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Sample records for alpha 1-antitrypsin deficiency

  1. Alpha-1 Antitrypsin Deficiency

    Science.gov (United States)

    ... by blood tests showing the low levels of alpha-1 antitrypsin and abnormal liver tests. Other tests such as ultrasound imaging or tests using specialized X-ray techniques may be necessary. A liver biopsy may ...

  2. Alpha1-antitrypsin deficiency

    DEFF Research Database (Denmark)

    Stolk, Jan; Seersholm, Niels; Kalsheker, Noor

    2006-01-01

    biennially to exchange views and research findings. The fourth biennial meeting was held in Copenhagen, Denmark, on 2-3 June 2005. This review covers the wide range of AAT deficiency-related topics that were addressed encompassing advances in genetic characterization, risk factor identification, clinical...... epidemiology, inflammatory and signalling processes, therapeutic advances, and lung imaging techniques....

  3. Molecular diagnosis of intermediate and severe alpha(1)-antitrypsin deficiency

    DEFF Research Database (Denmark)

    Dahl, Morten; Nordestgaard, B G; Lange, P;

    2001-01-01

    We tested whether intermediate (MZ, SZ) and severe (ZZ) alpha(1)-antitrypsin deficiency affects lung function in the population at large.......We tested whether intermediate (MZ, SZ) and severe (ZZ) alpha(1)-antitrypsin deficiency affects lung function in the population at large....

  4. Hereditary fructose intolerance and alpha(1) antitrypsin deficiency.

    Science.gov (United States)

    Hillebrand, G; Schneppenheim, R; Oldigs, H D; Santer, R

    2000-07-01

    A patient with coexisting hereditary fructose intolerance (HFI) and alpha(1) antitrypsin deficiency (alpha(1)ATD) is described. Protease inhibitor typing was not conclusive, presumably because of impaired N-glycosylation secondary to HFI. The case underlines the diagnostic role of molecular genetic techniques in inborn errors of metabolism.

  5. 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...

  6. Alpha-1 antitrypsin deficiency: diagnosis and treatment

    OpenAIRE

    2008-01-01

    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 de...

  7. Alpha1-antitrypsin deficiency: a clinical-genetic overview

    Directory of Open Access Journals (Sweden)

    Abboud RT

    2011-03-01

    Full Text Available Raja T Abboud1, Tanya N Nelson2, Benjamin Jung2, Andre Mattman31Department of Medicine, Respiratory Division, University of British Columbia, Vancouver, BC, Canada; 2Department of Pathology and Laboratory Medicine, Children's and Women's Health Centre of British Columbia, University of British Columbia, Vancouver, BC, Canada; 3Department of Pathology and Laboratory Medicine, St. Paul's Hospital, University of British Columbia, Vancouver, BC, CanadaAbstract: Severe α1-antitrypsin deficiency (AATD is an inherited disorder, leading to development of emphysema in smokers at a relatively young age with disability in their forties or fifties. The emphysema results from excessive elastin degradation by neutrophil elastase as a result of the severe deficiency of its major inhibitor α1-antitrypsin (AAT. The AAT expression is determined by the SERPINA1 gene which expresses codominant alleles. The three most common alleles are the normal M, the S with plasma levels of 60% of normal, and the severely deficient Z with levels of about 15% of normal. Homozygosity for the Z mutant allele is associated with retention of abnormal AAT in the liver, which may lead to neonatal hepatitis, liver disease in children, and liver disease in adults. Regular intravenous infusions of purified human AAT (AAT augmentation therapy have been used to partially correct the biochemical defect and protect the lung against further injury. Two randomized controlled trials showed a trend of slower progression of emphysema by chest computerized tomography. Integrated analysis of these two studies indicated significantly slower progression of emphysema. AAT is quantified by immunologic measurement of AAT in serum, the phenotype characterized by isoelectric focusing, the common genotypes by targeted DNA analysis, and by sequencing the coding region of the gene when the AAT abnormality remains undefined. AATD is often unrecognized, and diagnosis delayed. Testing for AATD is recommended

  8. An ECLIPSE View of Alpha-1 Antitrypsin Deficiency.

    Science.gov (United States)

    Lomas, David A

    2016-08-01

    Chronic obstructive pulmonary disease (COPD) is a multicomponent condition that is estimated to become the third leading cause of death in 2020. The ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study, funded by GlaxoSmithKline, is an observational study designed to define outcomes that can be used as endpoints in clinical trials in individuals with COPD. It allowed us to describe the heterogeneity of COPD, the stability of the exacerbation phenotype, and the factors associated with a progressive decline in lung function and the progression of emphysema on computed tomography scans. The cohort was also used to define genetic factors and biomarkers associated with COPD and disease progression. This review considers how the results from ECLIPSE can inform our understanding of the lung disease associated with alpha-1 antitrypsin deficiency.

  9. 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....

  10. Alpha-1-antitrypsin deficiency: An overview of recent advances

    Directory of Open Access Journals (Sweden)

    El Hazmi Mohsen

    1996-01-01

    Full Text Available Alpha 1-antitrypsin (αl AT, a serpine, is one of the most important proteinase inhibitor in the serum and plays an essential role in protection of the lung tissues against the proteolytic attach of elastase. The gene for a1AT is located on chromosome 14 q 32 and is highly susceptible to mutations. A large number of variants of α 1 AT are known and some including PiZ and PiS result in a1AT deficiency. In patients with PiZ, the most severe and common α1AT deficient variant, the α1AT protein accumulates in the liver and results in severe hepatic diseases. Other clinical consequences of α1AT deficiency include emphysema in majority of the patients. This state is further aggravated in patients who smoke. Several treatment strategies have been suggested, including replacement therapy by purified α1AT or recombinant α1AT given intravenously or as aerosol. Synthetic peptides. lung transplantation and volume reduction surgery are under investigation and evaluation. This paper updates the information on α1 AT and its deficiency state.

  11. 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.

  12. Hereditary alpha-1-antitrypsin deficiency and its clinical consequences

    Directory of Open Access Journals (Sweden)

    Stolk Jan

    2008-06-01

    Full Text Available Abstract Alpha-1-antitrypsin deficiency (AATD is a genetic disorder that manifests as pulmonary emphysema, liver cirrhosis and, rarely, as the skin disease panniculitis, and is characterized by low serum levels of AAT, the main protease inhibitor (PI in human serum. The prevalence in Western Europe and in the USA is estimated at approximately 1 in 2,500 and 1 : 5,000 newborns, and is highly dependent on the Scandinavian descent within the population. The most common deficiency alleles in North Europe are PI Z and PI S, and the majority of individuals with severe AATD are PI type ZZ. The clinical manifestations may widely vary between patients, ranging from asymptomatic in some to fatal liver or lung disease in others. Type ZZ and SZ AATD are risk factors for the development of respiratory symptoms (dyspnoea, coughing, early onset emphysema, and airflow obstruction early in adult life. Environmental factors such as cigarette smoking, and dust exposure are additional risk factors and have been linked to an accelerated progression of this condition. Type ZZ AATD may also lead to the development of acute or chronic liver disease in childhood or adulthood: prolonged jaundice after birth with conjugated hyperbilirubinemia and abnormal liver enzymes are characteristic clinical signs. Cirrhotic liver failure may occur around age 50. In very rare cases, necrotizing panniculitis and secondary vasculitis may occur. AATD is caused by mutations in the SERPINA1 gene encoding AAT, and is inherited as an autosomal recessive trait. The diagnosis can be established by detection of low serum levels of AAT and isoelectric focusing. Differential diagnoses should exclude bleeding disorders or jaundice, viral infection, hemochromatosis, Wilson's disease and autoimmune hepatitis. For treatment of lung disease, intravenous alpha-1-antitrypsin augmentation therapy, annual flu vaccination and a pneumococcal vaccine every 5 years are recommended. Relief of breathlessness

  13. Vitamin K deficiency bleeding in cholestatic infants with alpha-1-antitrypsin deficiency.

    NARCIS (Netherlands)

    Hasselt, P.M. van; Kok, K.F.; Vorselaars, A.D.; Vlerken, L. van; Nieuwenhuys, E.; Koning, T.J. de; Vries, R.A. de; Houwen, R.H.J.

