but more strongly to human platelet GPIb alpha, as evidenced by comparative binding to wild-type, GPVI(-/-), FcR gamma (-/-), and human GPIb transgenic mice. Third, the binding of CVX to human GPIb alpha is inhibited by soluble, recombinant human GPVI. Fourth, CVX binding to GPIb alpha is disrupted by phenylalanine substitutions at GPIb alpha tyrosine-276, tyrosine-278, and tyrosine-279, which also disrupts von Willebrand factor and alpha-thrombin binding to GPIb alpha. Fifth, CVX binding to GPIb alpha on Chinese hamster ovary cell transfectants is inhibited by function-blocking murine monoclonal anti-GPIb alpha antibodies. Lastly, CVX fails to bind to denatured GPIb alpha in detergent extracts of platelets. Three separate preparations of CVX (two purified by the authors; one obtained commercially) produced equivalent results. These results indicate that CVX exhibits dual specificity for both native GPIb alpha and GPVI. Furthermore, the binding site on GPIb alpha for CVX may be close to that for von Willebrand factor. Therefore, a contribution of GPIb alpha to CVX-induced platelet responses needs to be carefully re-evaluated.

  6. Fasting induces basolateral uptake transporters of the SLC family in the liver via HNF4alpha and PGC1alpha.

    Science.gov (United States)

    Dietrich, Christoph G; Martin, Ina V; Porn, Anne C; Voigt, Sebastian; Gartung, Carsten; Trautwein, Christian; Geier, Andreas

    2007-09-01

    Fasting induces numerous adaptive changes in metabolism by several central signaling pathways, the most important represented by the HNF4alpha/PGC-1alpha-pathway. Because HNF4alpha has been identified as central regulator of basolateral bile acid transporters and a previous study reports increased basolateral bile acid uptake into the liver during fasting, we hypothesized that HNF4alpha is involved in fasting-induced bile acid uptake via upregulation of basolateral bile acid transporters. In rats, mRNA of Ntcp, Oatp1, and Oatp2 were significantly increased after 48 h of fasting. Protein expression as determined by Western blot showed significant increases for all three transporters 72 h after the onset of fasting. Whereas binding activity of HNF1alpha in electrophoretic mobility shift assays remained unchanged, HNF4alpha binding activity to the Ntcp promoter was increased significantly. In line with this result, we found significantly increased mRNA expression of HNF4alpha and PGC-1alpha. Functional studies in HepG2 cells revealed an increased endogenous NTCP mRNA expression upon cotransfection with either HNF4alpha, PGC-1alpha, or a combination of both. We conclude that upregulation of the basolateral bile acid transporters Ntcp, Oatp1, and Oatp2 in fasted rats is mediated via the HNF4alpha/PGC-1alpha pathway.

  7. Alpha 1A and alpha 1B-adrenoceptors enhance inositol phosphate generation in rat renal cortex

    NARCIS (Netherlands)

    Michel, M. C.; Büscher, R.; Philipp, T.; Brodde, O. E.

    1993-01-01

    We have studied the role of alpha 1A- and alpha 1B-adrenoceptors in noradrenaline- and methoxamine-stimulated inositol phosphate accumulation in rat renal cortical slices. [3H]Prazosin binding studies with and without inactivation of alpha 1B-adrenoceptors by chloroethylclonidine treatment suggested

  8. 5alphaDH-DOC (5alpha-dihydro-deoxycorticosterone) activates androgen receptor in castration-resistant prostate cancer.

    Science.gov (United States)

    Uemura, Motohide; Honma, Seijiro; Chung, Suyoun; Takata, Ryo; Furihata, Mutsuo; Nishimura, Kazuo; Nonomura, Norio; Nasu, Yasutomo; Miki, Tsuneharu; Shuin, Taro; Fujioka, Tomoaki; Okuyama, Akihiko; Nakamura, Yusuke; Nakagawa, Hidewaki

    2010-08-01

    Prostate cancer often relapses during androgen-depletion therapy, even under the castration condition in which circulating androgens are drastically reduced. High expressions of androgen receptor (AR) and genes involved in androgen metabolism indicate a continued role for AR in castration-resistant prostate cancers (CRPCs). There is increasing evidence that some amounts of 5alpha-dihydrotestosterone (DHT) and other androgens are present sufficiently to activate AR within CRPC tissues, and enzymes involved in the androgen and steroid metabolism, such as 5alpha-steroid reductases, are activated in CRPCs. In this report, we screened eight natural 5alphaDH-steroids to search for novel products of 5alpha-steroid reductases, and identified 11-deoxycorticosterone (DOC) as a novel substrate for 5alpha-steroid reductases in CRPCs. 11-Deoxycorticosterone (DOC) and 5alpha-dihydro-deoxycorticosterone (5alphaDH-DOC) could promote prostate cancer cell proliferation through AR activation, and type 1 5alpha-steroid reductase (SRD5A1) could convert from DOC to 5alphaDH-DOC. Sensitive liquid chromatography-tandem mass spectrometric analysis detected 5alphaDH-DOC in some clinical CRPC tissues. These findings implicated that under an extremely low level of DHT, 5alphaDH-DOC and other products of 5alpha-steroid reductases within CRPC tissues might activate the AR pathway for prostate cancer cell proliferation and survival under castration.

  9. Structure of the alpha-1,6/alpha-1,4-specific glucansucrase GTFA from Lactobacillus reuteri 121

    NARCIS (Netherlands)

    Pijning, Tjaard; Vujicic-Zagar, Andreja; Kralj, Slavko; Dijkhuizen, Lubbert; Dijkstra, Bauke; Vujičić-Žagar, Andreja

    2012-01-01

    The reuteransucrase GTFA from Lactobacillus reuteri 121, which belongs to glycosyl hydrolase family GH70, synthesizes branched alpha-glucans with both alpha-1,6-and alpha-1,4-glycosidic linkages (reuteran) from sucrose. The crystal structure of GTFA-Delta N, a 118 kDa fragment of GTFA comprising

  10. Comparison of alpha 1A- and alpha 1B-adrenoceptor coupling to inositol phosphate formation in rat kidney

    NARCIS (Netherlands)

    Büscher, R.; Erdbrügger, W.; Philipp, T.; Brodde, O. E.; Michel, M. C.

    1994-01-01

    We have compared the coupling mechanisms of rat renal alpha 1A- and alpha 1B-like adrenoceptors to inositol phosphate formation. The experiments were performed in parallel in native renal tissue preparations and in those where alpha 1B-adrenoceptors had been inactivated by treatment with 10 mumol/l

  11. ALPHA, Mass Generation and Quantum Information

    Science.gov (United States)

    Goradia, Shantilal

    2008-05-01

    The generation of Planck energy 10E19 Gev/Planck time during the observable age of the universe (10E60 Planck times) would generate 10E79 Gev. 10E79 Gev approximates the energy of the baryon number, implying an increase of the baryon number by 10E19/Planck time. What is the source of energy for this mass generation? The ALPHA implicated as negative entropy in [1] must create vacuum energy. Vacuum energy is negative energy. Nature must balance negative energy by generating positive energy (mass), implying ALPHA balances the increasing entropy of the visible universe and generates baryonic mass. Additionally, the successful cloning of the sheep Dolly, and observed molecular blinking dots in biochemistry support the binary BITS of ON and OFF states in [1]. Vindicating Hermite's 1873 mathematical linkage of the base of natural logarithm to transcendentality will implicate natural log based ALPHA in [1] as connected to consciousness. [1] Goradia S: www.arXiv.org/pdf/physics/0210040v3.

  12. The Alpha Dynamo Effects in Laboratory Plasmas

    Energy Technology Data Exchange (ETDEWEB)

    Hantao Ji; Stewart C. Prager

    2001-10-16

    A concise review of observations of the alpha dynamo effect in laboratory plasmas is given. Unlike many astrophysical systems, the laboratory pinch plasmas are driven magnetically. When the system is overdriven, the resultant instabilities cause magnetic and flow fields to fluctuate, and their correlation induces electromotive forces along the mean magnetic field. This alpha-effect drives mean parallel electric current, which, in turn, modifies the initial background mean magnetic structure towards the stable regime. This drive-and-relax cycle, or the so-called self-organization process, happens in magnetized plasmas in a timescale much shorter than resistive diffusion time, thus it is a fast and unquenched dynamo process. The observed alpha-effect redistributes magnetic helicity (a measure of twistedness and knottedness of magnetic field lines) but conserves its total value. It can be shown that fast and unquenched dynamos are natural consequences of a driven system where fluctuations are statistically either not stationary in time or not homogeneous in space, or both. Implications to astrophysical phenomena will be discussed.

  13. Lectin interactions with alpha-galactosylated xenoantigens

    DEFF Research Database (Denmark)

    Kirkeby, Svend; Moe, Dennis

    2002-01-01

    alpha-Galactosylated xenoantigens (Galalpha1-3Galbeta1-4GlcNAcbeta1 and Galalpha1-3Galbeta1-4GlcNAcbeta1-3Galbeta1-4Glc) are often detected with the alpha-Gal specific lectin Griffonia simplicifolia 1 isolectin B4 (GS1 B4). However, this lectin exhibits a broad and variable specificity......-galactophilic lectins to alpha-galactosylated neoglycoproteins. The lectins were: Euonymus europaeus agglutinin (EEA), Griffonia simplicifolia 1 isolectin B4 (GS1 B4), Maclura pomifera agglutinin (MPA) and Pseudomonas aeruginosa agglutinin (PA-IL). Although both GS1 B4 and MPA strongly bound glycoconjugates terminating...... in Gal there seems to be some differentiation in their sugar binding preferences. MPA was the only lectin that showed high affinity for the pentasaccharide Galalpha1-3Galbeta1-4GlcNAcbeta1-3Galbeta1-4Glc and for the Galalpha-glycans on non-primate thyroglobulin. The length of the xenoantigenic...

  14. Hybrid (BDBB) interferon-alpha: preformulation studies.

    Science.gov (United States)

    Allen, J D; Bentley, D; Stringer, R A; Lowther, N

    1999-10-05

    A number of techniques, including RP-HPLC, HP-SEC and SDS-PAGE have been used in the delineation of degradative mechanisms of recombinant hybrid (BDBB) interferon-alpha (IFN-alpha) in the solution phase. Different degradation profiles are found according to medium pH. At pH 4.0 the major routes of degradation are via chemical transformation of the monomeric protein to a species which retains antiviral activity, and by self-proteolytic hydrolysis. At pH 7.6, methionine-oxidation is the major chemical degradative process. Protein aggregation is also a significant route of degradation at the higher pH. The results have assisted in a targeted preformulation screen of potentially stabilising excipients and possible parenteral solution dosage forms have been identified. Preliminary 'real-time' storage data confirm excellent chemical and physical stability of IFN-alpha in vehicles formulated at pH 7.6 or, especially, pH 4.0 under the proposed shelf conditions.

  15. Single particle level scheme for alpha decay

    International Nuclear Information System (INIS)

    Mirea, M.

    1998-01-01

    The fine structure phenomenon in alpha decay was evidenced by Rosenblum. In this process the kinetic energy of the emitted particle has several determined values related to the structure of the parent and the daughter nucleus. The probability to find the daughter in a low lying state was considered strongly dependent on the spectroscopic factor defined as the square of overlap between the wave function of the parent in the ground state and the wave functions of the specific excited states of the daughter. This treatment provides a qualitative agreement with the experimental results if the variations of the penetrability between different excited states are neglected. Based on single particle structure during fission, a new formalism explained quantitatively the fine structure of the cluster decay. It was suggested that this formalism can be applied also to alpha decay. For this purpose, the first step is to construct the level scheme of this type of decay. Such a scheme, obtained with the super-asymmetric two-center potential, is plotted for the alpha decay of 223 Ra. It is interesting to note that, diabatically, the level with spin 3/2 emerging from 1i 11/2 (ground state of the parent) reaches an excited state of the daughter in agreement with the experiment. (author)

  16. Alpha Particle Physics Experiments in the Tokamak Fusion Test Reactor

    Energy Technology Data Exchange (ETDEWEB)

    Budny, R.V.; Darrow, D.S.; Medley, S.S.; Nazikian, R.; Zweben, S.J.; et al.

    1998-12-14

    Alpha particle physics experiments were done on the Tokamak Fusion Test Reactor (TFTR) during its deuterium-tritium (DT) run from 1993-1997. These experiments utilized several new alpha particle diagnostics and hundreds of DT discharges to characterize the alpha particle confinement and wave-particle interactions. In general, the results from the alpha particle diagnostics agreed with the classical single-particle confinement model in magnetohydrodynamic (MHD) quiescent discharges. Also, the observed alpha particle interactions with sawteeth, toroidal Alfvén eigenmodes (TAE), and ion cyclotron resonant frequency (ICRF) waves were roughly consistent with theoretical modeling. This paper reviews what was learned and identifies what remains to be understood.

  17. Determination of $\\alpha_{s}$ via the Differential 2-Jet-Rate with ATLAS at LHC

    CERN Document Server

    Lichtnecker, Markus

    The first determination of the strong coupling constant alpha_s via the differential 2-jet-rate in pp collisions at the LHC (at a center-of-mass-energy of 7 TeV) is presented. Data gathered by the ATLAS experiment are fitted by next-to-leading order (NLO) perturbative QCD predictions from calculations with the program NLOJET++. As an observable, the jet-flip-parameter from 3 to 2 reconstructed jets is investigated, using the infrared and collinear safe kT jet algorithm in the exclusive reconstruction mode. The jet-flip-parameters from real data are compared to simulated data from Monte Carlo generators. For the determination of alpha_s, real data have been corrected for the jet-energy-scale, whereas the calculations from NLOJET++ have been corrected for the influence of hadronization effects as well as the impact of the Underlying Event by applying bin-by-bin corrections. The fit between real data and the calculations from NLOJET++ yields a value of alpha_s(M_Z)=0.120 +/-0.001(stat.) +/-0.005(syst.), which is...