    2009-01-01

    OBJECTIVE: Exclusively breastfed infants with unrecognised cholestatic jaundice are at high risk of a vitamin K deficiency (VKD) bleeding. It is presently unknown whether (the size of) this risk depends on the degree of cholestasis. Since alpha-1-antitrypsin deficiency (A1AD) induces a variable degr

  14. Safety and efficacy of alpha-1-antitrypsin augmentation therapy in the treatment of patients with alpha-1-antitrypsin deficiency

    Directory of Open Access Journals (Sweden)

    Irina Petrache

    2009-05-01

    Full Text Available Irina Petrache1, Joud Hajjar1, Michael Campos21Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA; 2Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Miller School of Medicine, University of Miami, Florida, USA Abstract: Alpha-1-antitrypsin deficiency (AATD, also known as alpha1-proteinase inhibitor deficiency, is an autosomal co-dominant condition. The genotypes associated with AATD include null, deficient, and dysfunctional alpha-1-antitrypsin (A1AT variants, which result in low levels of circulating functional A1AT, unbalanced protease activity, and an increased risk of developing lung emphysema, the leading cause of morbidity in these patients. Furthermore, the most common abnormal genotype, Pi*ZZ may also cause trapping of abnormally folded protein polymers in hepatocytes causing liver dysfunction. A major focus of therapy for patients with lung disease due to AATD is to correct the A1AT deficiency state by augmenting serum levels with intravenous infusions of human plasma-derived A1AT. This strategy has been associated with effective elevations of A1AT levels and function in serum and lung epithelial fluid and observational studies suggest that it may lead to attenuation in lung function decline, particularly in patients with moderate impairment of lung function. In addition, an observational study suggests that augmentation therapy is associated with a reduction of mortality in subjects with AATD and moderate to severe lung impairment. More recent randomized placebo-controlled studies utilizing computer scan densitometry suggest that this therapy attenuates lung tissue loss. Augmentation therapy has a relative paucity of side effects, but it is highly expensive. Therefore, this therapy is recommended for patients with AATD who have a high-risk A1AT genotype with plasma A1AT below protective levels (11 µM and evidence of obstructive lung disease. In this article, we

  15. 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.

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

    Directory of Open Access Journals (Sweden)

    Morris Valerie B

    2011-07-01

    Full Text Available 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.

  17. 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.

  18. Alpha1-antitrypsin deficiency with fatal intracranial hemorrhage in a newborn.

    Science.gov (United States)

    Israels, S J; Gilfix, B M

    1999-01-01

    A 4-week-old boy had a fatal intracranial hemorrhage resulting from vitamin K deficiency. The infant had received no vitamin K prophylaxis and was exclusively breastfed. At autopsy, examination of the liver showed cholestasis and fibrosis. DNA was isolated from a blood spot on a Gutherie sample card obtained from the infant for routine metabolic screening. This DNA was used for alpha1-antitrypsin genotyping studies. Genotyping studies identified homozygosity for the point mutation 9989G-->A, confirming a diagnosis of alpha1-antitrypsin deficiency (ZZ phenotype), and resulted in appropriate screening of siblings born after this child's death. Alpha1-antitrypsin deficiency should be considered in the differential diagnosis of infants with late hemorrhagic disease of the newborn. Use of blood from the metabolic screening card as a source of DNA allowed confirmation of this diagnosis after the infant's death.

  19. Alpha-1-antitrypsin deficiency resulting in a hitherto unseen presentation of hepatocellular carcinoma: Polycythemia but with normal alpha fetoprotein

    Institute of Scientific and Technical Information of China (English)

    David Ryan Owen; Ramachandran Sivakumar; Eui-Sik Suh; Murugiah Seevaratnam

    2006-01-01

    Polycythemia is a known paraneopastic manifestation of hepatoma, but only in the presence of alpha-fetopro (AFP). We present a case of polycythemia in the absence of AFP, and suggest concurrent alpha-1-antitrypsin deficiency as the cause for breaking this rule. We also suggest a reason for the apparent constant conjunction between polycythemia and AFP in hepatoma.

  20. 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

  1. 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.

  2. 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.

  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. Indications for active case searches and intravenous alpha-1 antitrypsin treatment for patients with alpha-1 antitrypsin deficiency chronic pulmonary obstructive disease: an update.

    Science.gov (United States)

    Casas, Francisco; Blanco, Ignacio; Martínez, María Teresa; Bustamante, Ana; Miravitlles, Marc; Cadenas, Sergio; Hernández, José M; Lázaro, Lourdes; Rodríguez, Esther; Rodríguez-Frías, Francisco; Torres, María; Lara, Beatriz

    2015-04-01

    The effect of hereditary alpha-1 antitrypsin (AAT) deficiency can manifest clinically in the form of chronic obstructive pulmonary disease (COPD). AAT deficiency (AATD) is defined as a serum concentration lower than 35% of the expected mean value or 50 mg/dl (determined by nephelometry). It is associated in over 95% of cases with Pi*ZZ genotypes, and much less frequently with other genotypes resulting from combinations of Z, S, rare and null alleles. A systematic qualitative review was made of 107 articles, focusing mainly on an active search for AATD in COPD patients and intravenous (iv) treatment with AAT. On the basis of this review, the consultant committee of the Spanish Registry of Patients with AATD recommends that all COPD patients be screened for AATD with the determination of AAT serum concentrations, and when these are low, the evaluation must be completed with phenotyping and, on occasions, genotyping. Patients with severe AATD COPD should receive the pharmacological and non-pharmacological treatment recommended in the COPD guidelines. There is enough evidence from large observational studies and randomized placebo-controlled clinical trials to show that the administration of iv AAT reduces mortality and slows the progression of emphysema, hence its indication in selected cases that meet the inclusion criteria stipulated in international guidelines. The administration of periodic infusions of AAT is the only specific treatment for delaying the progression of emphysema associated with AATD.

  5. Increased outer arm and core fucose residues on the N-glycans of mutated alpha-1 antitrypsin protein from alpha-1 antitrypsin deficient individuals.

    Science.gov (United States)

    McCarthy, Cormac; Saldova, Radka; O'Brien, M Emmet; Bergin, David A; Carroll, Tomás P; Keenan, Joanne; Meleady, Paula; Henry, Michael; Clynes, Martin; Rudd, Pauline M; Reeves, Emer P; McElvaney, Noel G

    2014-02-01

    Alpha-1 antitrypsin (AAT) is the major physiological inhibitor of a range of serine proteases, and in the lung, it maintains a protease-antiprotease balance. AAT deficiency (AATD) is an autosomal co-dominant condition with the Z mutation being the most common cause. Individuals homozygous for Z (PiZZ) have low levels of circulating mutant Z-AAT protein leading to premature emphysematous lung disease. Extensive glycoanalysis has been performed on normal AAT (M-AAT) from healthy individuals and the importance of glycosylation in affecting the immune modulatory roles of AAT is documented. However, no glycoanalysis has been carried out on Z-AAT from deficient individuals to date. In this study, we investigate whether the glycans present on Z-AAT differ to those found on M-AAT from healthy controls. Plasma AAT was purified from 10 individuals: 5 AATD donors with the PiZZ phenotype and 5 PiMM healthy controls. Glycoanalysis was performed employing N-glycan release, exoglycosidase digestion and UPLC analysis. No difference in branched glycans was identified between AATD and healthy controls. However, a significant increase in both outer arm (α1-3) (p = 0.04) and core (α1-6) fucosylated glycans (p < 0.0001) was found on Z-AAT compared to M-AAT. This study has identified increased fucosylation on N-glycans of Z-AAT indicative of ongoing inflammation in AATD individuals with implications for early therapeutic intervention.

  6. 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.

  7. Is PiSS Alpha-1 Antitrypsin Deficiency Associated with Disease?

    Directory of Open Access Journals (Sweden)

    Dawn McGee

    2010-01-01

    Full Text Available Background. Alpha-1 antitrypsin deficiency (AAT is an inherited condition that predisposes to lung and/or liver disease. Objective. The current study examined the clinical features of the PiSS genotype. Methods. Nineteen study participants (PiSS and 29 matched control participants (PiMM were telephone interviewed using a standardized questionnaire. Demographic features, cigarette smoking, vocation, medication history, and clinical diagnoses were compared. Statistical analysis was performed. Finally, a comprehensive literature review was performed by two investigators. Results. 12/19 (63.2% study participants reported the presence of lung and/or liver disease compared to 12/29 (41.4% control participants. There trended toward having a higher frequency of medication allergies in the study population (42.11% versus 20.69%. Conclusions. The PiSS genotype was associated with a similar incidence of obstructive lung disease to controls. Selective bias intrinsic in testing for AAT deficiency and the rarity of the PiSS genotype will make future study of this association dependent on population-based tests.

  8. Aberrant disulphide bonding contributes to the ER retention of alpha1-antitrypsin deficiency variants.

    Science.gov (United States)

    Ronzoni, Riccardo; Berardelli, Romina; Medicina, Daniela; Sitia, Roberto; Gooptu, Bibek; Fra, Anna Maria

    2016-02-15

    Mutations in alpha1-antitrypsin (AAT) can cause the protein to polymerise and be retained in the endoplasmic reticulum (ER) of hepatocytes. The ensuing systemic AAT deficiency leads to pulmonary emphysema, while intracellular polymers are toxic and cause chronic liver disease. The severity of this process varies considerably between individuals, suggesting the involvement of mechanistic co-factors and potential for therapeutically beneficial interventions. We show in Hepa1.6 cells that the mildly polymerogenic I (Arg39Cys) AAT mutant forms aberrant inter- and intra-molecular disulphide bonds involving the acquired Cys39 and the only cysteine residue in the wild-type (M) sequence (Cys232). Substitution of Cys39 to serine partially restores secretion, showing that disulphide bonding contributes to the intracellular retention of I AAT. Covalent homodimers mediated by inter-Cys232 bonding alone are also observed in cells expressing the common Z and other polymerising AAT variants where conformational behaviour is abnormal, but not in those expressing M AAT. Prevention of such disulphide linkage through the introduction of the Cys232Ser mutation or by treatment of cells with reducing agents increases Z AAT secretion. Our results reveal that disulphide interactions enhance intracellular accumulation of AAT mutants and implicate the oxidative ER state as a pathogenic co-factor. Redox modulation, e.g. by anti-oxidant strategies, may therefore be beneficial in AAT deficiency-associated liver disease.

  9. How Can We Improve the Detection of Alpha1-Antitrypsin Deficiency?

    Directory of Open Access Journals (Sweden)

    Ilaria Ferrarotti

    Full Text Available The Z deficiency in α1-antitrypsin (A1ATD is an under-recognized condition. Alpha1-antitrypsin (A1AT is the main protein in the α1-globulin fraction of serum protein electrophoresis (SPE; however, evaluation of the α1-globulin protein fraction has received very little attention. Serum Z-type A1AT manifests in polymeric forms, but their interference with quantitative immunoassays has not been reported. Here, 214 894 samples were evaluated by SPE at the G. Fracastoro Hospital of Verona, Italy. Patients with an A1AT level ≤ 0.92 g/L were recalled to complete A1ATD diagnosis. In parallel, to qualitatively and quantitatively characterize A1AT, sera samples from 10 PiZZ and 10 PiMM subjects obtained at the National Institute of Tuberculosis and Lung Diseases in Warsaw, Poland, were subjected to non-denaturing 7.5% PAGE and 7.5% SDS-PAGE followed by Western blot. Moreover, purified A1AT was heated at 60°C and analyzed by a non-denaturing PAGE and 4-15% gradient SDS-PAGE followed by Western blot as well as by isolelectrofocusing and nephelometry. A total of 966 samples manifested percentages ≤ 2.8 or a double band in the alpha1-zone. According to the nephelometry data, 23 samples were classified as severe (A1AT ≤ 0.49 g/L and 462 as intermediate (A1AT >0.49≤ 1.0 g/L A1ATD. Twenty subjects agreed to complete the diagnosis and an additional 21 subjects agreed to family screening. We detected 9 cases with severe and 26 with intermediate A1ATD. Parallel experiments revealed that polymerization of M-type A1AT, when measured by nephelometry or isolelectrofocusing, yields inaccurate results, leading to the erroneous impression that it was Z type and not M-type A1AT. We illustrate the need for confirmation of Z A1AT values by "state of the art" method. Clinicians should consider a more in-depth investigation of A1ATD in patients when they exhibit serum polymers and low α1-globulin protein levels by SPE.

  10. How Can We Improve the Detection of Alpha1-Antitrypsin Deficiency?

    Science.gov (United States)

    Trevisan, Maria Teresa; Dresel, Marc; Koczulla, Rembert; Ottaviani, Stefania; Baldo, Raffaele; Gorrini, Marina; Sala, Giorgia; Cavallon, Luana; Welte, Tobias; Chorostowska-Wynimko, Joanna; Luisetti, Maurizio; Janciauskiene, Sabina

    2015-01-01

    The Z deficiency in α1-antitrypsin (A1ATD) is an under-recognized condition. Alpha1-antitrypsin (A1AT) is the main protein in the α1-globulin fraction of serum protein electrophoresis (SPE); however, evaluation of the α1-globulin protein fraction has received very little attention. Serum Z-type A1AT manifests in polymeric forms, but their interference with quantitative immunoassays has not been reported. Here, 214 894 samples were evaluated by SPE at the G. Fracastoro Hospital of Verona, Italy. Patients with an A1AT level ≤ 0.92 g/L were recalled to complete A1ATD diagnosis. In parallel, to qualitatively and quantitatively characterize A1AT, sera samples from 10 PiZZ and 10 PiMM subjects obtained at the National Institute of Tuberculosis and Lung Diseases in Warsaw, Poland, were subjected to non-denaturing 7.5% PAGE and 7.5% SDS-PAGE followed by Western blot. Moreover, purified A1AT was heated at 60°C and analyzed by a non-denaturing PAGE and 4–15% gradient SDS-PAGE followed by Western blot as well as by isolelectrofocusing and nephelometry. A total of 966 samples manifested percentages ≤ 2.8 or a double band in the alpha1-zone. According to the nephelometry data, 23 samples were classified as severe (A1AT ≤ 0.49 g/L) and 462 as intermediate (A1AT >0.49≤ 1.0 g/L) A1ATD. Twenty subjects agreed to complete the diagnosis and an additional 21 subjects agreed to family screening. We detected 9 cases with severe and 26 with intermediate A1ATD. Parallel experiments revealed that polymerization of M-type A1AT, when measured by nephelometry or isolelectrofocusing, yields inaccurate results, leading to the erroneous impression that it was Z type and not M-type A1AT. We illustrate the need for confirmation of Z A1AT values by “state of the art” method. Clinicians should consider a more in-depth investigation of A1ATD in patients when they exhibit serum polymers and low α1-globulin protein levels by SPE. PMID:26270547

  11. Lung clearance index for monitoring early lung disease in alpha-1-antitrypsin deficiency.

    Science.gov (United States)

    Fuchs, Susanne I; Schwerk, Nicolaus; Pittschieler, Klaus; Ahrens, Frank; Baden, Winfried; Bals, Robert; Fähndrich, Sebastian; Gleiber, Wolfgang; Griese, Matthias; Hülskamp, Georg; Köhnlein, Thomas; Reckling, Ludmilla; Rietschel, Ernst; Staab, Doris; Gappa, Monika

    2016-07-01

    Patients with alpha-1-antitrypsin deficiency (AATD) and a PI-ZZ genotype are at high risk to develop severe emphysema during adulthood. However, little is known about early stages of emphysema and disease manifestation in other PI-types. Spirometry is commonly used for monitoring although early manifestation of emphysema is suspected within the peripheral airways that are not accessible by forced expiratory manoeuvres. We hypothesized that the Lung Clearance Index (LCI) derived from multiple breath nitrogen-washout (N2-washout) is useful to bridge this diagnostic gap. Patients from age 4 years onward and different PI-types performed N2-washout and spirometry. Results were compared to controls. 193 patients (4-79 years, 75% PI-ZZ) and 33 controls (8-60 years) were included. Mean (SD) LCI in patients was 9.1 (3.1) and 6.3 (0.6) in controls (p ≤ 0.001). 47% of adult patients with other than PI-ZZ genotypes and 39% of all patients with normal spirometry had abnormal LCIs. The LCI measured by N2-washout discriminates between patients with AATD and controls, reflects AATD related lung disease in all stages and appears to identify early peripheral lung changes in younger age than spirometry. We conclude that a normal spirometry does not exclude presence of AATD related lung disease even in genotypes other than PI-ZZ.