  18. Determination of $\\alpha_{s}$ using Jet Rates at LEP with the OPAL detector

    CERN Document Server

    Abbiendi, G.; Akesson, P.F.; Alexander, G.; Anagnostou, G.; Anderson, K.J.; Asai, S.; Axen, D.; Bailey, I.; Barberio, E.; Barillari, T.; Barlow, R.J.; Batley, R.J.; Bechtle, P.; Behnke, T.; Bell, Kenneth Watson; Bell, P.J.; Bella, G.; Bellerive, A.; Benelli, G.; Bethke, S.; Biebel, O.; Boeriu, O.; Bock, P.; Boutemeur, M.; Braibant, S.; Brown, Robert M.; Burckhart, H.J.; Campana, S.; Capiluppi, P.; Carnegie, R.K.; Carter, A.A.; Carter, J.R.; Chang, C.Y.; Charlton, D.G.; Ciocca, C.; Csilling, A.; Cuffiani, M.; Dado, S.; De Roeck, A.; De Wolf, E.A.; Desch, K.; Dienes, B.; Donkers, M.; Dubbert, J.; Duchovni, E.; Duckeck, G.; Duerdoth, I.P.; Etzion, E.; Fabbri, F.; Ferrari, P.; Fiedler, F.; Fleck, I.; Ford, M.; Frey, A.; Gagnon, P.; Gary, John William; Geich-Gimbel, C.; Giacomelli, G.; Giacomelli, P.; Giunta, Marina; Goldberg, J.; Gross, E.; Grunhaus, J.; Gruwe, M.; Gunther, P.O.; Gupta, A.; Hajdu, C.; Hamann, M.; Hanson, G.G.; Harel, A.; Hauschild, M.; Hawkes, C.M.; Hawkings, R.; Hemingway, R.J.; Herten, G.; Heuer, R.D.; Hill, J.C.; Horvath, D.; Igo-Kemenes, P.; Ishii, K.; Jeremie, H.; Jovanovic, P.; Junk, T.R.; Kanzaki, J.; Karlen, D.; Kawagoe, K.; Kawamoto, T.; Keeler, R.K.; Kellogg, R.G.; Kennedy, B.W.; Kluth, S.; Kobayashi, T.; Kobel, M.; Komamiya, S.; Kramer, T.; Krasznahorkay, A.; Krieger, P.; von Krogh, J.; Kuhl, T.; Kupper, M.; Lafferty, G.D.; Landsman, H.; Lanske, D.; Lellouch, D.; Lettso, J.; Levinson, L.; Lillich, J.; Lloyd, S.L.; Loebinger, F.K.; Lu, J.; Ludwig, A.; Ludwig, J.; Mader, W.; Marcellini, S.; Martin, A.J.; Mashimo, T.; Mattig, Peter; McKenna, J.; McPherson, R.A.; Meijers, F.; Menges, W.; Merritt, F.S.; Mes, H.; Meyer, Niels T.; Michelini, A.; Mihara, S.; Mikenberg, G.; Miller, D.J.; Mohr, W.; Mori, T.; Mutter, A.; Nagai, K.; Nakamura, I.; Nanjo, H.; Neal, H.A.; Nisius, R.; O'Neale, S.W.; Oh, A.; Oreglia, M.J.; Orito, S.; Pahl, C.; Pasztor, G.; Pater, J.R.; Pilcher, J.E.; Pinfold, J.; Plane, David E.; Pooth, O.; Przybycien, M.; Quadt, A.; Rabbertz, K.; Rembser, C.; Renkel, P.; Roney, J.M.; Rossi, A.M.; Rozen, Y.; Runge, K.; Sachs, K.; Saeki, T.; Sarkisyan, E.K.G.; Schaile, A.D.; Schaile, O.; Scharff-Hansen, P.; Schieck, J.; Schorner-Sadenius, T.; Schroder, Matthias; Schumacher, M.; Seuster, R.; Shears, T.G.; Shen, B.C.; Sherwood, P.; Skuja, A.; Smith, A.M.; Sobie, R.; Soldner-Rembold, S.; Spano, F.; Stahl, A.; Strom, David M.; Strohmer, R.; Tarem, S.; Tasevsky, M.; Teuscher, R.; Thomson, M.A.; Torrence, E.; Toya, D.; Tran, P.; Trigger, I.; Trocsanyi, Z.; Tsur, E.; Turner-Watson, M.F.; Ueda, I.; Ujvari, B.; Vollmer, C.F.; Vannerem, P.; Vertesi, R.; Verzocchi, M.; Voss, H.; Vossebeld, J.; Ward, C.P.; Ward, D.R.; Watkins, P.M.; Watson, A.T.; Watson, N.K.; Wells, P.S.; Wengler, T.; Wermes, N.; Wilson, G.W.; Wilson, J.A.; Wolf, G.; Wyatt, T.R.; Yamashita, S.; Zer-Zion, D.; Zivkovic, Lidija

    2006-01-01

    Hadronic events produced in e+e- collisions by the LEP collider and recorded by the OPAL detector were used to form distributions based on the number of reconstructed jets. The data were collected between 1995 and 2000 and correspond to energies of 91 GeV, 130-136 GeV and 161-209 GeV. The jet rates were determined using four different jet-finding algorithms (Cone, JADE, Durham and Cambridge). The differential two-jet rate and the average jet rate with the Durham and Cambridge algorithms were used to measure alpha(s) in the LEP energy range by fitting an expression in which order alpah_2s calculations were matched to a NLLA prediction and fitted to the data. Combining the measurements at different centre-of-mass energies, the value of alpha_s (Mz) was determined to be alpha(s)(Mz)=0.1177+-0.0006(stat.)+-0.0012$(expt.)+-0.0010(had.)+-0.0032

  19. Functional and genomic analyses of alpha-solenoid proteins.

    Directory of Open Access Journals (Sweden)

    David Fournier

    Full Text Available Alpha-solenoids are flexible protein structural domains formed by ensembles of alpha-helical repeats (Armadillo and HEAT repeats among others. While homology can be used to detect many of these repeats, some alpha-solenoids have very little sequence homology to proteins of known structure and we expect that many remain undetected. We previously developed a method for detection of alpha-helical repeats based on a neural network trained on a dataset of protein structures. Here we improved the detection algorithm and updated the training dataset using recently solved structures of alpha-solenoids. Unexpectedly, we identified occurrences of alpha-solenoids in solved protein structures that escaped attention, for example within the core of the catalytic subunit of PI3KC. Our results expand the current set of known alpha-solenoids. Application of our tool to the protein universe allowed us to detect their significant enrichment in proteins interacting with many proteins, confirming that alpha-solenoids are generally involved in protein-protein interactions. We then studied the taxonomic distribution of alpha-solenoids to discuss an evolutionary scenario for the emergence of this type of domain, speculating that alpha-solenoids have emerged in multiple taxa in independent events by convergent evolution. We observe a higher rate of alpha-solenoids in eukaryotic genomes and in some prokaryotic families, such as Cyanobacteria and Planctomycetes, which could be associated to increased cellular complexity. The method is available at http://cbdm.mdc-berlin.de/~ard2/.

  20. Determination of hCG-alpha subunit in threatened pregnancy

    International Nuclear Information System (INIS)

    Talas, M.; Pohanka, J.; Fingerova, H.; Janouskova, M.; Krikal, Z.; Prasilova, J.; Zupkova, H.

    1987-01-01

    Radioimmunoassay of the hCG-alpha subunit was made using an antibody anti hCG-alpha serum, highly purified hCG-alpha for 125 I-labelling and the standard hCG-alpha. Sera of healthy pregnant women sampled throughout the whole pregnancies were used to determine x-bar±S.D. of hCG-alpha for 14-day intervals. Included in the study were groups of women with high risk of premature labor, late toxemia of pregnancy, twins and fetal hypotrophy. It was shown that increased hCG-alpha is found in pregnant women in whom signs of late toxemia of pregnancy are combined with high risk of premature labor, or with twin pregnancies, while in those with fetal hypotrophy hCG-alpha is within normal limits. (author). 3 figs., 7 refs

  1. Benchmarks for targeted alpha therapy for cancer

    International Nuclear Information System (INIS)

    Allen, J.B.

    2011-01-01

    Full text: Targeted alpha therapy (TAT) needs to achieve certain benchmarks if t is to find its way into the clinic. This paper reviews the status of benchmarks for dose normalisation, microdosimetry, response of micrometastases to therapy, maximum tolerance doses and adequate supplies of alpha emitting radioisotopes. In comparing dose effect for different alpha immunoconjugates (IC), patients and diseases, it is appropriate to normalise dose according to specific factors that affect the efficacy of the treatment. Body weight and body surface area are two commonly used criteria. However, more advanced criteria are required, such as the volume of distribution. Alpha dosimetry presents a special challenge in clinical trials. Monte Carlo calculations can be used to determine specific energies, but these need validation. This problem could be resolved with micronuclei biological dosimetry and mutagenesis studies of radiation Jam age. While macroscopic disease can be monitored, the impact of therapy on subclinical microscopic disease is a real problem. Magnetic cell separation of cancer cells in the blood with magnetic microspheres coated with the targeting monoclonal antibody could provide the response data. Alpha therapy needs first to establish maximum tolerance doses for practical acceptance. This has been determined with 213Bi-IC for acute myelogenous leukaemia at ∼ I mCi/kg. The maximum tolerance dose has not yet been established for metastatic melanoma, but the efficacious dose for some melanomas is less than 0.3 mCi/kg and for intra-cavity therapy of GBM it is ∼ 0.14 mCi/kg for 211 At-Ie. In the case of Ra-223 for bone cancer, the emission of four alphas with a total energy of 27 MeV results in very high cytotoxicity and an effective dose of only ∼ 5 μCi/kg. The limited supplies of Ac-225 available after separation from Th-229 are adequate for clinical trials. However, should TAT become a clinical procedure, then new supplies must be found. Accelerator

  2. $\\alpha_{S}$ Evolution from 35 GeV to 202 GeV and Flavour Independence

    CERN Document Server

    Biebel, O.

    2000-01-01

    Determinations of the strong coupling constant alpha_S at centre-of-mass energies of 192 through 202 GeV at LEP are presented. The energy evolution of alpha_S is in agreement with the prediction of QCD. The combined investigation of OPAL and JADE data in the energy range of 35 through 189 GeV yields alpha_S(m_Z)=0.1187^{+0.0034}_{-0.0019}. The strenght of the strong coupling is flavour independent if quark mass effects are taken into account.

  3. The A and B variants of the alpha 3 integrin subunit: tissue distribution and functional characterization

    NARCIS (Netherlands)

    de Melker, A. A.; Sterk, L. M.; Delwel, G. O.; Fles, D. L.; Daams, H.; Weening, J. J.; Sonnenberg, A.

    1997-01-01

    The alpha subunits of the laminin-binding integrins alpha 3 beta 1, alpha 6 beta 1, and alpha 7 beta 1 have homologous sequences and are similar in structure. Two cytoplasmic variants, A and B, have been identified for each of these alpha subunits, although the alpha 3B splice variant has been

  4. alpha-MSH and its receptors in regulation of tumor necrosis factor-alpha production by human monocyte/macrophages.

    Science.gov (United States)

    Taherzadeh, S; Sharma, S; Chhajlani, V; Gantz, I; Rajora, N; Demitri, M T; Kelly, L; Zhao, H; Ichiyama, T; Catania, A; Lipton, J M

    1999-05-01

    The hypothesis that macrophages contain an autocrine circuit based on melanocortin [ACTH and alpha-melanocyte-stimulating hormone (alpha-MSH)] peptides has major implications for neuroimmunomodulation research and inflammation therapy. To test this hypothesis, cells of the THP-1 human monocyte/macrophage line were stimulated with lipopolysaccharide (LPS) in the presence and absence of alpha-MSH. The inflammatory cytokine tumor necrosis factor (TNF)-alpha was inhibited in relation to alpha-MSH concentration. Similar inhibitory effects on TNF-alpha were observed with ACTH peptides that contain the alpha-MSH amino acid sequence and act on melanocortin receptors. Nuclease protection assays indicated that expression of the human melanocortin-1 receptor subtype (hMC-1R) occurs in THP-1 cells; Southern blots of RT-PCR product revealed that additional subtypes, hMC-3R and hMC-5R, also occur. Incubation of resting macrophages with antibody to hMC-1R increased TNF-alpha concentration; the antibody also markedly reduced the inhibitory influence of alpha-MSH on TNF-alpha in macrophages treated with LPS. These results in cells known to produce alpha-MSH at rest and to increase secretion of the peptide when challenged are consistent with an endogenous regulatory circuit based on melanocortin peptides and their receptors. Targeting of this neuroimmunomodulatory circuit in inflammatory diseases in which myelomonocytic cells are prominent should be beneficial.

  5. Excitation of states with the large moment in reactions (alpha, d) and (alpha, p)

    CERN Document Server

    Burtebaev, N; Dujsebaev, B A; Sakuta, S B

    2002-01-01

    In this work reaction (alpha, d) and (alpha, p) on light nuclei is investigated. Systematization of three-body high-spin states in such a sup 1 sup 5 N, sup 1 sup 6 N, sup 1 sup 7 O, sup 1 sup 9 F nuclei is carried out. On its basis the energy estimation of residual interaction of three nucleons for (d sub 5 sub / sub 2) sub 1 sub 3 sub / 2 sub + sub , sub 1 sub / sub 2 configuration is obtained. (author)

  6. Flavonoids-induced accumulation of hypoxia-inducible factor (HIF)-1alpha/2alpha is mediated through chelation of iron.

    Science.gov (United States)

    Park, Sung-Soo; Bae, Insoo; Lee, Yong J

    2008-04-15

    Hypoxia-inducible factor-1 alpha (HIF-1alpha) is the regulatory subunit of the heterodimeric transcription factor HIF-1 that is the key regulator of cellular response to low oxygen tension. Under normoxic conditions, HIF-1alpha is continuously degraded by the ubiquitin-proteasome pathway through pVHL (von Hippel-Lindau tumor suppressor protein). Under hypoxic conditions, HIF-1alpha is stabilized and induces the transcription of HIF-1 target genes. Quercetin, a flavonoid with anti-oxidant, anti-inflammatory, and kinase modulating properties, has been found to induce HIF-1alpha accumulation and VEGF secretion in normoxia. In this study, the molecular mechanisms of quercetin-mediated HIF-1alpha accumulation were investigated. Previous studies have shown that, in addition to being induced by hypoxia, HIF-1alpha can be induced through the phosphatidylinositol 3-kinase (PI3K)/Akt and p53 signaling pathways. But our study revealed, through p53 mutant-type as well as p53 null cell lines, that neither the PI3K/Akt nor the p53 signaling pathway is required for quercetin-induced HIF-1alpha accumulation. And we observed that HIF-1alpha accumulated by quercetin is not ubiquitinated and the interaction of HIF-1alpha with pVHL is reduced, compared with HIF-1alpha accumulated by the proteasome inhibitor MG132. The use of quercetin's analogues showed that only quercetin and galangin induce HIF-1/2alpha accumulation and this effect is completely reversed by additional iron ions. This is because quercetin and galangin are able to chelate cellular iron ions that are cofactors of HIF-1/2alpha proline hydroxylase (PHD). These data suggest that quercetin inhibits the ubiquitination of HIF-1/2alpha in normoxia by hindering PHD through chelating iron ions.

  7. Characteristics of alpha males in Nepal gray langurs.

    Science.gov (United States)

    Borries, Carola; Perlman, Rachel F; Koenig, Andreas

    2017-07-01

    In species with strong male-male competition, access to females in multimale-multifemale groups is usually regulated via a dominance hierarchy. The highest ranking (alpha) male often has priority of access and sires most offspring. The alpha male can change in three basic ways: (i) a recent immigrant or a resident challenges and becomes the new alpha; (ii) formation of a new group; (iii) succession-becoming alpha after higher ranking males have left. When, in a given primate population, the alpha male changes in different ways, two questions arise: (a) which is the most successful tactic and (b) do male attributes, such as age, aggressiveness or propensity to commit infanticide, affect the outcome? We examined these questions in the seasonally breeding Nepal gray langurs (Semnopithecus schistaceus) at Ramnagar, where new alpha males were either recent immigrants or residents. Success was measured as alpha tenure, residency duration, and the number of offspring sired (paternity exclusion based on DNA analysis, 28 infants). We documented 12 alpha-male tenures across two multimale-multifemale groups between 1991 and 1997. The predominant mode of change was the immigrant tactic. Age had no effect perhaps because alpha males were among the youngest adult males in their group. As expected, infanticidal males performed similarly to non-infanticidal ones. Alpha tenure was highly variable and longer for immigrant alphas and hyper-aggressive ones. However, none of the tactics or attributes examined resulted in significantly longer residencies or more offspring, likely because of the timing of immigrations and stochastic effects (i.e., the number of conceptions occurring per alpha tenure). The influence of female mate choice on male reproductive success requires further investigation. Furthermore, it remains to be examined why resident alpha males-with their presumed better knowledge of their opponents -performed so poorly. Am. J. Primatol. 79:e22437, 2017. © 2015 Wiley

  8. alpha-MSH in systemic inflammation. Central and peripheral actions.