  12. Conductivity in Exhaled Breath Condensate from Subjects with Emphysema and Type ZZ alpha-1-Antitrypsin Deficiency.

    Science.gov (United States)

    Stolk, Jan; Fumagalli, Marco; Viglio, Simona; Iadarola, Paolo

    2015-05-01

    The assessment of biomarkers in biological samples from the lung has long been employed. Upon cooling water vapor present in exhaled breath, variable amounts of droplets of condensate (EBC) containing volatile and non-volatile compounds may be easily and non-invasively obtained from patients of any age.Objective of the present study was to compare the level of EBC conductivity determined for cohorts of individuals with different inflammatory lung disorders with that of healthy never-smoking individuals.The conductivity in EBC of PiZZ-Alpha-1-antitrypsin deficiency patients with a diagnosis of emphysema (PiZZ-AATD) was 3 fold lower than in spouse controls (54.5 ± 11.6 vs 165.3 ± 10.7 μS/cm). Non-PiZZ emphysema patients had conductivity in EBC of 59.6 ± 5.8 μS/cm and patients with sarcoidosis without airflow obstruction had EBC conductivity of 178,8 ± 6,2 μS/cm, 
not significantly different (p = 0.5) from healthy controls. Conductivity in serial EBC samples from patients with PiZZ-AATD emphysema and healthy controls was stable in 6 different samples collected over a period of 14 months. We conclude that conductivity values in EBC can be used as a correction factor for dilution of non-volatile components in EBC.

  13. Individualized lung function trends in alpha-1-antitrypsin deficiency: a need for patience in order to provide patient centered management?

    Directory of Open Access Journals (Sweden)

    Stockley RA

    2016-08-01

    Full Text Available Robert A Stockley,1 Ross G Edgar,1 Anilkumar Pillai,1 Alice M Turner2 1Department of Lung Function and Sleep, University Hospitals Birmingham NHS Foundation Trust, 2Department of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham, UK Background: Chronic obstructive pulmonary disease (COPD is characterized by fixed airflow obstruction and accelerated decline of forced expired volume in 1 second (FEV1. Alpha-1-antitrypsin deficiency is a genetic cause of COPD and associated with more rapid decline in lung function, even in some never smokers (NS but the potential for individualized assessment to reveal differences when compared to group analyses has rarely been considered. Methods: We analyzed decline in post-bronchodilator FEV1 and gas transfer (% predicted over at least 3 years (mean= 6.11, 95% CI 5.80–6.41 in our unique data set of 482 patients with alpha-1-antitrypsin deficiency (PiZ to determine individual rates of decline, implications for prognosis, and potential clinical management. Findings: There was a marked variation in individual rates of FEV1 decline from levels consistent with normal aging (observed in 23.5% of patients with established COPD, 57.5% of those without to those of rapidly declining COPD. Gas transfer did not decline in 12.8% of NS and 20.7% of ex-smokers with established COPD (33.3% and 25.0%, respectively, for those without COPD. There was no correlation between decline in gas transfer and FEV1 for those with COPD, although a weak relationship existed for those without (r=0.218; P<0.025. Conclusion: These data confirm differing individual rates of lung function decline in alpha-1-antitrypsin deficiency, indicating the importance of comprehensive physiological assessment and a personalized approach to patient management. Keywords: alpha-1-antitrypsin deficiency, COPD, emphysema, lung function

  14. Vitamin K deficiency bleeding in cholestatic infants with alpha-1-antitrypsin deficiency

    NARCIS (Netherlands)

    van Hasselt, P. M.; Kok, K.; Vorselaars, A. D. M.; van Vlerken, L.; Nieuwenhuys, E.; de Koning, T. J.; de Vries, Rindert; Houwen, R. H. J.

    2009-01-01

    Objective: Exclusively breastfed infants with unrecognised cholestatic jaundice are at high risk of a vitamin K deficiency (VKD) bleeding. It is presently unknown whether (the size of) this risk depends on the degree of cholestasis. Since alpha-l-antitrypsin deficiency (A1AD) induces a variable degr

  15. Alpha-1 proteinase inhibitors for the treatment of alpha-1 antitrypsin deficiency: safety, tolerability, and patient outcomes

    Directory of Open Access Journals (Sweden)

    Chotirmall SH

    2015-01-01

    Full Text Available Sanjay H Chotirmall,1 Mazen Al-Alawi,2 Thomas McEnery,2 Noel G McElvaney2 1Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; 2Department of Respiratory Medicine, Beaumont Hospital, Dublin, Republic of Ireland Abstract: Alpha-1 antitrypsin (AAT deficiency remains an underrecognized genetic disease with predominantly pulmonary and hepatic manifestations. AAT is derived primarily from hepatocytes; however, macrophages and neutrophils are secondary sources. As the natural physiological inhibitor of several proteases, most importantly neutrophil elastase (NE, it plays a key role in maintaining pulmonary protease–antiprotease balance. In deficient states, unrestrained NE activity promotes damage to the lung matrix, causing structural defects and impairing host defenses. The commonest form of AAT deficiency results in a mutated Z AAT that is abnormally folded, polymerized, and aggregated in the liver. Consequently, systemic levels are lower, resulting in diminished pulmonary concentrations. Hepatic disease occurs due to liver aggregation of the protein, while lung destruction ensues from unopposed protease-mediated damage. In this review, we will discuss AAT deficiency, its clinical manifestations, and augmentation therapy. We will address the safety and tolerability profiles of AAT replacement in the context of patient outcomes and cost-effectiveness and outline future directions for work in this field. Keywords: alpha-1, augmentation, deficiency, replacement, emphysema

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

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    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.

  17. Alpha-1 antitrypsin deficiency and the risk of hepatocellularcarcinoma in end-stage liver disease

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    AIM To evaluate the association between alpha-1antitrypsin deficiency (A1ATD) and hepatocellularcarcinoma (HCC) in patients with end-stage liver disease(ESLD).METHODS: Patients with cirrhosis and ESLD referred tothe Cleveland Clinic Foundation for liver transplantationbetween 2003 and 2014 were included in the study (N =675). ESLD was defined as having histological features ofcirrhosis and/or radiological evidence of cirrhosis in thecontext of portal hypertension (ascites, variceal bleeding,thrombocytopenia, or hepatic encephalopathy). A1ATDwas diagnosed using phenotype characterization (MZor ZZ), liver biopsy detection of PAS-positive diastaseresistant(PAS+) globules, or both. Patients with othercauses of liver diseases such as hepatitis C virus (HCV),alcoholic liver disease and non-alcoholic steatohepatitis(NASH) or NASH were also included in the study. HCCwas diagnosed by using imaging modalities, biopsyfindings, or explanted liver inspection. Follow-up timewas defined as the number of years from the diagnosisof cirrhosis to the diagnosis of hepatocellular carcinoma,or from the diagnosis of cirrhosis to the last follow upvisit. The rate of HCC was assessed using time-tointervalanalysis for interval censored data.RESULTS: This study included 675 patients. 7% ofsubjects had A1ATD (n = 47). Out of all subjects whodid not have A1ATD, 46% had HCV, 17% had alcoholicliver disease, 19% had NASH and 18% had anotherprimary diagnosis. Of the 47 subjects with A1ATD, 15had a primary diagnosis of A1ATD (PI*ZZ phenotypeand PAS+ globules), 8 had a PI*MZ phenotype alone,14 had PAS+ alone, and 10 had both the PI*MZphenotype and PAS+. Median follow-up time was 3.4(25th, 75th percentiles: 1, 5.2) years. The overall rate ofhepatocellular carcinoma in all subjects was 29% (n =199). In the A1ATD group, the incidence rate of HCCwas 8.5% compared to 31% in the group of patientswith other causes of cirrhosis (P = 0