    Science.gov (United States)

    Catania, A; Delgado, R; Airaghi, L; Cutuli, M; Garofalo, L; Carlin, A; Demitri, M T; Lipton, J M

    1999-10-20

    Until recently, inflammation was believed to arise from events taking place exclusively in the periphery. However, it is now clear that central neurogenic influences can either enhance or modulate peripheral inflammation. Therefore, it should be possible to improve treatment of inflammation by use of antiinflammatory agents that reduce peripheral host responses and inhibit proinflammatory signals in the central nervous system (CNS). One such strategy could be based on alpha-melanocyte stimulating hormone (alpha-MSH). Increases in circulating TNF-alpha and nitric oxide (NO), induced by intraperitoneal administration of endotoxin in mice, were modulated by central injection of a small concentration of alpha-MSH. Inducible nitric oxide synthase (iNOS) activity and iNOS mRNA in lungs and liver were likewise modulated by central alpha-MSH. Increase in lung myeloperoxidase (MPO) activity was significantly less in lungs of mice treated with central alpha-MSH. Proinflammatory agents induced by endotoxin were significantly greater after blockade of central alpha-MSH. The results suggest that antiinflammatory influences of neural origin that are triggered by alpha-MSH could be used to treat systemic inflammation. In addition to its central influences, alpha-MSH has inhibitory effects on peripheral host cells, in which it reduces release of proinflammatory mediators. alpha-MSH reduces chemotaxis of human neutrophils and production of TNF-alpha, neopterin, and NO by monocytes. In research on septic patients, alpha-MSH inhibited release of TNF-alpha, interleukin-1 beta (IL-1 beta), and interleukin-8 (IL-8) in whole blood samples in vitro. Combined central and peripheral influences can be beneficial in treatment of sepsis.

  9. Synthesis of high specific activity 17{alpha}-cyanomethyl-17{beta} -hydroxy-[14{alpha}, 15{alpha}-{sup 3}H]estra-4,9-dien-3-one

    Energy Technology Data Exchange (ETDEWEB)

    Droescher, P. [VEB Jenapharm, Jena (Germany); Roemer, J. [Forschungszentrum Rossendorf e.V. (FZR), Dresden (Germany)

    1995-02-01

    An improved synthesis of the tritium labelled form of the new pharmacon DIENOGEST is described. The [14{alpha}, 15{alpha}-{sup 3}H]DIENOGEST was obtained with a specific activity of 51 Ci/mmol and a radiochemical purity > 98%. (Author).

  10. Complex rearrangements within the human J delta-C delta/J alpha-C alpha locus and aberrant recombination between J alpha segments

    NARCIS (Netherlands)

    Baer, R.; Boehm, T.; Yssel, H.; Spits, H.; Rabbitts, T. H.

    1988-01-01

    We have examined DNA rearrangements within a 120 kb cloned region of the human T cell receptor J delta-C delta/J alpha-C alpha locus. Three types of pattern emerge from an analysis of T cell lines and clones. Firstly, cells with two rearrangements within J delta-C delta; secondly, cells with one

  11. Chronic hepatitis

    African Journals Online (AJOL)

    infection by four diagnostic systems: first generation and second generation. ELlSA, second generation recombinant immunoblot assay and nested polymerase chain reaction analysis. HepatoJogy 1992; 16: 300-305. 14. Van der Poel CL, ... Alpha-1-antitrypsin deficiency. Alcoholic hepatitis. Non-alcoholic steatohepatitis.

  12. INVITRO RELEASE OF NEUTROPHIL ELASTASE, MYELOPEROXIDASE AND BETA-GLUCURONIDASE IN PATIENTS WITH EMPHYSEMA AND HEALTHY-SUBJECTS

    NARCIS (Netherlands)

    RENKEMA, TEJ; POSTMA, DS; NOORDHOEK, JA; SLUITER, HJ; KAUFFMAN, HF

    1991-01-01

    Evidence is accumulating that cigarette smoking plays an important role in the protease-antiprotease imbalance in alpha-1-antitrypsin-sufficient emphysema. Since most smokers, however, do not develop emphysema, it has to be presumed that other factors in addition to smoking contribute to the origin

  13. Cytogenetic study of Ascaris trypsin inhibitor in cultured human ...

    Indian Academy of Sciences (India)

    2009-04-01

    Apr 1, 2009 ... Lee D. E. and Xie C. Y. 1995 IgE regulation by nematodes: the body fluid of Ascaris contains a B-cell mitogen. J. Allergy Clin. Immunol. 96, 1246–1254. Lipski J. J., Berninger R. W., Hyman L. R. and Talama R. C. 1979. Presence of alpha-1-antitrypsin on mitogen-stimulated human lymphocytes. J. Immunol.

  14. Chronic obstructive pulmonary disease – diagnosis and ...

    African Journals Online (AJOL)

    family history of COPD, consider testing for alpha-1 antitrypsin deficiency. Assessment of severity. COPD and asthma are graded according to severity, and management recommendations are based on severity categories. Tradition- ally, management was decided on by lung function severity alone, but there has been.

  15. Administration of C1 inhibitor reduces neutrophil activation in patients with sepsis

    NARCIS (Netherlands)

    Zeerleder, Sacha; Caliezi, Christoph; van Mierlo, Gerard; Eerenberg-Belmer, Anke; Sulzer, Irmela; Hack, C. Erik; Wuillemin, Walter A.

    2003-01-01

    Forty patients with severe sepsis or septic shock recently received C1 inhibitor. In the present study we studied the effect of C1 inhibitor therapy on circulating elastase-alpha(1)-antitrypsin complex (EA) and lactoferrin (LF) levels in these patients to gain further insight about agonists involved

  16. Solid and papillary neoplasm of the pancreas

    DEFF Research Database (Denmark)

    Jørgensen, L J; Hansen, A B; Burcharth, F

    1992-01-01

    In two cases of solid and papillary neoplasm of the pancreas (SPN), positive staining for argyrophil granules, chromogranin-A, neuron-specific enolase, chymotrypsin, alpha 1-antitrypsin, vimentin, cytokeratin, and estrogen receptors was present. Ultrastructurally, neurosecretory as well as zymoge...

  17. A case-control study in chronic obstructive pulmonary disease

    African Journals Online (AJOL)

    Alpha-1 antitrypsin (AAT) deficiency is an inherited disorder that causes low levels of, or no AAT in the blood. The most common illness in adults with AAT deficiency is lung disease during the third and fourth decades of life. Most commonly, it is associated with chronic obstructive pulmonary disease (COPD). Mutations in the ...

  18. ORIGINAL ARTICLES Liver transplantation at Red Cross War ...

    African Journals Online (AJOL)

    The liver transplant programme for infants and children at Red. Cross War Memorial Children's Hospital is at present the only established paediatric service in sub-Saharan Africa. The first paediatric transplant was performed on 6 December 1987 for end-stage liver disease due to alpha-1-antitrypsin deficiency. The patient ...

  19. Cloning of the pig aminopeptidase N gene. Identification of possible regulatory elements and the exon distribution in relation to the membrane-spanning region

    DEFF Research Database (Denmark)

    Sjöström, H; Norén, O; Olsen, Jørgen

    1989-01-01

    . By sequence comparisons we have found three domains showing similarity to promoter regions of the genes encoding human alpha 1-antitrypsin and human intestinal alkaline phosphatase. The gene sequence includes the first three exons and two introns. It shows that a single exon encodes the cytoplasmic tail...

  20. The Worst Headache of Life: Evaluation of Nontraumatic Subarachnoid Hemorrhage

    Science.gov (United States)

    2005-09-06

    include autosomal dominant polycystic kidney disease, hypertension, aortic coarctation , alpha-1 -antitrypsin deficiency, connective tissue diseases...which is highest immediately after the initial subarachnoid hemorrhage, is through early surgical or endovascular treatment of the ruptured aneurysm...Endovascular treatment is particularly useful in posterior circulation aneurysms, such as a basilar tip aneurysm, in which the surgical approach is

  1. Author Details

    African Journals Online (AJOL)

    Chibani, JB. Vol 1, No 5 (2012) - Articles Origins and spreads of Alpha 1 antitrypsin variants in world human populations: a synthetic review. Abstract PDF · Vol 1, No 5 (2012) - Articles Synthetic review on the different anthropological aspects of hemoglobinopathies in Tunisia Abstract PDF. ISSN: 1737-8176. AJOL African ...

  2. International Journal of Modern Anthropology - Vol 1, No 5 (2012)

    African Journals Online (AJOL)

    Origins and spreads of Alpha 1 antitrypsin variants in world human populations: a synthetic review · EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT. S Denden, JB Chibani, AH Khelil, 40-58. http://dx.doi.org/10.4314/ijma.v1i5.3 ...

  3. Cluster and alpha decay of superheavy nuclei

    Science.gov (United States)

    Poenaru, D. N.; Stöcker, H.; Gherghescu, R. A.

    2018-02-01

    We investigated cluster radioactivity and alpha decay of some superheavy nuclei with atomic numbers Z = 119, 120 , which may be produced in the future. Two models are used to calculate the half-lives against cluster radioactivity: ASAF (Analytical Super-Asymmetric Fission) and UNIV (Universal Formula). For α decay half-lives we are based on four models: ASAF, UNIV, semFIS (semi-empirical formula based on Fission Theory) and AKRA (first author Akrawy). The Q -values are calculated using the theoretical model of atomic masses WS10, which sometimes is called W4.

  4. Alpha Fuels Environmental Test Facility impact gun

    International Nuclear Information System (INIS)

    Anderson, C.G.

    1978-01-01

    The Alpha Fuels Environmental Test Facility (AFETF) impact gun is a unique tool for impact testing 238 PuO 2 -fueled heat sources of up to 178-mm dia at velocities to 300 m/s. An environmentally-sealed vacuum chamber at the muzzle of the gun allows preheating of the projectile to 1,000 0 C. Immediately prior to impact, the heat source projectile is completely sealed in a vacuum-tight catching container to prevent escape of its radioactive contents should rupture occur. The impact velocity delivered by this gas-powered gun can be regulated to within +-2%

  5. Fetal dosimetry from natural alpha emitters

    Energy Technology Data Exchange (ETDEWEB)

    Purnell, S.J

    1999-09-01

    The size of marrow cavities in fetal vertebra, rib and sternum was investigated using an image analysis system. The average chord lengths through marrow spaces in the vertebrae were found to increase approximately linearly with gestational age from 140 {mu}m at 20 weeks to 300 {mu}m at 40 weeks. Average chord lengths through marrow spaces in fetal rib and sternum were 330 {mu}m at 35 weeks in both cases. These results can be compared with an average chord length across marrow spaces in adult vertebra of 1172 {mu}m. At natural background UK exposure, activity concentrations of supported {sup 210}Po in fetal bone of 0.075 Bq kg{sup -1} and 0.15 Bq kg{sup -1} at mid- and late gestation respectively were calculated. Monte Carlo simulations modelling the paths of alpha-particles in fetal vertebra gave a total alpha-radiation dose to marrow over the second and third trimesters of 32.0 {+-} 0.8 {mu}Sv with the {sup 210}Po in bone contributing 8.9 {+-} 0.9 {mu}Sv. The dose to primitive haemopoietic stem cells, the target cells for acute lymphoblastic leukaemia, and the survival of these stem cells following a hit by an alpha-particle was investigated, also using Monte Carlo simulations. Alpha-particles emitted from bone and marrow contributed an average dose of 1.9 Gy to stem cells with a nuclear diameter of 3.8 {mu}m. This study has estimated that 1% of babies born each year are born with a mutated primitive haemopoietic stem cell due to in utero irradiation from high LET radiation. That is 7,320 babies compared to an estimated 300 incidences of cALL each year initiated in utero. The probability that a mutated cell will go on to give rise to leukaemia is unknown but it would seem not unlikely that irradiation in utero plays a substantial part in the induction of childhood leukaemia. (author)

  6. Alpha transport and blistering in tokamaks

    International Nuclear Information System (INIS)

    Bauer, W.; Wilson, K.L.; Bisson, C.L.; Haggmark, L.G.; Goldston, R.J.

    1978-12-01

    The particle flux and angular distribution of 3.5 MeV alpha particles impinging on the first wall from uncontained banana orbits in an axisymmetric tokamak reactor have been calculated. The resulting helium concentration profiles in the first wall can give rise to surface exfoliation under specified conditions. The major mitigating factor is the simultaneous surface recession due to sputtering by the D-T charge exchange neutral flux. For the parameters used in these calculations blistering in high sputtering rate materials such as Be is unlikely whereas in low sputtering rate materials such as Nb, He induced surface deformation is quite probable

  7. Risk estimates for exposure to alpha emitters

    International Nuclear Information System (INIS)

    1982-07-01

    The primary scope of this report is to evaluate the risk of lung cancer from occupational exposure to short-lived daughters of radon and thoron. The Subcommittee on Risk Estimates considers that inhalation of radon and thoron daughters is the major radiation hazard from alpha radiation in uranium mining. The secondary scope of this report is the consideration of the applicability of the risk estimates derived from miners to the general public. The risk to members of the public from radium-226 in drinking water is also considered. Some research requirments are suggested

  8. Sterol synthesis. A novel reductive rearrangement of an alpha,beta-unsaturated steroidal epoxide; a new chemical synthesis of 5alpha-cholest-8(14)-en-3beta, 15alpha-diol.

    Science.gov (United States)

    Parish, E J; Schroepfer, G J

    1977-04-01

    Reduction of 3beta-benzoyloxy-14alpha,15alpha-epoxy-5alpha-cholest-7-ene with either lithium triethylboro-hydride or lithium aluminum hydride (4 molar excess) gave 5-alpha-cholest-8(14)-en-3beta,15alpha-diol in high yield. Reduction of the epoxy ester with lithium triethylborodeuteride or lithium aluminum deuteride (4 molar excess) gave [7alpha-2-H]-5alpha-cholest-8(14)-en-3beta,15alpha-diol. Reduction of 2beta-benzoyloxy-14alpha,15alpha-epoxy-5alpha-cholest-7-ene with a large excess (24 molar excess) of lithium aluminum hydride gave, in addition to the expected 5alpha-cholest-8(14)-en-3beta,15alpha-diol, a significant yield (33%) of 5alpha-cholest-8(14)-en-3beta-o1. Reduction of the epoxy ester with a large excess (24 molar excess) of lithium aluminum deuteride gave [7alpha-2H]-5alpha-cholest-8(14)-en-3beta,15alpha-diol and 5alpha-cholest-8(14)-en-3beta-o1 which contained two atoms of stably bound deuterium.