  18. 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

  19. A challenging diagnosis of alpha-1-antitrypsin deficiency: identification of a patient with a novel F/Null phenotype

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    Ringenbach Michael R

    2011-11-01

    Full Text Available Abstract Alpha-1-antitrypsin (A1AT deficiency is a genetic disease characterized by low levels and/or function of A1AT protein. A1AT deficiency can result in the development of COPD, liver disease, and certain skin conditions. The disease can be diagnosed by demonstrating a low level of A1AT protein and genotype screening for S and Z mutations, which are the most common. However, there are many genetic variants in A1AT deficiency, and this screening may miss rarer cases, such as those caused by dysfunctional protein. We identified a patient with a previously unreported F/null phenotype that was missed by routine screening. This case highlights the wide variation in possible mutations, limitations in diagnostics, and the importance of combining clinical suspicion with measurement of protein levels, phenotypic analysis, and in appropriate cases expanded genetic analysis.

  20. 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

    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......-point was change in CT lung density, and an exploratory approach was adopted to identify optimal methodology, including two methods of adjustment for lung volume variability and two statistical approaches. Other end-points were exacerbations, health status and physiological indices. CT was more sensitive than...... other measures of emphysema progression, and the changes in CT and forced expiratory volume in 1 s were correlated. All methods of densitometric analysis concordantly showed a trend suggestive of treatment benefit (p-values for Prolastin versus placebo ranged 0.049-0.084). Exacerbation frequency...

  1. A comparative ultrastructural and molecular biological study on Chlamydia psittaci infection in alpha-1 antitrypsin deficiency and non-alpha-1 antitrypsin deficiency emphysema versus lung tissue of patients with hamartochondroma

    Directory of Open Access Journals (Sweden)

    Mogilevski Grigori

    2004-09-01

    Full Text Available Abstract Background Chlamydiales are familiar causes of acute and chronic infections in humans and animals. Human pulmonary emphysema is a component of chronic obstructive pulmonary disease (COPD and a condition in which chronic inflammation manifested as bronchiolitis and intra-alveolar accumulation of macrophages is common. It is generally presumed to be of infectious origin. Previous investigations based on serology and immunohistochemistry indicated Chlamydophila pneumoniae infection in cases of COPD. Furthermore, immunofluorescence with genus-specific antibodies and electron microscopy suggested involvement of chlamydial infection in most cases of pulmonary emphysema, but these findings could not be verified by PCR. Therefore, we examined the possibility of other chlamydial species being present in these patients. Methods Tissue samples from patients having undergone lung volume reduction surgery for advanced alpha-1 antitrypsin deficiency (AATD, n = 6 or non-alpha-1 antitrypsin deficiency emphysema (n = 34 or wedge resection for hamartochondroma (n = 14 were examined by transmission electron microscopy and PCR. Results In all cases of AATD and 79.4% of non-AATD, persistent chlamydial infection was detected by ultrastructural examination. Intra-alveolar accumulation of macrophages and acute as well as chronic bronchiolitis were seen in all positive cases. The presence of Chlamydia psittaci was demonstrated by PCR in lung tissue of 66.7% AATD vs. 29.0% non-AATD emphysema patients. Partial DNA sequencing of four positive samples confirmed the identity of the agent as Chlamydophila psittaci. In contrast, Chlamydophila pneumoniae was detected only in one AATD patient. Lung tissue of the control group of non-smokers with hamartochondroma was completely negative for chlamydial bodies by TEM or chlamydial DNA by PCR. Conclusions These data indicate a role of Chlamydophila psittaci in pulmonary emphysema by linking this chronic inflammatory process

  2. Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency

    Directory of Open Access Journals (Sweden)

    Kim Woo Jin

    2012-02-01

    Full Text Available Abstract Background The development of COPD in subjects with alpha-1 antitrypsin (AAT deficiency is likely to be influenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD have demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3 (cholinergic nicotine receptor alpha3 and IREB2 (iron regulatory binding protein 2. We investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in AAT deficiency. Methods The current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication cohort of 458 subjects from the UK AAT Deficiency National Registry. Nine SNPs in LOC123688, CHRNA3 and IREB2 were selected for genotyping. FEV1 percent of predicted and FEV1/FVC ratio were analyzed as quantitative phenotypes. Family-based association analysis was performed in the AAT Genetic Modifiers Study. In the replication set, general linear models were used for quantitative phenotypes and logistic regression models were used for the presence/absence of emphysema or COPD. Results Three SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3 were associated with pre-bronchodilator FEV1 percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and rs1051730 were associated with the post-bronchodilator FEV1 percent of predicted and pre-bronchodilator FEV1/FVC ratio; SNP-by-gender interactions were observed. In the UK National Registry dataset, rs2568494 was significantly associated with emphysema in the male subgroup; significant SNP-by-smoking interactions were observed. Conclusions IREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact.

  3. Refractory Classical Hodgkin Lymphoma Presenting with Atypical Cutaneous Involvement and Diagnosis of ZZ Phenotype Alpha-1 Antitrypsin Deficiency

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    Mohamad Khawandanah

    2014-01-01

    Full Text Available Cutaneous Hodgkin lymphoma is a rare condition. Specific neoplastic involvement can be primary (confined to the skin or secondary to systemic involvement (metastatic. Cutaneous involvement by HL usually occurs late in the course and is associated with poor prognosis; however in some cases it can exhibit indolent behavior. Skin involvement with nonspecific cutaneous findings may represent a paraneoplastic syndrome. We describe a case of 46-year-old white male patient presented with rash and lymphadenopathy which led to the diagnosis of stage IVE mixed cellularity classical Hodgkin lymphoma with skin involvement. His disease was refractory to multiple lines of chemotherapy including (1 AVD (doxorubicin/bleomycin/dacarbazine, (2 brentuximab, and (3 bendamustine, he later achieved complete remission with (4 GCD (gemcitabine/carboplatin/dexamethasone salvage regimen. Bleomycin was not given secondary to poor pulmonary function tests. His treatment was complicated after AVD with multiple pneumothoraces which unmasked the diagnosis of ZZ phenotype alpha-1 antitrypsin (ATT deficiency. Simultaneous existence of Hodgkin lymphoma and ATT is rarely reported.

  4. 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.

  5. Screening for Alpha 1 antitrypsin deficiency in Tunisian subjects with obstructive lung disease: a feasibility report

    Directory of Open Access Journals (Sweden)

    Chibani Jemni

    2009-04-01

    Full Text Available Abstract Background AATD is one of the most common inherited disorders in the World. However, it is generally accepted that AATD in North African populations is not a risk factor for lung and/or liver disease, based on a number of small studies. We therefore planned a screening study for detection of AATD in patients with OLD in a cohort of patients from Kairouan in central Tunisia. Methods: One hundred twenty patients with OLD (asthma, emphysema, COPD were enrolled in the screening programme. Laboratory diagnosis for AATD was performed according to current diagnostic standards. Results We found that 6/120 OLD patients carried an AAT deficient allele, 1 PI*MZ, 1 PI*MPlowel, 3 PI*MMmalton, 1 PI*MMwurzburg. Conclusion this pilot study demonstrated that alleles related to deficiency of AAT are not absent in the Tunisian population, and that rare AATD variants prevailed over commonest PI*Z variant. These results would support a larger scale screening for AATD in Tunisia.

  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

    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...... [MLD] and voxel index at a threshold of -910 [VI-910] and -950 [VI-950] Hounsfield Units) obtained from whole lung scans at baseline and at 24 to 30 months. Targeted regional sampling was compared with whole lung assessment. RESULTS: Whole lung analysis of the total change (baseline to last CT scan...