  9. The alpha3 laminin subunit, alpha6beta4 and alpha3beta1 integrin coordinately regulate wound healing in cultured epithelial cells and in the skin

    DEFF Research Database (Denmark)

    Goldfinger, L E; Hopkinson, S B; deHart, G W

    1999-01-01

    . In these cells, integrin alpha3beta1 occasionally colocalizes with the staining generated by the 12C4 antibody but alpha6beta4 integrin does not. In wounded MCF-10A cell cultures, the 12C4 antibody stains the extracellular matrix beneath those cells at the very edge of the cellular sheet that moves to cover......Previously, we demonstrated that proteolytic processing within the globular domain of the alpha3 subunit of laminin-5 (LN5) converts LN5 from a cell motility-inducing factor to a protein complex that can trigger the formation of hemidesmosomes, certain cell-matrix attachment sites found...... in epithelial cells. We have prepared a monoclonal antibody (12C4) whose epitope is located toward the carboxy terminus of the globular domain of the alpha3 laminin subunit. This epitope is lost from the alpha3 subunit as a consequence of proteolytic processing. Antibody 12C4 stains throughout the matrix...

  10. The Alpha-1A Adrenergic Receptor in the Rabbit Heart.

    Directory of Open Access Journals (Sweden)

    R Croft Thomas

    Full Text Available The alpha-1A-adrenergic receptor (AR subtype is associated with cardioprotective signaling in the mouse and human heart. The rabbit is useful for cardiac disease modeling, but data on the alpha-1A in the rabbit heart are limited. Our objective was to test for expression and function of the alpha-1A in rabbit heart. By quantitative real-time reverse transcription PCR (qPCR on mRNA from ventricular myocardium of adult male New Zealand White rabbits, the alpha-1B was 99% of total alpha-1-AR mRNA, with <1% alpha-1A and alpha-1D, whereas alpha-1A mRNA was over 50% of total in brain and liver. Saturation radioligand binding identified ~4 fmol total alpha-1-ARs per mg myocardial protein, with 17% alpha-1A by competition with the selective antagonist 5-methylurapidil. The alpha-1D was not detected by competition with BMY-7378, indicating that 83% of alpha-1-ARs were alpha-1B. In isolated left ventricle and right ventricle, the selective alpha-1A agonist A61603 stimulated a negative inotropic effect, versus a positive inotropic effect with the nonselective alpha-1-agonist phenylephrine and the beta-agonist isoproterenol. Blood pressure assay in conscious rabbits using an indwelling aortic telemeter showed that A61603 by bolus intravenous dosing increased mean arterial pressure by 20 mm Hg at 0.14 μg/kg, 10-fold lower than norepinephrine, and chronic A61603 infusion by iPRECIO programmable micro Infusion pump did not increase BP at 22 μg/kg/d. A myocardial slice model useful in human myocardium and an anthracycline cardiotoxicity model useful in mouse were both problematic in rabbit. We conclude that alpha-1A mRNA is very low in rabbit heart, but the receptor is present by binding and mediates a negative inotropic response. Expression and function of the alpha-1A in rabbit heart differ from mouse and human, but the vasopressor response is similar to mouse.

  11. Application of Micro-coprecipitation Method to Alpha Source Preparation for Measuring Alpha Nuclides

    International Nuclear Information System (INIS)

    Lee, Myung Ho; Park, Jong Ho; Oh, Se Jin; Song, Byung Chul; Song, Kyuseok

    2011-01-01

    Among the source preparations, an electrodeposition is a commonly used method for the preparation of sources for an alpha spectrometry, because this technique is simple and produces a very thin deposit, which is essential for a high resolution of the alpha peak. Recently, micro-coprecipitation with rare earths have been used to yield sources for -spectrometry. In this work, the Pu, Am and Cm isotopes were purified from hindrance nuclides and elements with an a TRU resin in radioactive waste samples, and the activity concentrations of the Pu, Am and Cm isotopes were determined by radiation counting methods after alpha source preparation like micro coprecipitation. After the Pu isotopes in the radioactive waste samples were separated from the other nuclides with an anion exchange resin, the Am isotopes were purified with a TRU resin and an anion exchange resin or a TRU resin. Activity concentrations and chemical recoveries of 241 Am purified with the TRU resin were similar to those with the TRU resin and anion exchange resin. In this study, to save on the analytical time and cost, the Am isotopes were purified with the TRU resin without using an additional anion exchange resin. After comparing the electrodeposition method with the micro-coprecipitation method, the micro-coprecipitation method was used for the alpha source preparation, because the micro-coprecipitation method is simple and more reliable for source preparation of the Pu, Am and Cm isotopes

  12. Role of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in acute lung injury in rats

    DEFF Research Database (Denmark)

    Shanley, T P; Schmal, H; Friedl, H P

    1995-01-01

    in bronchoalveolar lavage (BAL) fluids by Western blot analysis. Anti-MIP-1 alpha administered at commencement of IgG immune complex- or LPS-induced injury resulted in significant reductions in BAL neutrophils as well as in injury as measured by pulmonary vascular permeability. Under such conditions, in both models...

  13. Workshop on High-precision $\\alpha_s$ measurements from LHC to FCC-ee

    CERN Document Server

    S. Alekhin; d'Enterria, David; A. Banfi; S. Bethke; J. Blümlein; K.G. Chetyrkin; D. d’Enterria; G. Dissertori; X. Garcia i Tormo; A. H. Hoang; M. Klasen; T. Klijnsma; S. Kluth; J.-L. Kneur; B.A. Kniehl; D. W. Kolodrubetz; J. Kühn; P. Mackenzie; B. Malaescu; V. Mateu; L. Mihaila; S. Moch; K. Mönig; R. Pérez-Ramos; A. Pich; J. Pires; K. Rabbertz; G. P. Salam; F. Sannino; J. Soto i Riera; M. Srebre; I. W. Stewart

    2015-01-01

    This document provides a writeup of all contributions to the workshop on "High precision measurements of $\\alpha_s$: From LHC to FCC-ee" held at CERN, Oct. 12--13, 2015. The workshop explored in depth the latest developments on the determination of the QCD coupling $\\alpha_s$ from 15 methods where high precision measurements are (or will be) available. Those include low-energy observables: (i) lattice QCD, (ii) pion decay factor, (iii) quarkonia and (iv) $\\tau$ decays, (v) soft parton-to-hadron fragmentation functions, as well as high-energy observables: (vi) global fits of parton distribution functions, (vii) hard parton-to-hadron fragmentation functions, (viii) jets in $e^\\pm$p DIS and $\\gamma$-p photoproduction, (ix) photon structure function in $\\gamma$-$\\gamma$, (x) event shapes and (xi) jet cross sections in $e^+e^-$ collisions, (xii) W boson and (xiii) Z boson decays, and (xiv) jets and (xv) top-quark cross sections in proton-(anti)proton collisions. The current status of the theoretical and experiment...

  14. Chemoenzymatic synthesis of alpha-L-rhamnosides using recombinant alpha-L-rhamnosidase from Aspergillus terreus

    Czech Academy of Sciences Publication Activity Database

    De Winter, K.; Šimčíková, Daniela; Schlack, B.; Weignerová, Lenka; Pelantová, Helena; Soetaert, W.; Desmet, T.; Křen, Vladimír

    2013-01-01

    Roč. 147, NOV 2013 (2013), s. 640-644 ISSN 0960-8524 R&D Projects: GA MŠk(CZ) LD13042; GA MŠk(CZ) 7E11011 Institutional support: RVO:61388971 Keywords : alpha-L-Rhamnosidase * Aspergillus terreus * Glycosylation Subject RIV: CE - Biochemistry Impact factor: 5.039, year: 2013

  15. alpha AD alpha hybrids of Cryptococcus neoformans: evidence of same-sex mating in nature and hybrid fitness.

    Directory of Open Access Journals (Sweden)

    Xiaorong Lin

    2007-10-01

    Full Text Available Cryptococcus neoformans is a ubiquitous human fungal pathogen that causes meningoencephalitis in predominantly immunocompromised hosts. The fungus is typically haploid, and sexual reproduction involves two individuals with opposite mating types/sexes, alpha and a. However, the overwhelming predominance of mating type (MAT alpha over a in C. neoformans populations limits alpha-a mating in nature. Recently it was discovered that C. neoformans can undergo same-sex mating under laboratory conditions, especially between alpha isolates. Whether same-sex mating occurs in nature and contributes to the current population structure was unknown. In this study, natural alpha AD alpha hybrids that arose by fusion between two alpha cells of different serotypes (A and D were identified and characterized, providing definitive evidence that same-sex mating occurs naturally. A novel truncated allele of the mating-type-specific cell identity determinant SXI1 alpha was also identified as a genetic factor likely involved in this process. In addition, laboratory-constructed alpha AD alpha strains exhibited hybrid vigor both in vitro and in vivo, providing a plausible explanation for their relative abundance in nature despite the fact that AD hybrids are inefficient in meiosis/sporulation and are trapped in the diploid state. These findings provide insights on the origins, genetic mechanisms, and fitness impact of unisexual hybridization in the Cryptococcus population.

  16. Taraxacum officinale induces cytotoxicity through TNF-alpha and IL-1alpha secretion in Hep G2 cells.

    Science.gov (United States)

    Koo, Hyun-Na; Hong, Seung-Heon; Song, Bong-Keun; Kim, Cheorl-Ho; Yoo, Young-Hyun; Kim, Hyung-Min

    2004-01-16

    Taraxacum officinale (TO) has been frequently used as a remedy for women's disease (e.g. breast and uterus cancer) and disorders of the liver and gallbladder. Several earlier studies have indicated that TO exhibits anti-tumor properties, but its mechanism remains to be elucidated. In this study, we investigated the effect of TO on the cytotoxicity and production of cytokines in human hepatoma cell line, Hep G2. Our results show that TO decreased the cell viability by 26%, and significantly increased the tumor necrosis factor (TNF)-alpha and interleukin (IL)-1alpha production compared with media control (about 1.6-fold for TNF-alpha, and 2.4-fold for IL-1alpha, P < 0.05). Also, TO strongly induced apoptosis of Hep G2 cells as determined by flow cytometry. Increased amounts of TNF-alpha and IL-1alpha contributed to TO-induced apoptosis. Anti-TNF-alpha and IL-1alpha antibodies almost abolished it. These results suggest that TO induces cytotoxicity through TNF-alpha and IL-1alpha secretion in Hep G2 cells.

  17. Alpha decay calculations with a new formula

    Science.gov (United States)

    Akrawy, D. T.; Poenaru, D. N.

    2017-10-01

    A new semi-empirical formula for calculations of α decay half-lives is presented. It was derived from the Royer relationship by introducing new parameters which are fixed by fit to a set of experimental data. We are using three sets: set A with 130 e-e (even-even), 119 e-o (even-odd), 109 o-e, and 96 o-o, set B with 188 e-e, 147 e-o, 131 o-e and 114 o-o, and set C with 136 e-e, 84 e-o, 76 o-e and 48 o-o alpha emitters. A comparison of results obtained with the new formula (newF) and the following well known relationships: semiempirical relationship based on fission theory (semFIS), analytical superasymmetric fission (ASAF) model and universal formula (UNIV) made in terms of rms standard deviation. We also introduced a weighted mean value of this quantity, allowing us to compare the global properties of a given model. For set B the order of the four models is the following: semFIS, UNIV, newF and ASAF. Nevertheless for even-even alpha emitters, UNIV gives the second best result after semFIS, and for odd-even parents the second is newF. Despite its simplicity in comparison with semFIS, newF, presented in this article, behaves quite well, competing with the other well known relationships.

  18. Nonlinear feedback control for high alpha flight

    Science.gov (United States)

    Stalford, Harold

    1990-01-01

    Analytical aerodynamic models are derived from a high alpha 6 DOF wind tunnel model. One detail model requires some interpolation between nonlinear functions of alpha. One analytical model requires no interpolation and as such is a completely continuous model. Flight path optimization is conducted on the basic maneuvers: half-loop, 90 degree pitch-up, and level turn. The optimal control analysis uses the derived analytical model in the equations of motion and is based on both moment and force equations. The maximum principle solution for the half-loop is poststall trajectory performing the half-loop in 13.6 seconds. The agility induced by thrust vectoring capability provided a minimum effect on reducing the maneuver time. By means of thrust vectoring control the 90 degrees pitch-up maneuver can be executed in a small place over a short time interval. The agility capability of thrust vectoring is quite beneficial for pitch-up maneuvers. The level turn results are based currently on only outer layer solutions of singular perturbation. Poststall solutions provide high turn rates but generate higher losses of energy than that of classical sustained solutions.

  19. Alpha decay calculations with a new formula

    International Nuclear Information System (INIS)

    Akrawy, D T; Poenaru, D N

    2017-01-01

    A new semi-empirical formula for calculations of α  decay half-lives is presented. It was derived from the Royer relationship by introducing new parameters which are fixed by fit to a set of experimental data. We are using three sets: set A with 130 e–e (even–even), 119 e–o (even–odd), 109 o–e, and 96 o–o, set B with 188 e–e, 147 e–o, 131 o–e and 114 o–o, and set C with 136 e–e, 84 e–o, 76 o–e and 48 o–o alpha emitters. A comparison of results obtained with the new formula (newF) and the following well known relationships: semiempirical relationship based on fission theory (semFIS), analytical superasymmetric fission (ASAF) model and universal formula (UNIV) made in terms of rms standard deviation. We also introduced a weighted mean value of this quantity, allowing us to compare the global properties of a given model. For set B the order of the four models is the following: semFIS, UNIV, newF and ASAF. Nevertheless for even–even alpha emitters, UNIV gives the second best result after semFIS, and for odd–even parents the second is newF. Despite its simplicity in comparison with semFIS, newF, presented in this article, behaves quite well, competing with the other well known relationships. (paper)

  20. Alpha-amylase inhibition kinetics by caulerpenyne

    Directory of Open Access Journals (Sweden)

    S. CENGIZ

    2010-03-01

    Full Text Available Many algae have important secretions which are generally used for defensive purposes. These secretions take attentions of a lot of researchers who are wondering if these metabolites can be used for medical researches or not. Among these metabolites, caulerpenyne (CYN which is the main metabolite of Caulerpa species, have had an important place in Caulerpa researches since the results related to its determined properties such as cytotoxic, antiviral, antiproliferative and apoptotic effects have been proven by many scientific reports. In the present study, the inhibitory effect of CYN isolated from C. prolifera on alpha-amylase was investigated. The inhibition experiments were done with CYN by spectrophotometric determination method. In order to evaluate the type of inhibition Lineweaver–Burk plot was produced. The results obtained from enzyme kinetic studies exhibited an un-competitive type of inhibition, which is characterized by the difference of Vmax and KM from those of the free enzyme, of alpha-amylase in the presence of CYN. The present study showed that Caulerpa species can be a potential target for producing diabetic drugs in the light of the results obtained for CYN.

  1. MFTF-. cap alpha. + T progress report

    Energy Technology Data Exchange (ETDEWEB)

    Nelson, W.D. (ed.)

    1985-04-01

    Early in FY 1983, several upgrades of the Mirror Fusion Test Facility (MFTF-B) at Lawrence Livermore National Laboratory (LLNL) were proposed to the fusion community. The one most favorably received was designated MFTF-..cap alpha..+T. The engineering design of this device, guided by LLNL, has been a principal activity of the Fusion Engineering Design Center during FY 1983. This interim progress report represents a snapshot of the device design, which was begun in FY 1983 and will continue for several years. The report is organized as a complete design description. Because it is an interim report, some parts are incomplete; they will be supplied as the design study proceeds. As described in this report, MFTF-..cap alpha..+T uses existing facilities, many MFTF-B components, and a number of innovations to improve on the physics parameters of MFTF-B. It burns deuterium-tritium and has a central-cell Q of 2, a wall loading GAMMA/sub n/ of 2 MW/m/sup 2/ (with a central-cell insert module), and an availability of 10%. The machine is fully shielded, allows hands-on maintenance of components outside the vacuum vessel 24 h after shutdown, and has provisions for repair of all operating components.

  2. Variation in the number of alpha-globin loci in sheep.

    Science.gov (United States)

    Rando, A; Ramunno, L; Masina, P

    1986-03-01

    Southern blot analysis was used to compare sheep and goat restriction-endonuclease maps of the DNA region containing the alpha-globin genes. The identical digestion patterns observed in both species with three endonucleases (BamHI, BstEII, and PstI) show that in sheep a single chromosome normally bears two nonallelic alpha-globin genes positioned at the same distance as in goat. Variant digestion patterns with enzymes that cleave outside (BamHI and HindIII) and within (EcoRI) the alpha-globin loci allowed us to infer that chromosomes with different numbers of alpha-globin loci are also present in sheep. In particular, in the 60 sheep considered, four individuals were heterozygous (alpha alpha/alpha alpha alpha) and one was homozygous (alpha alpha alpha/alpha alpha alpha) for chromosomes with three loci and one individual was heterozygous for a chromosome with four loci (alpha alpha/alpha alpha alpha alpha). This variation in the number of copies of alpha-globin loci can be explained by means of unequal crossovers.

  3. Expression and secretion of Bacillus amyloliquefaciens alpha-amylase by using the yeast pheromone alpha-factor promoter and leader sequence in Saccharomyces cerevisiae.

    OpenAIRE

    Southgate, V J; Steyn, A J; Pretorius, I S; Van Vuuren, H J

    1993-01-01

    Replacement of the regulatory and secretory signals of the alpha-amylase gene (AMY) from Bacillus amylolique-faciens with the complete yeast pheromone alpha-factor prepro region (MF alpha 1p) resulted in increased levels of extracellular alpha-amylase production in Saccharomyces cerevisiae. However, the removal of the (Glu-Ala)2 peptide from the MF alpha 1 spacer region (Lys-Arg-Glu-Ala-Glu-Ala) yielded decreased levels of extracellular alpha-amylase.

  4. Increased 5. cap alpha. -reductase activity in idiopathic hirsutism

    Energy Technology Data Exchange (ETDEWEB)

    Serafini, P.; Lobo, R.A.

    1985-01-01

    In vitro, genital skin 5..cap alpha..-reductase activity (5..cap alpha..-RA) was measured in ten hirsute women with normal androgen levels (idiopathic hirsutism (IH)) and in ten hirsute women with elevated androgen levels (polycystic ovary syndrome (PCO)) in order to determine the influence of secreted androgens on 5..cap alpha..-RA. In vitro 5..cap alpha..-RA was assessed by incubations of skin with /sup 14/C-testosterone (T) for 2 hours, after which steroids were separated and the radioactivity of dihydrotestosterone (DHT) and 5..cap alpha..-androstane 3..cap alpha..-17..beta..-estradiol (3..cap alpha..-diol) in specific eluates were determined. All androgens were normal in IH with the exception of higher levels of 3..cap alpha..-diol glucuronide which were similar to the levels of PCO. The conversion ratio (CR) of T to DHT in IH and PCO were similar, yet significantly greater than the CR of control subjects. The CR of T to 3..cap alpha..-diol in IH and PCO were similar, yet higher than in control subjects. Serum androgens showed no correlation with 5..cap alpha..-RA, while the CR of T to DHT showed a significant positive correlation with the Ferriman and Gallwey score. The increased 5..cap alpha..-RA in IH appears to be independent of serum androgen levels and is, therefore, an inherent abnormality. The term idiopathic is a misnomer, because hirsutism in these patients may be explained on the basis of increased skin 5..cap alpha..-RA.

  5. Alpha-decay within Feshbach theory of nuclear reactions

    International Nuclear Information System (INIS)

    Sandulescu, A.; Silisteanu, I.; Wunsch, R.

    1977-01-01

    In the frame of Feshbach theory of nuclear reactions the alpha-decay widths are determined by the alpha-daughter nucleus optical potential and by the formation factors. It is shown that the calculated absolute values of the alpha widths for Po light isotopes are in good agreement with experimental data, if the real part of the optical potential with the parameters fitted by the low energy α-scattering is used

  6. Numerical analysis of alpha spectra using two different codes

    International Nuclear Information System (INIS)

    Hurtado, S.; Jimenez-Ramos, M.C.; Villa, M.; Vioque, I.; Manjon, G.; Garcia-Tenorio, R.

    2008-01-01

    This work presents an intercomparison between commercial software for alpha-particle spectrometry, Genie 2000, and the new free available software, Winalpha, developed by International Atomic Energy Agency (IAEA). In order to compare both codes, different environmental spectra containing plutonium, uranium, thorium and polonium have been analyzed, together with IAEA test alpha spectra. A statistical study was performed in order to evaluate the precision and accuracy in the analyses, and to enhance the confidence in using the software on alpha spectrometric studies

  7. Evidence for Alpha Receptors in the Human Ureter

    Science.gov (United States)

    Madeb, Ralph; Knopf, Joy; Golijanin, Dragan; Bourne, Patricia; Erturk, Erdal

    2007-04-01

    An immunohistochemical and western blot expression analysis of human ureters was performed in order to characterize the alpha-1-adrenergic receptor distribution along the length of the human ureteral wall. Mapping the distribution will assist in understanding the potential role alpha -1-adrenergic receptors and their subtype density might have in the pathophysiology of ureteral colic and stone passage. Patients diagnosed with renal cancer or bladder cancer undergoing nephrectomy, nephroureterectomy, or cystectomy had ureteral specimens taken from the proximal, mid, distal and tunneled ureter. Tissues were processed for fresh frozen examination and fixed in formalin. None of the ureteral specimens were involved with cancer. Serial histologic sections and immunohistochemical studies were performed using antibodies specific for alpha-1-adrenergic receptor subtypes (alpha 1a, alpha 1b, alpha 1d). The sections were examined under a light microscope and scored as positive or negative. In order to validate and quantify the alpha receptor subtypes along the human ureter. Western blotting techniques were applied. Human ureter stained positively for alpha -1-adrenergic receptors. Immunostaining appeared red, with intense reaction in the smooth muscle of the ureter and endothelium of the neighboring blood vessels. There was differential expression between all the receptors with the highest staining for alpha-1D subtype. The highest protein expression for all three subtypes was in the renal pelvis and decreased with advancement along the ureter to the distal ureter. At the distal ureter, there was marked increase in expression as one progressed towards the ureteral orifice. The same pattern of protein expression was exhibited for all three alpha -1-adrenergic receptor subtypes. We provide preliminary evidence for the ability to detect and quantify the alpha-1-receptor subtypes along the human ureter which to the best of our knowledge has never been done with

  8. A stable lipid-induced aggregate of alpha-synuclein.

    Science.gov (United States)

    Drescher, Malte; van Rooijen, Bart D; Veldhuis, Gertjan; Subramaniam, Vinod; Huber, Martina

    2010-03-31

    The Parkinson's disease-related protein alpha-Synuclein (alphaS) is a 140 residue intrinsically disordered protein. Its membrane-binding properties are thought to be relevant for its physiological or pathologic activity. Here, the interaction of alphaS with POPG [1-Palmitoyl-2-Oleoyl-sn-Glycero-3-(Phosphorac-(1-glycerol))] small unilamellar vesicles (SUVs) is investigated by spin-label EPR using double electron-electron resonance (DEER). Intermolecular distances between four single mutants reveal that well-defined aggregates are formed. The data suggest a coexistence of two dimer structures with main interactions in the helix 2, encompassing residues 50-100. Previously, the horseshoe conformation was detected by intramolecular restraints obtained by DEER on alphaS double mutants (Drescher et al. J. Am. Chem. Soc. 2008, 130, 7796). The present study suggests that interdigitation of two monomers in the aggregate fills the void between the two helices of each of the monomers thus providing a rationale for the horseshoe structure. This aggregate is lipid induced and affects the structure of the POPG SUVs, which become leaky and diminish in size upon contact with alphaS suggesting a possible origin of conflicting results in the recent literature (Jao et al. Proc. Natl. Acad. Sci. U.S.A. 2008, 105 (50), 19666; Georgieva et al. J. Am. Chem. Soc. 2008, 130 (39), 12856; Bortolus et al. J. Am. Chem. Soc. 2008, 130, 6690).

  9. A study on alpha particles range in Cr-39

    International Nuclear Information System (INIS)

    Ibrahim, Z.A.; Talaat, T.M.; Abdel-Aziz, Kh.M.A.; El-Asser, M.R.

    2000-01-01

    Cr-39 plastic nuclear track detector has been used in range determination of alpha particles. A set of experiments was carried out for studying alpha energy and track diameter relationships. This work was done under the optimum conditions of Cr-39 etching in 6.25 N NaOH at 70 degree C for various etching times. Determination of alpha range in Cr-39 recorders was studied at different energy values using the over etched track profile technique. Data are discussed within the framework of track formation theory in plastic foils, comparison between experimental and theoretical values of alpha range is included

  10. Alpha particle loss in the TFTR DT experiments

    International Nuclear Information System (INIS)

    Zweben, S.J.; Darrow, D.S.; Herrmann, H.W.

    1995-01-01

    Alpha particle loss was measured during the TFTR DT experiments using a scintillator detector located at the vessel bottom in the ion grad-B drift direction. The DT alpha particle loss to this detector was consistent with the calculated first-orbit loss over the whole range of plasma current I=0.6-2.7 MA. In particular, the alpha particle loss rate per DT neutron did not increase significantly with fusion power up to 10.7 MW, indicating the absence of any new ''collective'' alpha particle loss processes in these experiments

  11. Genetic and biosynthetic studies of families carrying hemoglobin J alpha Mexico: association of alpha-thalassemia with HbJ.

    Science.gov (United States)

    Trabuchet, G; Benabadji, M; Labie, D

    1978-06-09

    Hemoglobin J Mexico, an alpha chain mutant, was studied in eight unrelated Algerian families. The quantities of the abnormal hemoglobin in 116 subjects are trimodally distributed: 55% in homozygotes, 31% and 38% in heterozygotes. Both hematological data and the alpha/beta chain biosynthetic ratio are normal in heterozygotes with 31% Hb J and in homozygotes. In contrast, the MCV and MCH as well as the alpha/beta biosynthetic ratio are slightly reduced in heterozygotes with 38% Hb J and in their relatives carrying Hb A. The elevated expression of alphaJ chains in heterozygotes with 38% Hb J may be due to an alpha thalassemia gene trans to the alphaJ locus.

  12. Biochemical characterization of CK2alpha and alpha' paralogues and their derived holoenzymes: evidence for the existence of a heterotrimeric CK2alpha'-holoenzyme forming trimeric complexes

    DEFF Research Database (Denmark)

    Olsen, Birgitte; Rasmussen, Tine; Niefind, Karsten

    2008-01-01

    Altogether 2 holoenzymes and 4 catalytic CK2 constructs were expressed and characterized i.e. CK2alpha (2) (1-335) beta(2); CK2alpha'-derived holoenzyme; CK2alpha(1-335); MBP-CK2alpha'; His-tagged CK2alpha and His-tagged CK2alpha'. The two His-tagged catalytic subunits were expressed in insect...... cells, all others in Escherichia coli. IC(50) studies involving the established CK2 inhibitors DMAT, TBBt, TBBz, apigenin and emodin were carried out and the K(i) values calculated. Although the differences in the K(i) values found were modest, there was a general tendency showing that the CK2...... holoenzymes were more sensitive towards the inhibitors than the free catalytic subunits. Thermal inactivation experiments involving the individual catalytic subunits showed an almost complete loss of activity after only 2 min at 45 degrees C. In the case of the two holoenzymes, the CK2alpha...

  13. The alpha3 laminin subunit, alpha6beta4 and alpha3beta1 integrin coordinately regulate wound healing in cultured epithelial cells and in the skin

    DEFF Research Database (Denmark)

    Goldfinger, L E; Hopkinson, S B; deHart, G W

    1999-01-01

    Previously, we demonstrated that proteolytic processing within the globular domain of the alpha3 subunit of laminin-5 (LN5) converts LN5 from a cell motility-inducing factor to a protein complex that can trigger the formation of hemidesmosomes, certain cell-matrix attachment sites found in epithe......-inhibiting antibodies, we provide evidence that LN5 and its two integrin receptors (alpha6beta4 and alpha3beta1) appear necessary for wound healing to occur in MCF-10A cell culture wounds. We propose a model for healing of wounded epithelial tissues based on these results....... in epithelial cells. We have prepared a monoclonal antibody (12C4) whose epitope is located toward the carboxy terminus of the globular domain of the alpha3 laminin subunit. This epitope is lost from the alpha3 subunit as a consequence of proteolytic processing. Antibody 12C4 stains throughout the matrix...... the wound site. A similar phenomenon is observed in human skin wounds, since we also detect expression of the unprocessed alpha3 laminin subunit at the leading tip of the sheet of epidermal cells that epithelializes skin wounds in vivo. In addition, using alpha3 laminin subunit and integrin function...

  14. HIF-1alpha and HIF-2alpha are differentially activated in distinct cell populations in retinal ischaemia.

    Directory of Open Access Journals (Sweden)

    Freya M Mowat

    2010-06-01

    Full Text Available Hypoxia plays a key role in ischaemic and neovascular disorders of the retina. Cellular responses to oxygen are mediated by hypoxia-inducible transcription factors (HIFs that are stabilised in hypoxia and induce the expression of a diverse range of genes. The purpose of this study was to define the cellular specificities of HIF-1alpha and HIF-2alpha in retinal ischaemia, and to determine their correlation with the pattern of retinal hypoxia and the expression profiles of induced molecular mediators.We investigated the tissue distribution of retinal hypoxia during oxygen-induced retinopathy (OIR in mice using the bio-reductive drug pimonidazole. We measured the levels of HIF-1alpha and HIF-2alpha proteins by Western blotting and determined their cellular distribution by immunohistochemistry during the development of OIR. We measured the temporal expression profiles of two downstream mediators, vascular endothelial growth factor (VEGF and erythropoietin (Epo by ELISA. Pimonidazole labelling was evident specifically in the inner retina. Labelling peaked at 2 hours after the onset of hypoxia and gradually declined thereafter. Marked binding to Müller glia was evident during the early hypoxic stages of OIR. Both HIF-1alpha and HIF-2alpha protein levels were significantly increased during retinal hypoxia but were evident in distinct cellular distributions; HIF-1alpha stabilisation was evident in neuronal cells throughout the inner retinal layers whereas HIF-2alpha was restricted to Müller glia and astrocytes. Hypoxia and HIF-alpha stabilisation in the retina were closely followed by upregulated expression of the downstream mediators VEGF and EPO.Both HIF-1alpha and HIF-2alpha are activated in close correlation with retinal hypoxia but have contrasting cell specificities, consistent with differential roles in retinal ischaemia. Our findings suggest that HIF-2alpha activation plays a key role in regulating the response of Müller glia to hypoxia.