  7. 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....

  8. Rapid DNA extraction protocol for detection of alpha-1 antitrypsin deficiency from dried blood spots by real-time PCR.

    Science.gov (United States)

    Struniawski, R; Szpechcinski, A; Poplawska, B; Skronski, M; Chorostowska-Wynimko, J

    2013-01-01

    The dried blood spot (DBS) specimens have been successfully employed for the large-scale diagnostics of α1-antitrypsin (AAT) deficiency as an easy to collect and transport alternative to plasma/serum. In the present study we propose a fast, efficient, and cost effective protocol of DNA extraction from dried blood spot (DBS) samples that provides sufficient quantity and quality of DNA and effectively eliminates any natural PCR inhibitors, allowing for successful AAT genotyping by real-time PCR and direct sequencing. DNA extracted from 84 DBS samples from chronic obstructive pulmonary disease patients was genotyped for AAT deficiency variants by real-time PCR. The results of DBS AAT genotyping were validated by serum IEF phenotyping and AAT concentration measurement. The proposed protocol allowed successful DNA extraction from all analyzed DBS samples. Both quantity and quality of DNA were sufficient for further real-time PCR and, if necessary, for genetic sequence analysis. A 100% concordance between AAT DBS genotypes and serum phenotypes in positive detection of two major deficiency S- and Z- alleles was achieved. Both assays, DBS AAT genotyping by real-time PCR and serum AAT phenotyping by IEF, positively identified PI*S and PI*Z allele in 8 out of the 84 (9.5%) and 16 out of 84 (19.0%) patients, respectively. In conclusion, the proposed protocol noticeably reduces the costs and the hand-on-time of DBS samples preparation providing genomic DNA of sufficient quantity and quality for further real-time PCR or genetic sequence analysis. Consequently, it is ideally suited for large-scale AAT deficiency screening programs and should be method of choice.

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

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    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

  10. 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....

  11. Relationship between frequency, length, and treatment outcome of exacerbations to baseline lung function and lung density in alpha-1 antitrypsin-deficient COPD

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    Vijayasaratha K

    2012-11-01

    Full Text Available Kesavaperumal Vijayasaratha,1 Robert A Stockley21Lung Investigation Unit, 2Research and Development, University Hospital Birmingham NHS Trust, Birmingham, UKBackground: Diary cards are useful for analyzing exacerbations in chronic obstructive pulmonary disease (COPD, although factors influencing the length and frequency of each episode are poorly understood. This study investigated factors that influence the features of exacerbations in patients with alpha-1 antitrypsin (AAT deficiency (PiZ phenotype and COPD.Methods: Daily diary cards were collected over 2 years. Patients had emphysema visualized and quantified by computed tomography scan, and had at least one documented exacerbation in the previous year.Results: The patients (n = 23 had a mean age of 52.5 years, forced expiratory volume in one second (FEV1 of 1.2 L (38.4% predicted, corrected gas transfer (KCO of 0.90 mmol/min/kPa/L (59.7% predicted, and 15th percentile lung density of 44.55 g/L. Two hundred and sixty-three exacerbations (164 treated were identified. The frequency of treated exacerbations correlated negatively with KCO% predicted (r = −0.432; P = 0.022. Exacerbation length (determined for 17 of the patients for whom diary card data through the episode were available correlated negatively with baseline 15th percentile lung density (r = −0.361; P = 0.003, and increased the longer treatment was delayed (r = 0.503; P < 0.001. Treatment delay was shorter with higher day 1 symptom score, lower baseline FEV1, FEV1/forced vital capacity, and lower 15th percentile lung density (r = −0.368, 0.272, 0.461, and 0.786; P = 0.004, 0.036, <0.001, and <0.001, respectively. Time to resolution of exacerbation after treatment initiation was not affected by treatment delay, but correlated negatively with KCO% predicted (r = −0.647; P = 0.007.Conclusion: In alpha-1 antitrypsin deficiency, the frequency and length of resolution of exacerbation were related to baseline gas transfer. Treatment

  12. 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...

  13. 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...

  14. Congruence-Incongruence Patterns in Alpha-1 Antitrypsin Deficiency Couples' Genetic Determinist Beliefs and Perceived Control over Genes: Implications for Clinical and Public Health Genomic Communication.

    Science.gov (United States)

    Parrott, Roxanne L; Smith, Rachel A; Hong, Soo Jung; Worthington, Amber

    2015-06-01

    Genomics makes possible the isolation of multiple genes as co-factors that increase, but do not determine, risk for many adult-onset medical conditions, including alpha-1 antitrypsin deficiency (AATD). Those diagnosed with an adult-onset medical condition, such as AATD, are often married and make decisions about testing and care as a couple. We examined genetic essentialist and threat beliefs, focusing on beliefs about the genetic contribution to disease susceptibility and severity, as well as perceptions of control related to genes and health for married couples (N =59), in which one spouse has been tested for genetic mutations associated with AATD. The intraclass correlation for spouses' beliefs about genetic essentialism was strong and statistically significant, but the associations for their other beliefs were not. Incongruence between AATD participants and their spouses regarding genes' influence on disease severity directly related to incongruent perceptions of control and genetic contribution to disease susceptibility. Results revealed an inverse relationship to AATD participants' perceptions of behavioral control and a direct relationship to their beliefs about genes' influence on disease severity. This suggests a pattern of incongruence in which AATD participants have low levels of perceived control over genes' influence on health and high levels of perceived genetic influence on disease severity compared to spouses. With public health communication efforts lagging behind the science of genomics, insights regarding the congruence or incongruence associated with married couples' beliefs about genes' influence on disease afford pathways to guide clinical and public health communication about genomics.

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

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    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

  16. A1ATVar: a relational database of human SERPINA1 gene variants leading to alpha1-antitrypsin deficiency and application of the VariVis software.

    Science.gov (United States)

    Zaimidou, Sophia; van Baal, Sjozef; Smith, Timothy D; Mitropoulos, Konstantinos; Ljujic, Mila; Radojkovic, Dragica; Cotton, Richard G; Patrinos, George P

    2009-03-01

    We have developed a relational database of human SERPINA1 gene mutations, leading to alpha(1)-antitrypsin (AAT) deficiency, called A(1)ATVar, which can be accessed over the World Wide Web at www.goldenhelix.org/A1ATVar. Extensive information has been extracted from the literature and converted into a searchable database, including genotype information, clinical phenotype, allelic frequencies for the commonest AAT variant alleles, methods of detection, and references. Mutation summaries are automatically displayed and user-generated queries can be formulated based on fields in the database. A separate module, linked to the FINDbase database for frequencies of inherited disorders allows the user to access allele frequency information for the three most frequent AAT alleles, namely PiM, PiS, and PiZ. The available experimental protocols to detect AAT variant alleles at the protein and DNA levels have been archived in a searchable format. A visualization tool, called VariVis, has been implemented to combine A(1)ATVar variant information with SERPINA1 sequence and annotation data. A direct data submission tool allows registered users to submit data on novel AAT variant alleles as well as experimental protocols to explore SERPINA1 genetic heterogeneity, via a password-protected interface. Database access is free of charge and there are no registration requirements for querying the data. The A(1)ATVar database is the only integrated database on the Internet offering summarized information on AAT allelic variants and could be useful not only for clinical diagnosis and research on AAT deficiency and the SERPINA1 gene, but could also serve as an example for an all-in-one solution for locus-specific database (LSDB) development and curation.

  17. Efficacy of alpha1-antitrypsin augmentation therapy in conditions other than pulmonary emphysema

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    de Serres Frederick

    2011-04-01

    Full Text Available Abstract Up to now alpha 1-antitrypsin (AAT augmentation therapy has been approved only for commercial use in selected adults with severe AAT deficiency-related pulmonary emphysema (i.e. PI*ZZ genotypes as well as combinations of Z, rare and null alleles expressing AAT serum concentrations

  18. alpha 1-Antitrypsin and coeliac disease in spain.

    Science.gov (United States)

    Klasen, E C; Polanco, I; Biemond, I; Vazquez, C; Peña, A S

    1980-01-01

    Ninety-three Spanish children suffering from coeliac disease and 103 control subjects from the same area were screened for the amount of alpha 1-antitrypsin (alpha 1AT) and for any electrophoretic variations in it. In this case-control study no significant differences were detected either in phenotype distribution or amount. The present results indicate that no genetic association exists between alpha 1AT and coeliac disease. PMID:6969683

  19. Role of alpha-1 antitrypsin in human health and disease.

    Science.gov (United States)

    de Serres, F; Blanco, I

    2014-10-01

    Alpha-1 antitrypsin (AAT) deficiency is an under-recognized hereditary disorder associated with the premature onset of chronic obstructive pulmonary disease, liver cirrhosis in children and adults, and less frequently, relapsing panniculitis, systemic vasculitis and other inflammatory, autoimmune and neoplastic diseases. Severe AAT deficiency mainly affects Caucasian individuals and has its highest prevalence (1 : 2000-1 : 5000 individuals) in Northern, Western and Central Europe. In the USA and Canada, the prevalence is 1: 5000-10 000. Prevalence is five times lower in Latin American countries and is rare or nonexistent in African and Asian individuals. The key to successful diagnosis is by measuring serum AAT, followed by the determination of the phenotype or genotype if low concentrations are found. Case detection allows implementation of genetic counselling and, in selected cases, the application of augmentation therapy. Over the past decade, it has been demonstrated that AAT is a broad-spectrum anti-inflammatory, immunomodulatory, anti-infective and tissue-repair molecule. These new capacities are promoting an increasing number of clinical studies, new pharmacological formulations, new patent applications and the search for alternative sources of AAT (including transgenic and recombinant AAT) to meet the expected demand for treating a large number of diseases, inside and outside the context of AAT deficiency.

  20. Plasma levels of alpha1-antichymotrypsin and secretory leukocyte proteinase inhibitor in healthy and chronic obstructive pulmonary disease (COPD subjects with and without severe α1-antitrypsin deficiency

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    Sveger Tomas

    2007-01-01

    Full Text Available Abstract Background Individuals with severe Z α1-antitrypsin (AAT deficiency have a considerably increased risk of developing chronic obstructive lung disease (COPD. It has been hypothesized that compensatory increases in levels of other protease inhibitors mitigate the effects of this AAT deficiency. We analysed plasma levels of AAT, α1-antichymotrypsin (ACT and secretory leukocyte protease inhibitor (SLPI in healthy (asymptomatic and COPD subjects with and without AAT deficiency. Methods Studied groups included: 71 asymptomatic AAT-deficient subjects (ZZ, n = 48 and SZ, n = 23, age 31 ± 0.5 identified during Swedish neonatal screening for AAT deficiency between 1972 and 1974; age-matched controls (MM, n = 57, age 30.7 ± 0.6; older asymptomatic ZZ (n = 10; healthy MM (n = 20, age 53 ± 9.6; and COPD patients (ZZ, n = 10, age 47.4 ± 11 and MM, n = 10, age 59.4 ± 6.7. Plasma levels of SLPI, AAT and ACT were analysed using ELISA and immunoelectrophoresis. Results No significant difference was found in plasma ACT and SLPI levels between the healthy MM and the ZZ or SZ subjects in the studied groups. Independent of the genetic variant, subjects with COPD (n = 19 had elevated plasma levels of SLPI and ACT relative to controls (n = 153 (49.5 ± 7.2 vs 40.7 ± 9.1 ng/ml, p Conclusion Our findings show that plasma levels of ACT and SLPI are not elevated in subjects with genetic AAT deficiency compared MM controls and do not appear to compensate for the deficiency of plasma AAT.

  1. Safety and pharmacokinetics of 120 mg/kg versus 60 mg/kg weekly intravenous infusions of alpha-1 proteinase inhibitor in alpha-1 antitrypsin deficiency: a multicenter, randomized, double-blind, crossover study (SPARK).

    Science.gov (United States)

    Campos, Michael A; Kueppers, Friedrich; Stocks, James M; Strange, Charlie; Chen, Junliang; Griffin, Rhonda; Wang-Smith, Laurene; Brantly, Mark L

    2013-12-01

    Augmentation therapy with the approved dose of 60 mg/kg weekly intravenous (IV) alpha-1 proteinase inhibitor (alpha1-PI), achieves a trough serum level of 11 μM in individuals with alpha-1 antitrypsin deficiency (AATD), yet this is still below the level observed in healthy individuals. This study assessed the safety and pharmacokinetic profile of weekly infusions of a 120 mg/kg dose of alpha1-PI in 30 adults with AATD. Subjects with symptomatic, genetically determined (genotypes PI*ZZ, PI*Z(null), PI*(null)(null) or PI*(Z)Mmalton) AATD were randomly assigned to weekly infusions of 60 or 120 mg/kg alpha1-PI (Prolastin-C®) for 8 weeks before crossing over to the alternate dose for 8 weeks. Adverse events (AEs) (including exacerbations), vital signs, pulmonary function tests, and laboratory assessments were recorded. Pharmacokinetic measurements included AUC0-7days, Cmax, trough, tmax, and t1/2, based on serum alpha1-PI concentrations. In total for both treatments, 112 AEs were reported, with exacerbation of COPD being the most frequent, consistent with the subjects' diagnoses. Mean steady-state serum alpha1-PI concentrations following 120 mg/kg weekly IV alpha1-PI were higher than with the 60 mg/kg dose and mean trough concentrations were 27.7 versus 17.3 μM, respectively. Dose proportionality was demonstrated for AUC0-7days and Cmax, with low inter-subject variability. The 120 mg/kg alpha1-PI weekly dose was considered to be safe and well tolerated, and provided more favorable physiologic alpha1-PI serum levels than the currently recommended 60 mg/kg dose. The effect of this dosing regimen on slowing and/or preventing emphysema progression in subjects with AATD warrants further investigation.

  2. In silico analysis of alpha1-antitrypsin variants: the effects of a novel mutation

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    Sabri Denden

    2010-01-01

    Full Text Available Alpha1-antitrypsin (AAT is a highly polymorphic protein with more than 120 variants that are classified as normal (normal protein secretion, deficient (reduced circulating AAT level caused by defective secretion or null (no protein secretion. Alpha1-antitrypsin deficiency, one of the most common genetic disorders, predisposes adults to pulmonary emphysema and, to a lesser extent, chronic liver disease and cirrhosis. In this report, we provide additional sequence data for alpha1-antitrypsin based on the characterization of a novel variant detected in a 53-year-old heterozygous patient with chronic obstructive pulmonary disease. The mutation occurred on a PI*M2 base allele and was characterized by a T → C transition at nt 97 in exon II that led to the replacement of phenylalanine by leucine (F33L. Since the mutation was found in the heterozygous state with the expression of a normally secreted variant (PI*M1 it was not possible to assess the pattern of F33L secretion. However, computational analyses based on evolutionary, structural and functional information indicated a reduction of 23 ų in the side chain volume and the creation of a cavity in the protein hydrophobic core that likely disturbed the tridimensional structure and folding of AAT. The accuracy of the in silico prediction was confirmed by testing known mutations.

  3. 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

    BACKGROUND: The efficacy of α1 proteinase inhibitor (A1PI) augmentation treatment for α1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in α1 antitrypsin deficiency emphysema ...

  4. Targeted screening programmes in COPD: how to identify individuals with α1-antitrypsin deficiency.

    Science.gov (United States)

    Chorostowska-Wynimko, Joanna

    2015-03-01

    α1-antitrypsin deficiency (AATD) is a significantly under-recognised autosomal genetic disorder with individuals being clinically diagnosed. Moreover, rigorous genetic epidemiological data regarding AATD are lacking. The majority of findings come from the USA and Western Europe, and no information is available for many countries. To address this concern, an α1-antitrypsin (AAT) laboratory was set up in 2009 at the National Institute of Tuberculosis and Lung Diseases (Warsaw, Poland). In 2010, an AATD screening programme targeting patients with respiratory disorders was initiated in Poland. This targeted survey has provided valuable information regarding AAT-deficient genotypes, clinical disease and levels of expertise at the physician level. After 4 years, almost 2500 patients with chronic obstructive pulmonary disorders have been screened and, in this cohort, ∼13% had AATD alleles. In these patients, the detection frequency for S and Z alleles was four times greater, and the frequency of homozygous PI*ZZ was 16 times greater than that of the general population. These results highlight the need to build awareness in the medical community, and the project is currently being extended to cover central Eastern Europe, with the creation of the Central Eastern European Alpha-1 Antitrypsin Network.