  15. Screening alpha-glucosidase and alpha-amylase inhibitors from natural compounds by molecular docking in silico.

    Science.gov (United States)

    Jhong, Chien-Hung; Riyaphan, Jirawat; Lin, Shih-Hung; Chia, Yi-Chen; Weng, Ching-Feng

    2015-01-01

    The alpha-glucosidase inhibitor is a common oral anti-diabetic drug used for controlling carbohydrates normally converted into simple sugars and absorbed by the intestines. However, some adverse clinical effects have been observed. The present study seeks an alternative drug that can regulate the hyperglycemia by down-regulating alpha-glucosidase and alpha-amylase activity by molecular docking approach to screen the hyperglycemia antagonist against alpha-glucosidase and alpha-amylase activities from the 47 natural compounds. The docking data showed that Curcumin, 16-hydroxy-cleroda-3,13-dine-16,15-olide (16-H), Docosanol, Tetracosanol, Antroquinonol, Berberine, Catechin, Quercetin, Actinodaphnine, and Rutin from 47 natural compounds had binding ability towards alpha-amylase and alpha-glucosidase as well. Curcumin had a better biding ability of alpha-amylase than the other natural compounds. Analyzed alpha-glucosidase activity reveals natural compound inhibitors (below 0.5 mM) are Curcumin, Actinodaphnine, 16-H, Quercetin, Berberine, and Catechin when compared to the commercial drug Acarbose (3 mM). A natural compound with alpha-amylase inhibitors (below 0.5 mM) includes Curcumin, Berberine, Docosanol, 16-H, Actinodaphnine/Tetracosanol, Catechin, and Quercetin when compared to Acarbose (1 mM). When taken together, the implication is that molecular docking is a fast and effective way to screen alpha-glucosidase and alpha-amylase inhibitors as lead compounds of natural sources isolated from medicinal plants. © 2015 International Union of Biochemistry and Molecular Biology.

  16. The H alpha Galaxy Survey. III. Constraints on supernova progenitors from spatial correlations with H alpha emission

    OpenAIRE

    James, P. A.; Anderson, J. P.

    2006-01-01

    Aims: We attempt to constrain progenitors of the different types of supernovae from their spatial distributions relative to star formation regions in their host galaxies, as traced by H alpha + NII line emission. Methods: We analyse 63 supernovae which have occurred within galaxies from our H alpha survey of the local Universe. Three statistical tests are used, based on pixel statistics, H alpha radial growth curves, and total galaxy emission-line fluxes. Results: Many more type II supernovae...

  17. Olefination of alpha-hydroxy or alpha-aminoaldehyde derivatives via reaction of their arylsulfonylhydrazones with sulfonyl anions.

    Science.gov (United States)

    Wicha, Jerzy; Zarecki, Andrzej

    2004-08-20

    Reaction of tosylhydrazones of O-substituted alpha-hydroxy or N-substituted alpha-amino aldehydes (2, 7, 11, 15, 17, and 20) with selected alpha-magnesio alkyl phenyl sulfones afforded the respective derivatives of allylic alcohols or allylic amines. 2,3-O-Isopropylidene-D-glyceraldehyde (1) was transformed into its tosylhydrazone (2) and then olefins 4a with retention of optical purity. Copyright 2004 American Chemical Society

  18. Serum concentrations of interleukin-1 alpha, interleukin-6 and tumor necrosis factor-alpha in neonatal sepsis and meningitis

    International Nuclear Information System (INIS)

    Fida, Nadia M.; Fadelallah, Mohamed F.; Al-Mughales, Jamil A.

    2006-01-01

    To investigate whether serum levels of interleukin-1alpha (IL-1alpha), IL-6, tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP) are useful in the diagnosis of neonatal sepsis and meningitis and differentiate them. Blood samples were collected from 35 full term neonates with suspected infection who admitted to the Neonatology Unit, Pediatric Department, King Abdul-Aziz University Hospital, Jeddah, Saudi Arabia during January 2002 - June 2003. On the basis of laboratory and bacteriological results, newborns were classified into: sepsis (n=28), meningitis (n=7), and healthy controls (n=16). Sepsis groups were further subdivided according to culture results into: group 1 = proven sepsis (n=6), group 2 = clinical sepsis (n=14), and group 3 = possible-infected (n=8). Serum levels of IL-1alpha, IL-6, TNF-alpha were measured using Enzyme-Linked Immunosorbent Assay while CRP by nephelometer: In sepsis and meningitis patients, serum levels of CRP (p<0.01, p<0.05,) and IL-1alpha (p<0.001, p<0.05) were elevated than controls. C-reactive protein levels elevated in proven sepsis (p<0.001) and IL-1alpha elevated in all subgroups of sepsis (groups 1, 2, 3) compared with (p<0.05, p<0.001, p<0.01) controls. Interleukin-6, TNF-alpha showed no significant differences between studied groups. In sepsis and meningitis, IL-1alpha had a highest sensitivity (89%, 86%), and negative predictive values (89% and 93%). Interleukin-1alpha and CRP increased in neonatal sepsis and meningitis, but cannot differentiate between them. Interleukin-1alpha had a highest sensitivity in prediction of neonatal infection and its assessment may improve accuracy of diagnosis. (author)

  19. Study of ({alpha}, {sup 3}He) and ({alpha}, t) reactions on {sup 28}Si at 45 MeV

    Energy Technology Data Exchange (ETDEWEB)

    Darshan, V.P.; Sathyavathiamma, M.P.; Ramaswamy, C.R.; Raja Rao, M.; Puttaswamy, N.G.; Banerjee, S.R.; Chintalapudi, S.N. [Dept. of Phys., Bangalore Univ. (India)

    1995-03-01

    The {sup 28}Si({alpha}, {sup 3}He){sup 29}Si, {sup 28}Si({alpha}, t){sup 29}P and Si({alpha}, {alpha})Si reactions were studied at E{sub {alpha}} = 45 MeV. Exact finite-range (EFR) DWBA analysis was carried out for the transitions to the ground state and to five excited states in {sup 29}Si and {sup 29}P. Spectroscopic strengths G were extracted for all the states and were compared with the predictions from shell-model and quasi-particle core-coupling calculations. Similar EFR-DWBA analyses were carried out from available (unpublished) data for the {sup 28}Si({alpha}, {sup 3}He){sup 29}Si reaction at E{sub {alpha}} = 64.9 and 120 MeV, and for the {sup 28}Si({alpha}, t){sup 29}P reaction at E{sub {alpha}} = 50 and 64.9 MeV. The comparison of experimental and theoretical values of G are provided. (author)

  20. Analysis of cadmium in high alpha solutions

    International Nuclear Information System (INIS)

    Gray, L.W.; Overman, L.A.; Hodgens, H.F.

    1977-07-01

    Cadmium nitrate is occasionally used as a neutron poison for convenience in the separation of uranium, neptunium, and plutonium. As the classical methods of analysis for cadmium are very time-consuming, a method to isolate it in solution using solvent extraction of uranium, neptunium, and plutonium with TBP in an n-paraffin hydrocarbon was investigated. After removal of the radionuclides, the cadmium is determined by atomic absorption spectroscopy. Precision of the method at the 95 percent confidence level is +-2.4 percent. Alpha content of the solutions was typically reduced from 1-10 x 10 11 dis/(min ml) 238 Pu to 1-15 x 10 4 dis/(min ml). Analysis time was typically reduced from approximately 24 hours per sample to less than 1 hour

  1. Solid waste combustion for alpha waste incineration

    International Nuclear Information System (INIS)

    Orloff, D.I.

    1981-02-01

    Radioactive waste incinerator development at the Savannah River Laboratory has been augmented by fundamental combustion studies at the University of South Carolina. The objective was to measure and model pyrolysis and combustion rates of typical Savannah River Plant waste materials as a function of incinerator operating conditions. The analytical models developed in this work have been incorporated into a waste burning transient code. The code predicts maximum air requirement and heat energy release as a function of waste type, package size, combustion chamber size, and temperature. Historically, relationships have been determined by direct experiments that did not allow an engineering basis for predicting combustion rates in untested incinerators. The computed combustion rates and burning times agree with measured values in the Savannah River Laboratory pilot (1 lb/hr) and full-scale (12 lb/hr) alpha incinerators for a wide variety of typical waste materials

  2. Effect of Pilates Training on Alpha Rhythm

    Science.gov (United States)

    Bian, Zhijie; Sun, Hongmin; Lu, Chengbiao; Yao, Li; Chen, Shengyong; Li, Xiaoli

    2013-01-01

    In this study, the effect of Pilates training on the brain function was investigated through five case studies. Alpha rhythm changes during the Pilates training over the different regions and the whole brain were mainly analyzed, including power spectral density and global synchronization index (GSI). It was found that the neural network of the brain was more active, and the synchronization strength reduced in the frontal and temporal regions due to the Pilates training. These results supported that the Pilates training is very beneficial for improving brain function or intelligence. These findings maybe give us some line evidence to suggest that the Pilates training is very helpful for the intervention of brain degenerative diseases and cogitative dysfunction rehabilitation. PMID:23861723

  3. Effect of Pilates Training on Alpha Rhythm

    Directory of Open Access Journals (Sweden)

    Zhijie Bian

    2013-01-01

    Full Text Available In this study, the effect of Pilates training on the brain function was investigated through five case studies. Alpha rhythm changes during the Pilates training over the different regions and the whole brain were mainly analyzed, including power spectral density and global synchronization index (GSI. It was found that the neural network of the brain was more active, and the synchronization strength reduced in the frontal and temporal regions due to the Pilates training. These results supported that the Pilates training is very beneficial for improving brain function or intelligence. These findings maybe give us some line evidence to suggest that the Pilates training is very helpful for the intervention of brain degenerative diseases and cogitative dysfunction rehabilitation.

  4. Chromosomal aberrations induced by alpha particles

    International Nuclear Information System (INIS)

    Guerrero C, C.; Brena V, M.

    2005-01-01

    The chromosomal aberrations produced by the ionizing radiation are commonly used when it is necessary to establish the exposure dose of an individual, it is a study that is used like complement of the traditional physical systems and its application is only in cases in that there is doubt about what indicates the conventional dosimetry. The biological dosimetry is based on the frequency of aberrations in the chromosomes of the lymphocytes of the individual in study and the dose is calculated taking like reference to the dose-response curves previously generated In vitro. A case of apparent over-exposure to alpha particles to which is practiced analysis of chromosomal aberrations to settle down if in fact there was exposure and as much as possible, to determine the presumed dose is presented. (Author)

  5. Alpha-like resonances in nuclei

    Science.gov (United States)

    Baran, V. V.; Delion, D. S.

    2018-03-01

    We investigate normal dipole oscillations in a system of protons, neutrons and α-particles within the Brink approach. We introduce an effective mass of α-clusters in terms of the spectroscopic factor. The Pauli exclusion principle is taken into account by using the Wildermuth rule. The ratio between alpha and giant resonance energy weighted sum rule (EWSR) is investigated for N = Z and N> Z systems. In both cases we notice an unexpected decrease of this ratio versus the increase of the spectroscopic factor. Due to this fact the possibility to experimentally detect α-like oscillations is enhanced in nuclei above 100Sn. The occurrence of the pygmy mode in N> Z systems decreases the EWSR for the α-like oscillations.

  6. Towards antihydrogen trapping and spectroscopy at ALPHA

    International Nuclear Information System (INIS)

    Butler, E.; Andresen, G. B.; Ashkezari, M. D.; Baquero-Ruiz, M.; Bertsche, W.; Bowe, P. D.; Bray, C. C.; Cesar, C. L.; Chapman, S.; Charlton, M.; Fajans, J.; Friesen, T.; Fujiwara, M. C.; Gill, D. R.; Hangst, J. S.; Hardy, W. N.; Hayano, R. S.; Hayden, M. E.; Humphries, A. J.; Hydomako, R.

    2011-01-01

    Spectroscopy of antihydrogen has the potential to yield high-precision tests of the CPT theorem and shed light on the matter-antimatter imbalance in the Universe. The ALPHA antihydrogen trap at CERN’s Antiproton Decelerator aims to prepare a sample of antihydrogen atoms confined in an octupole-based Ioffe trap and to measure the frequency of several atomic transitions. We describe our techniques to directly measure the antiproton temperature and a new technique to cool them to below 10 K. We also show how our unique position-sensitive annihilation detector provides us with a highly sensitive method of identifying antiproton annihilations and effectively rejecting the cosmic-ray background.

  7. Ripple enhanced transport of suprathermal alpha particles

    International Nuclear Information System (INIS)

    Tani, K.; Takizuka, T.; Azumi, M.

    1986-01-01

    The ripple enhanced transport of suprathermal alpha particles has been studied by the newly developed Monte-Carlo code in which the motion of banana orbit in a toroidal field ripple is described by a mapping method. The existence of ripple-resonance diffusion has been confirmed numerically. We have developed another new code in which the radial displacement of banana orbit is given by the diffusion coefficients from the mapping code or the orbit following Monte-Carlo code. The ripple loss of α particles during slowing down has been estimated by the mapping model code as well as the diffusion model code. From the comparison of the results with those from the orbit-following Monte-Carlo code, it has been found that all of them agree very well. (author)

  8. Follow-Up Multicenter Alpha Counting Comparison

    Science.gov (United States)

    Wilkinson, J. D.; Clark, B. M.; Wong, R.; Slayman, C.; Gordon, M. S.; He, Y.; Marckmann, J.; McNally, B. D.; Wu, T.

    2014-08-01

    A follow-up alpha emissivity study was conducted to examine the wide variability observed in previous work that was hypothesized to be due to differences in the pulse height discrimination threshold among participant's equipment. Two samples, one mixed energy and one monoenergetic, were prepared and sequentially circulated to all participants for counting. Analysis of the data demonstrates that only a small portion of the variability is explained by this mechanism. The role of the sample to entrance window gap for some counters was analyzed post hoc using the same data set and may be responsible for a large amount of the variability. The results of this large-scale study demonstrate the continuing uncertainty for these measurements and the importance of interpreting their results appropriately when estimating soft error rates.

  9. Alpha-synuclein structure, functions, and interactions

    Directory of Open Access Journals (Sweden)

    Fatemeh Nouri Emamzadeh

    2016-01-01

    Full Text Available At present, when a clinical diagnosis of Parkinson′s disease (PD is made, serious damage has already been done to nerve cells of the substantia nigra pars compacta. The diagnosis of PD in its earlier stages, before this irreversible damage, would be of enormous benefit for future treatment strategies designed to slow or halt the progression of this disease that possibly prevents accumulation of toxic aggregates. As a molecular biomarker for the detection of PD in its earlier stages, alpha-synuclein (α-syn, which is a key component of Lewy bodies, in which it is found in an aggregated and fibrillar form, has attracted considerable attention. Here, α-syn is reviewed in details.

  10. Alpha Radiation Effects on Silicon Oxynitride Waveguides

    Energy Technology Data Exchange (ETDEWEB)

    Morichetti, Francesco; Grillanda, Stefano; Manandhar, Sandeep; Shutthanandan, Vaithiyalingam; Kimerling, Lionel; Melloni, Andrea; Agarwal, Anuradha M.

    2016-09-21

    Photonic technologies are today of great interest for use in harsh environments, such as outer space, where they can potentially replace current communication systems based on radiofrequency components. However, very much alike to electronic devices, the behavior of optical materials and circuits can be strongly altered by high-energy and high-dose ionizing radiations. Here, we investigate the effects of alpha () radiation with MeV-range energy on silicon oxynitride (SiON) optical waveguides. Irradiation with a dose of 5×1015 cm-2 increases the refractive index of the SiON core by nearly 10-2, twice as much that of the surrounding silica cladding, leading to a significant increase of the refractive index contrast of the waveguide. The higher mode confinement induced by -radiation reduces the loss of tightly bent waveguides. We show that this increases the quality factor of microring resonators by 20%, with values larger than 105 after irradiation.

  11. Fluorescent Protein Approaches in Alpha Herpesvirus Research

    Directory of Open Access Journals (Sweden)

    Ian B. Hogue

    2015-11-01

    Full Text Available In the nearly two decades since the popularization of green fluorescent protein (GFP, fluorescent protein-based methodologies have revolutionized molecular and cell biology, allowing us to literally see biological processes as never before. Naturally, this revolution has extended to virology in general, and to the study of alpha herpesviruses in particular. In this review, we provide a compendium of reported fluorescent protein fusions to herpes simplex virus 1 (HSV-1 and pseudorabies virus (PRV structural proteins, discuss the underappreciated challenges of fluorescent protein-based approaches in the context of a replicating virus, and describe general strategies and best practices for creating new fluorescent fusions. We compare fluorescent protein methods to alternative approaches, and review two instructive examples of the caveats associated with fluorescent protein fusions, including describing several improved fluorescent capsid fusions in PRV. Finally, we present our future perspectives on the types of powerful experiments these tools now offer.

  12. Alpha-emitting radionuclides in cigarette tobacco

    International Nuclear Information System (INIS)

    Neton, James W.; Ibrahim, Shawki Amin

    1978-01-01

    As part of general studies of the concentration of 239/240 Pu, 238 Pu and 228,230,232 Th in the tissues of non-occupationally exposed individuals, it became evident that there was little or no information on their content in cigarette tobacco. To better understand this possible route of intake and its potential for lung exposure we have measured these nuclides in tobacco samples, from the U.S. Department of Agriculture (USDA), which have a well-known growing history, and in brand name cigarettes purchased commercially. The concentration of 239/240 Pu in both USDA and brand name tobacco has a range of 0.4-0.7 pCi/kg of tobacco while the 238 Pu concentration was ≤ 0.05 pCi/kg. The 228 Th concentration for USDA tobacco was 200 pCi/kg tobacco while the 232 Th was only 14 pCi/kg. The high 228/232 Th ratio may result from a lower uptake of 232 Th compared to that of 228 Ra. By comparing the concentration of these measured nuclides to other alpha emitters in tobacco that have been reported in the literature, i.e. 210 Po (400 pCi/kg) and 226 Ra (150 pCi/kg), it is apparent that 228 Th represents a significant fraction of the total alpha activity. It is also evident there is a much greater potential for exposure of the lung to radiation from 228 Th than from 239/240 Pu as a result of cigarette smoking. (author)

  13. Jet Production in ep Collisions at Low Q^2 and Determination of $\\alpha_{s}$

    CERN Document Server

    Aaron, F.D.; Alexa, C.; Andreev, V.; Antunovic, B.; Backovic, S.; Baghdasaryan, A.; Barrelet, E.; Bartel, W.; Begzsuren, K.; Belousov, A.; Bizot, J.C.; Boudry, V.; Bozovic-Jelisavcic, I.; Bracinik, J.; Brandt, G.; Brinkmann, M.; Brisson, V.; Bruncko, D.; Bunyatyan, A.; Buschhorn, G.; Bystritskaya, L.; Campbell, A.J.; Cantun Avila, K.B.; Cerny, K.; Cerny, V.; Chekelian, V.; Cholewa, A.; Contreras, J.G.; Coughlan, J.A.; Cozzika, G.; Cvach, J.; Dainton, J.B.; Daum, K.; Deak, M.; Delcourt, B.; Delvax, J.; De Wolf, E.A.; Diaconu, C.; Dodonov, V.; Dossanov, A.; Dubak, A.; Eckerlin, G.; Efremenko, V.; Egli, S.; Eliseev, A.; Elsen, E.; Falkiewicz, A.; Favart, L.; Fedotov, A.; Felst, R.; Feltesse, J.; Ferencei, J.; Fischer, D.J.; Fleischer, M.; Fomenko, A.; Gabathuler, E.; Gayler, J.; Ghazaryan, Samvel; Glazov, A.; Glushkov, I.; Goerlich, L.; Gogitidze, N.; Gouzevitch, M.; Grab, C.; Greenshaw, T.; Grell, B.R.; Grindhammer, G.; Habib, S.; Haidt, D.; Helebrant, C.; Henderson, R.C.W.; Hennekemper, E.; Henschel, H.; Herbst, M.; Herrera, G.; Hildebrandt, M.; Hiller, K.H.; Hoffmann, D.; Horisberger, R.; Hreus, T.; Jacquet, M.; Janssen, X.; Jonsson, L.; Jung, A.W.; Jung, H.; Kapichine, M.; Katzy, J.; Kenyon, I.R.; Kiesling, C.; Klein, M.; Kleinwort, C.; Kluge, T.; Knutsson, A.; Kogler, R.; Kosior, E.; Kostka, P.; Kraemer, M.; Krastev, K.; Kretzschmar, J.; Kropivnitskaya, A.; Kruger, K.; Kutak, K.; Landon, M.P.J.; Lange, W.; Lastovicka-Medin, G.; Laycock, P.; Lebedev, A.; Lendermann, V.; Levonian, S.; Li, G.; Lipka, K.; Liptaj, A.; List, B.; List, J.; Loktionova, N.; Lopez-Fernandez, R.; Lubimov, V.; Makankine, A.; Malinovski, E.; Marage, P.; Marti, Ll.; Martyn, H.U.; Maxfield, S.J.; Mehta, A.; Meyer, A.B.; Meyer, H.; Meyer, H.; Meyer, J.; Mikocki, S.; Milcewicz-Mika, I.; Moreau, F.; Morozov, A.; Morris, J.V.; Mozer, M.U.; Mudrinic, M.; Muller, K.; Murin, P.; Naumann, Th.; Newman, P.R.; Niebuhr, C.; Nikiforov, A.; Nikitin, D.; Nowak, G.; Nowak, K.; Olsson, J.E.; Osman, S.; Ozerov, D.; Palichik, V.; Panagoulias, I.; Pandurovic, M.; Papadopoulou, Th.; Pascaud, C.; Patel, G.D.; Pejchal, O.; Perez, E.; Petrukhin, A.; Picuric, I.; Piec, S.; Pitzl, D.; Placakyte, R.; Pokorny, B.; Polifka, R.; Povh, B.; Radescu, V.; Rahmat, A.J.; Raicevic, N.; Raspiareza, A.; Ravdandorj, T.; Reimer, P.; Rizvi, E.; Robmann, P.; Roland, B.; Roosen, R.; Rostovtsev, A.; Rotaru, M.; Tabasco, J.E.Ruiz; Rusakov, S.; Salek, D.; Sankey, D.P.C.; Sauter, M.; Sauvan, E.; Schmitt, S.; Schoeffel, L.; Schoning, A.; Schultz-Coulon, H.C.; Sefkow, F.; Shaw-West, R.N.; Shtarkov, L.N.; Shushkevich, S.; Sloan, T.; Smiljanic, Ivan; Soloviev, Y.; Sopicki, P.; South, D.; Spaskov, V.; Specka, A.; Staykova, Z.; Steder, M.; Stella, B.; Stoicea, G.; Straumann, U.; Sunar, D.; Sykora, T.; Tchoulakov, V.; Thompson, G.; Thompson, P.D.; Toll, T.; Tomasz, F.; Tran, T.H.; Traynor, D.; Trinh, T.N.; Truol, P.; Tsakov, I.; Tseepeldorj, B.; Turnau, J.; Urban, K.; Valkarova, A.; Vallee, C.; Van Mechelen, P.; Trevino, A.Vargas; Vazdik, Y.; Vinokurova, S.; Volchinski, V.; von den Driesch, M.; Wegener, D.; Wissing, Ch.; Wunsch, E.; Zacek, J.; Zalesak, J.; Zhang, Z.; Zhokin, A.; Zimmermann, T.; Zohrabyan, H.; Zomer, F.

    2010-01-01

    The production of jets is studied in deep-inelastic e+p scattering at low negative four momentum transfer squared 5alpha_s.

  14. Peginterferon alpha-2a versus peginterferon alpha-2b for chronic hepatitis C

    DEFF Research Database (Denmark)

    Hauser, Goran; Awad, Tahany; Thorlund, Kristian

    2014-01-01

    : We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and LILACS until October 2013. We also searched conference abstracts, journals, and grey...... compared peginterferon alpha-2a plus ribavirin versus peginterferon alpha-2b plus ribavirin in 5847 patients. All trials had a high risk of bias. Very few trials reported data on very few patients for the patient-relevant outcomes all-cause mortality, liver-related morbidity, serious adverse events......, and quality of life. Accordingly, we were unable to conduct meta-analyses on all-cause mortality, liver-related morbidity, and quality of life. Twelve trials reported on adverse events leading to discontinuation of treatment without clear evidence of a difference between the two peginterferons (197/2171 (9...

  15. Alpha spectrometry of thick sources. I. Application to alpha emitters determination

    International Nuclear Information System (INIS)

    Acena, M.L.; Garcia-Torano, E.; Rivero, M.C.

    1977-01-01

    A method for determining alpha emitters by silicon surface barrier detector spectroscopy using thick sources is studied. Two types of spectra have been obtained. They have different shapes of line according to the procedure used for preparing the sources. For both spectra a computing least square programme has been developed. In this way it is possible to calculate line intensities with accuracy better than 20 percent. (author) [es

  16. Measurement of radon daughters in air samples by alpha spectroscopy

    International Nuclear Information System (INIS)

    Acena, M.L.; Crespo, M.T.

    1989-01-01

    The concentration of radon progeny in air has been determined by alpha spectrometry measurement of polonium 214 and polonium 218. A known volume of air was passed through a filter, then the alpha activity was directly measured on this filter (Author)

  17. Immunotoxicity of the pyrethroid insecticides deltametrin and alpha-cypermetrin

    DEFF Research Database (Denmark)

    Madsen, Charlotte Bernhard; Claesson, M. H.; Ropke, C.

    1996-01-01

    The synthetic pyrethroids deltametrin and alpha-cypermetrin were studied for effects on the immune system in 28-day studies in F344 male rats. Sixteen rats per group were dosed with either deltametrin 0, 1, 5, or 10 mg/kg body wt./day or alpha-cypermetrin 0, 4, 8, or 12 mg/kg body wt./day in soy...

  18. Reproductive partitioning among polyandrous alpha and beta pale ...

    African Journals Online (AJOL)

    Although, polyandrous males participated equally in building nests, provisioning prey and incubating, in the fertility window the dominant alpha males copulated 31–5 days before the females laid, whereas subordinate beta males only copulated 5–3 days before laying. If this copulation timing by alpha males was indicative ...

  19. Does formate reduce alpha-ketoglutarate and ammonia to glutamate?

    Science.gov (United States)

    Maughan, Q.; Miller, S. L.; Bada, J. L. (Principal Investigator)

    1999-01-01

    The reported reduction of alpha-ketoglutarate and ammonia by formate is much slower than described (Morowitz et al., 1995). The formate reduction if any is small under these conditions. Glutamate is produced from a reduction by a second molecule of alpha-ketoglutarate involving an oxidative decarboxylation.

  20. Alpha-deuteron elastic scattering around 40 MeV

    International Nuclear Information System (INIS)

    De, A.; Karmakar, S.; Roychaudhury, T.; Dasgupta, S.S.; Chintalapudi, S.N.; Ismail, M.; Banerjee, S.R.; Divatia, A.S.

    1989-01-01

    Differential cross section for alpha-deuteron elastic scattering has been measured at several energies around 40 MeV incident alpha. General behaviour of angular distributions remaining close to that predicted by Faddeev type calculations, a sharp energy dependence is observed. (author). 8 refs

  1. Method for using a yeast alpha-amylase promoter

    Science.gov (United States)

    Gao, Johnway; Skeen, Rodney S.; Hooker, Brian S.; Anderson, Daniel B.

    2003-04-22

    The present invention provides the promoter clone discovery of an alpha-amylase gene of a starch utilizing yeast strain Schwanniomyces castellii. The isolated alpha-amylase promoter is an inducible promoter, which can regulate strong gene expression in starch culture medium.

  2. Gauge-invariant perturbations of varying-alpha cosmologies

    CERN Document Server

    Barrow, J D

    2003-01-01

    Using a gauge-invariant formalism we derive and solve the perturbed cosmological equations for the BSBM theory of varying fine structure 'constant'. We calculate the time evolution of inhomogeneous perturbations of the fine structure constant, delta alpha/alpha on small and large scales with respect to the Hubble radius. In a radiation-dominated universe, small inhomogeneities in alpha will decrease on large scales but on scales smaller than the Hubble radius they will undergo stable oscillations. In a dust-dominated universe small inhomogeneous perturbations in alpha will become constant on large scales and on small scales they will increase as t sup 2 sup / sup 3 , and delta alpha/alpha will track delta rho sub m /rho sub m. If the expansion accelerates, as in the case of a LAMBDA or quintessence-dominated phase, inhomogeneities in alpha will decrease on both large and small scales. The amplitude of perturbations in alpha will be much smaller than that of matter or radiation perturbations. We also present a...

  3. DT results of TFTR`s alpha collector

    Energy Technology Data Exchange (ETDEWEB)

    Herrmann, H.W.; Zweben, S.J.; Darrow, D.S.; Timberlake, J.R. [Princeton Univ., NJ (United States). Princeton Plasma Physics Lab.; Chong, G.P.; Haasz, A.A. [Univ. of Toronto, Downsview, Ontario (Canada). Inst. for Aerospace Studies; Pitcher, C.S. [Max-Planck-Inst. fuer Plasmaphysik, Garching (Germany); Macaulay-Newcombe, R.G. [McMaster Univ., Hamilton, Ontario (Canada). Dept. of Engineering Physics

    1996-11-01

    An escaping alpha collector probe has been developed for TFTR`s DT phase to complement the results of the lost alpha scintillator detectors which have been operating on TFTR since 1988. Measurements of the energy distribution of escaping alphas have been made by measuring the range of alphas implanted into nickel foils located within the alpha collector. Exposed samples have been analyzed for 4 DT plasma discharges at plasma currents of 1.0 and 1.8 MA. The results at 1.0 MA are in good agreement with predictions for first orbit alpha loss at 3.5 MeV. The 1.8 MA results, however, indicate a large anomalous loss of partially thermalized alphas at an energy {approximately}30% below the birth energy and at a total fluence nearly an order of magnitude above expected first orbit loss. This anomalous loss is not observed with the lost alpha scintillator detectors in DT plasmas but does resemble the anomalous delayed loss seen in DD plasmas. Several potential explanations for this loss process are examined. None of the candidate explanations proposed thus far are fully consistent with the anomalous loss observations.

  4. Differential vascular alpha1-adrenoceptor antagonism by tamsulosin and terazosin

    NARCIS (Netherlands)

    Schäfers, R. F.; Fokuhl, B.; Wasmuth, A.; Schumacher, H.; Taguchi, K.; de Mey, C.; Philipp, T.; Michel, M. C.

    1999-01-01

    AIMS: In patients with lower urinary tract symptoms suggestive of benign prostatic obstruction the alpha1-adrenoceptor antagonist terazosin lowers blood pressure whereas only very small if any alterations were reported with the alpha1-adrenoceptor antagonist tamsulosin. Therefore, we have compared

  5. [Oxidation of 17alpha,20beta- and 17alpha,20alpha-dihydroxysipregn-4-en-ones--side products of biotransformation of progesterone by recombinant microorganisms expressing cytochrome P45017alpha].

    Science.gov (United States)

    Shkumatov, V M; Usova, E V; Radiuk, V G; Kashkan, Zh N; Kovganko, N V; Juretzek, T; Mauersberger, S

    2003-01-01

    Progesterone biotransformation with recombinant yeast Yarrowia lipolytica E129A15 and Saccharomyces cerevisiae GRF18/YEp5117 alpha expressing bovine adrenocortical cytochrome P45017 alpha yielded 17 alpha-hydroxyprogesterone and two diols, 17 alpha, 20 beta- and 17 alpha, 20 alpha-dihydroxypregn-4-en-3-one. The oxidation of mixtures of the three steroids with chromic acid resulted in the cleavage of 17-20 bonds in the diols with the formation of androst-4-ene-3,17-dione. The biotransformation of pregn-4-ene-20 beta-ol-3-one by means of Y. lipolytica E129A15 was accompanied by the following reactions: the primary oxidation of these compounds to progesterone and the subsequent successive reactions of 17 alpha-hydroxylation and 20 alpha- and 20 beta-reduction. The results widen the possibilities for enzymatic and chemical modifications of steroids. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2003, vol. 29, no. 6; see also http://www.maik.ru.

  6. Metathesis process for preparing an alpha, omega-functionalized olefin

    Science.gov (United States)

    Burdett, Kenneth A.; Mokhtarzadeh, Morteza; Timmers, Francis J.

    2010-10-12

    A cross-metathesis process for preparing an .alpha.,.omega.-functionalized olefin, such as methyl 9-decenoate, and an .alpha.-olefin having three or more carbon atoms, such as 1-decene. The process involves contacting in a first reaction zone an .alpha.-functionalized internal olefin, such as methyl oleate, and an .alpha.-olefinic monomer having three or more carbon atoms, such as 1-decene, with a first metathesis catalyst to prepare an effluent stream containing the .alpha.,.omega.-functionalized olefin, such as methyl 9-decenoate, an unfunctionalized internal olefin, such as 9-octadecene, unconverted reactant olefins, and optionally, an .alpha.,.omega.-difunctionalized internal olefinic dimer, such as dimethyl 9-octadecen-1,18-dioate; separating said effluent streams; then contacting in a second reaction zone the unfunctionalized internal olefin with ethylene in the presence of a second metathesis catalyst to obtain a second product effluent containing the .alpha.-olefinic monomer having three or more carbon atoms; and cycling a portion of the .alpha.-olefinic monomer stream(s) to the first zone.

  7. alpha-Amanitin induced apoptosis in primary cultured dog hepatocytes.

    Directory of Open Access Journals (Sweden)

    Adam Szelag

    2010-06-01

    Full Text Available Amatoxin poisoning is caused by mushroom species belonging to the genera Amanita, Galerina and Lepiota with the majority of lethal mushroom exposures attributable to Amanita phalloides. High mortality rate in intoxications with these mushrooms is principally a result of the acute liver failure following significant hepatocyte damage due to hepatocellular uptake of amatoxins. A wide variety of amatoxins have been isolated; however, alpha-amanitin (alpha-AMA appears to be the primary toxin. Studies in vitro and in vivo suggest that alpha-AMA does not only cause hepatocyte necrosis, but also may lead to apoptotic cell death. The objective of this study was to evaluate the complex hepatocyte apoptosis in alpha-AMA cytotoxicity. All experiments were performed on primary cultured canine hepatocytes. The cells were incubated for 12 h with alpha-AMA at a final concentration of 1, 5, 10 and 20 microM. Viability test (MTT assay, apoptosis evaluation (TUNEL reaction, detection of DNA laddering and electron microscopy were performed at 6 and 12 h of exposure to alpha-AMA. There was a clear correlation between hepatocyte viability, concentration of alpha-AMA and time of exposure to this toxin. The decline in cultured dog hepatocyte viability during the exposure to alpha-AMA is most likely preceded by enhanced cellular apoptosis. Our results demonstrate that apoptosis might contribute to pathogenesis of the severe liver injury in the course of amanitin intoxication, particularly during the early phase of poisoning.

  8. (ALPHA)2(BETA)1 Integrin-Induced Breast Cancer Differentiation

    National Research Council Canada - National Science Library

    Kamata, Tetsuji

    1998-01-01

    .... The integrin alpha 2 beta 1 functions as a collagen and/or laminin receptor. Previous reports suggest that alpha 2 beta 1 plays a critical role in normal mammary cell differentiation as well as in the pathogenesis of breast cancer...

  9. Subcloning and expression of human alpha-fetoprotein gene in ...

    African Journals Online (AJOL)

    Subcloning and expression of human alpha-fetoprotein gene in Pichia pastoris. ... in inducing protein production in auxotrophic media lacking histidine. This protein could be useful in monoclonal antibody production and in diagnostic kit preparations. Keywords: Alpha-fetoprotein, Pichia pastoris, cloning, expression ...

  10. Intraperitoneal alpha-radioimmunotherapy in mice using different specific activities

    DEFF Research Database (Denmark)

    Elgqvist, Jörgen; Andersson, Håkan; Haglund, Elin

    2009-01-01

    The aim of this study was to investigate the therapeutic efficacy of the alpha-radioimmunotherapy of ovarian cancer in mice, using different specific activities. This study was performed by using the monoclonal antibody, MX35 F(ab')(2), labeled with the alpha-particle-emitter, 211At....

  11. Molecular characterization of an. alpha. sub 2B -adrenergic receptor

    Energy Technology Data Exchange (ETDEWEB)

    Harrison, J.K.; Dewan Zeng; D' Angelo, D.D.; Tucker, A.L.; Zhihong Lu; Barber, C.M.; Lynch, K.R. (Univ. of Virginia Health Sciences Center, Charlottesville (United States))

    1990-02-26

    {alpha}{sub 2}-Adrenergic receptors comprise a heterogeneous population based on pharmacologic and molecular evidence. The authors have isolated a cDNA clone (pRNG{alpha}2) encoding a previously undescribed third subtype of an {alpha}{sub 2}-adrenergic receptor from a rat kidney cDNA library. The library was screened with an oligonucleotide encoding a highly conserved region found in all biogenic amine receptors described to date. The deduced amino acid sequence displays many features of G-protein coupled receptors with exception of the absence of the consensus N-linked glycosylation site at the amino terminus. Membranes prepared from COS-1 cells transfected with pRNG{alpha}2 display high affinity and saturable binding to {sup 3}H-rauwolscine (K{sub d}=2 nM).Competition curve data analysis shows that pRNG{alpha}2 protein binds to a variety of adrenergic drugs with the following rank order of potency: yohimbine {ge} cholorpromazine > prazosin {ge} clonidine > norepinephrine {ge} oxymetazoline. pRNG{alpha}2 RNA accumulates in both adult rat kidney and rat neonatal lung (predominant species is 4.0 kb). They conclude that pRNG{alpha}2 likely represents a cDNA for the {alpha}{sub 2B}-adrenergic receptor.

  12. Production of secreted guar alpha-galactosidase by Lactococcus lactis

    NARCIS (Netherlands)

    Leenhouts, KJ; Bolhuis, A; Ledeboer, A; Venema, G; Kok, J

    1995-01-01

    A plant alpha-galactosidase gene was inserted in the expression vector pGKV259. The resulting plasmid pGAL2 consisted of the replication functions of the broad-host-range lactococcal plasmid pWVO1, the lactococcal promoter P59, and the DNA sequences encoding the alpha-amylase signal sequence from

  13. Concentration of Radon Progeny in Air by Alpha Spectrometry Measurement

    International Nuclear Information System (INIS)

    Acena, M. L.; Crespo, M. T.

    1989-01-01

    The concentration of radon progeny in air has been determined by alpha spectrometry measurement of 214 Po and 318 Po. A known volume of air was passed through a filter, then the alpha activity was directly measured on this filter. (Author) 15 refs

  14. Immunotoxicity of the pyrethroid insecticides deltametrin and alpha-cypermetrin

    DEFF Research Database (Denmark)

    Madsen, Charlotte Bernhard; Claesson, M. H.; Ropke, C.

    1996-01-01

    The synthetic pyrethroids deltametrin and alpha-cypermetrin were studied for effects on the immune system in 28-day studies in F344 male rats. Sixteen rats per group were dosed with either deltametrin 0, 1, 5, or 10 mg/kg body wt./day or alpha-cypermetrin 0, 4, 8, or 12 mg/kg body wt./day in soy ...

  15. Tumor necrosis factor-alpha increases myocardial microvascular transport in vivo

    DEFF Research Database (Denmark)

    Hansen, P R; Svendsen, Jesper Hastrup; Høyer, S

    1994-01-01

    Tumor necrosis factor-alpha (TNF-alpha) is a primary mediator in the pathogenesis of tissue injury, and high circulating levels of TNF-alpha are found in a variety of pathological conditions. In open-chest anesthetized dogs, the effects of intracoronary recombinant human TNF-alpha (rTNF-alpha; 100...

  16. A new alpha(0)-thalassemia deletion found in a Dutch family (--(AW)).

    NARCIS (Netherlands)

    Phylipsen, M.; Vogelaar, I.P.; Schaap, R.A.; Arkesteijn, S.G.; Boxma, G.L.; Helden, W.C. van; Wildschut, I.C.; Bruin-Roest, A.C. de; Giordano, P.C.; Harteveld, C.L.

    2010-01-01

    Alpha-thalassemia is an inherited hemoglobin disorder characterized by a microcytic hypochromic anemia caused by a quantitative reduction of the alpha-globin chain. The majority of the alpha-thalassemias is caused by deletions in the alpha-globin gene cluster. A deletion in the alpha-globin gene

  17. Binding of [alpha, alpha]-Disubstituted Amino Acids to Arginase Suggests New Avenues for Inhibitor Design

    Energy Technology Data Exchange (ETDEWEB)

    Ilies, Monica; Di Costanzo, Luigi; Dowling, Daniel P.; Thorn, Katherine J.; Christianson, David W. (MIT); (Episcopal U); (Rutgers); (Drexel); (Penn)

    2011-10-21

    Arginase is a binuclear manganese metalloenzyme that hydrolyzes L-arginine to form L-ornithine and urea, and aberrant arginase activity is implicated in various diseases such as erectile dysfunction, asthma, atherosclerosis, and cerebral malaria. Accordingly, arginase inhibitors may be therapeutically useful. Continuing our efforts to expand the chemical space of arginase inhibitor design and inspired by the binding of 2-(difluoromethyl)-L-ornithine to human arginase I, we now report the first study of the binding of {alpha},{alpha}-disubstituted amino acids to arginase. Specifically, we report the design, synthesis, and assay of racemic 2-amino-6-borono-2-methylhexanoic acid and racemic 2-amino-6-borono-2-(difluoromethyl)hexanoic acid. X-ray crystal structures of human arginase I and Plasmodium falciparum arginase complexed with these inhibitors reveal the exclusive binding of the L-stereoisomer; the additional {alpha}-substituent of each inhibitor is readily accommodated and makes new intermolecular interactions in the outer active site of each enzyme. Therefore, this work highlights a new region of the protein surface that can be targeted for additional affinity interactions, as well as the first comparative structural insights on inhibitor discrimination between a human and a parasitic arginase.

  18. Context based Coding of Quantized Alpha Planes for Video Objects

    DEFF Research Database (Denmark)

    Aghito, Shankar Manuel; Forchhammer, Søren

    2002-01-01

    In object based video, each frame is a composition of objects that are coded separately. The composition is performed through the alpha plane that represents the transparency of the object. We present an alternative to MPEG-4 for coding of alpha planes that considers their specific properties. Co....... Comparisons in terms of rate and distortion are provided, showing that the proposed coding scheme for still alpha planes is better than the algorithms for I-frames used in MPEG-4.......In object based video, each frame is a composition of objects that are coded separately. The composition is performed through the alpha plane that represents the transparency of the object. We present an alternative to MPEG-4 for coding of alpha planes that considers their specific properties...

  19. Tumor necrosis factor-alpha modulates human in vivo lipolysis

    DEFF Research Database (Denmark)

    Plomgaard, Peter; Fischer, Christian P; Ibfelt, Tobias

    2008-01-01

    in lipolysis, increasing circulatory free fatty acid (FFA) levels. SUBJECTS AND METHODS: Using a randomized controlled, crossover design, healthy young male individuals (n = 10) received recombinant human (rh) TNF-alpha (700 ng/m(-2).h(-1)) for 4 h, and energy metabolism was evaluated using a combination...... of tracer dilution methodology and arterial-venous differences over the leg. RESULTS: Plasma TNF-alpha levels increased from 0.7 +/- 0.04 to 16.7 +/- 1.8 pg/ml, and plasma IL-6 increased from 1.0 +/- 0.2 to 9.2 +/- 1.0 pg/ml (P rhTNF-alpha infusion. Here, we demonstrate that 4-h rh......TNF-alpha infusion increases whole body lipolysis by 40% (P rhTNF-alpha infusion. CONCLUSION...

  20. Performance of an alpha air monitor in a dusty environment

    International Nuclear Information System (INIS)

    Hoover, M.D.; Newton, G.J.; Yeh, H.C.; Seiler, F.A.; Boecker, B.B.

    1988-01-01

    The Eberline Alpha-6 Continuous Air Monitor (CAM) was evaluated for use in detecting alpha radiation from 238 Pu and 239 Pu in the presence of background aerosols of salt dust and radon progeny. The Alpha-6 method uses an embedded, multichannel analyzer and real-time computer to correct for the presence of alpha-emitting radon progeny and to accurately report plutonium air concentration in dust-free environments. However, accumulation of mg/cm 2 salt dust on the sample collection filter was found to be equivalent to an infinitely thick layer. Dust loading raises the limit of detection in proportion to the concentration of airborne salt. Proper detection of 239 Pu is impaired by airborne concentrations of salt greater than 2 mg/m 3 . Alpha spectral analysis at a central monitoring computer is recommended to avoid detection errors at higher salt concentrations. (author)