  5. 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...

  6. Longer telomere length in COPD patients with α1-antitrypsin deficiency independent of lung function.

    Directory of Open Access Journals (Sweden)

    Aabida Saferali

    Full Text Available Oxidative stress is involved in the pathogenesis of airway obstruction in α1-antitrypsin deficient patients. This may result in a shortening of telomere length, resulting in cellular senescence. To test whether telomere length differs in α1-antitrypsin deficient patients compared with controls, we measured telomere length in DNA from peripheral blood cells of 217 α1-antitrypsin deficient patients and 217 control COPD patients. We also tested for differences in telomere length between DNA from blood and DNA from lung tissue in a subset of 51 controls. We found that telomere length in the blood was significantly longer in α1-antitrypsin deficient COPD patients compared with control COPD patients (p = 1×10(-29. Telomere length was not related to lung function in α1-antitrypsin deficient patients (p = 0.3122 or in COPD controls (p = 0.1430. Although mean telomere length was significantly shorter in the blood when compared with the lungs (p = 0.0078, telomere length was correlated between the two tissue types (p = 0.0122. Our results indicate that telomere length is better preserved in α1-antitrypsin deficient COPD patients than in non-deficient patients. In addition, measurement of telomere length in the blood may be a suitable surrogate for measurement in the lung.

  7. Longer telomere length in COPD patients with α1-antitrypsin deficiency independent of lung function.

    Science.gov (United States)

    Saferali, Aabida; Lee, Jee; Sin, Don D; Rouhani, Farshid N; Brantly, Mark L; Sandford, Andrew J

    2014-01-01

    Oxidative stress is involved in the pathogenesis of airway obstruction in α1-antitrypsin deficient patients. This may result in a shortening of telomere length, resulting in cellular senescence. To test whether telomere length differs in α1-antitrypsin deficient patients compared with controls, we measured telomere length in DNA from peripheral blood cells of 217 α1-antitrypsin deficient patients and 217 control COPD patients. We also tested for differences in telomere length between DNA from blood and DNA from lung tissue in a subset of 51 controls. We found that telomere length in the blood was significantly longer in α1-antitrypsin deficient COPD patients compared with control COPD patients (p = 1×10(-29)). Telomere length was not related to lung function in α1-antitrypsin deficient patients (p = 0.3122) or in COPD controls (p = 0.1430). Although mean telomere length was significantly shorter in the blood when compared with the lungs (p = 0.0078), telomere length was correlated between the two tissue types (p = 0.0122). Our results indicate that telomere length is better preserved in α1-antitrypsin deficient COPD patients than in non-deficient patients. In addition, measurement of telomere length in the blood may be a suitable surrogate for measurement in the lung.

  8. Disposition of Alpha-1-Antitrypsin in the Isolate Perfused Rabbit Lung

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    MOHAMMAD K. HASSANZADEH PHILIP R. MAYER

    1999-08-01

    Full Text Available The potential for delivering large molecular weight proteins into the lungs to reach local or systemic sites of action was investigated by examining the disposition of alpha-1-antitrypsin in the isolated rabbit lung. Alpha-1-antitrypsin, a model protein, was measured in the periusion medium following intravascular administration and was found to remain constant, indicating limited uptake or metabolism by lung tissue. Intrabronchial instillation of 10 mg of alpha-1-antitrypsin in water resulted in no measurable concentration in the recirculating perfusate during the two hours experiment. These data suggest that transport of large proteins may be limited across lung-blood membrane barriers in either direction. Though this would limit the ability of inhaled drugs with large molecular weights to reach the general circulation, proteins which are used to treat respiratory diseases, such as alpha-1-antitrypsin, might be delivered locally by inhalation with only negligible systemic exposure.

  9. Inhibition of Lassa virus glycoprotein cleavage and multicycle replication by site 1 protease-adapted alpha(1-antitrypsin variants.

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    Anna Maisa

    Full Text Available BACKGROUND: Proteolytic processing of the Lassa virus envelope glycoprotein precursor GP-C by the host proprotein convertase site 1 protease (S1P is a prerequisite for the incorporation of the subunits GP-1 and GP-2 into viral particles and, hence, essential for infectivity and virus spread. Therefore, we tested in this study the concept of using S1P as a target to block efficient virus replication. METHODOLOGY/PRINCIPAL FINDING: We demonstrate that stable cell lines inducibly expressing S1P-adapted alpha(1-antitrypsin variants inhibit the proteolytic maturation of GP-C. Introduction of the S1P recognition motifs RRIL and RRLL into the reactive center loop of alpha(1-antitrypsin resulted in abrogation of GP-C processing by endogenous S1P to a similar level observed in S1P-deficient cells. Moreover, S1P-specific alpha(1-antitrypsins significantly inhibited replication and spread of a replication-competent recombinant vesicular stomatitis virus expressing the Lassa virus glycoprotein GP as well as authentic Lassa virus. Inhibition of viral replication correlated with the ability of the different alpha(1-antitrypsin variants to inhibit the processing of the Lassa virus glycoprotein precursor. CONCLUSIONS/SIGNIFICANCE: Our data suggest that glycoprotein cleavage by S1P is a promising target for the development of novel anti-arenaviral strategies.

  10. Molecular Mechanism of Z α1-Antitrypsin Deficiency.

    Science.gov (United States)

    Huang, Xin; Zheng, Ying; Zhang, Fei; Wei, Zhenquan; Wang, Yugang; Carrell, Robin W; Read, Randy J; Chen, Guo-Qiang; Zhou, Aiwu

    2016-07-22

    The Z mutation (E342K) of α1-antitrypsin (α1-AT), carried by 4% of Northern Europeans, predisposes to early onset of emphysema due to decreased functional α1-AT in the lung and to liver cirrhosis due to accumulation of polymers in hepatocytes. However, it remains unclear why the Z mutation causes intracellular polymerization of nascent Z α1-AT and why 15% of the expressed Z α1-AT is secreted into circulation as functional, but polymerogenic, monomers. Here, we solve the crystal structure of the Z-monomer and have engineered replacements to assess the conformational role of residue Glu-342 in α1-AT. The results reveal that Z α1-AT has a labile strand 5 of the central β-sheet A (s5A) with a consequent equilibrium between a native inhibitory conformation, as in its crystal structure here, and an aberrant conformation with s5A only partially incorporated into the central β-sheet. This aberrant conformation, induced by the loss of interactions from the Glu-342 side chain, explains why Z α1-AT is prone to polymerization and readily binds to a 6-mer peptide, and it supports that annealing of s5A into the central β-sheet is a crucial step in the serpins' metastable conformational formation. The demonstration that the aberrant conformation can be rectified through stabilization of the labile s5A by binding of a small molecule opens a potential therapeutic approach for Z α1-AT deficiency.

  11. Alpha 1-antitrypsin does not inhibit human monocyte caspase-1.

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    Mohd Akhlakur Rahman

    Full Text Available Alpha 1-antitrypsin (A1AT is a 52 kDa serine protease inhibitor produced largely by hepatocytes but also by mononuclear phagocytes. A1AT chiefly inhibits neutrophil elastase and proteinase-3 but has also been reported to have immune modulatory functions including the ability to inhibit caspases. Its clinical availability for infusion suggests that A1AT therapy might modulate caspase related inflammation. Here we tested the ability of A1AT to modulate caspase-1 function in human mononuclear phagocytes.Purified plasma derived A1AT was added to active caspase-1 in a cell-free system (THP-1 lysates as well as added exogenously to cell-culture models and human whole blood models of caspase-1 activation. Functional caspase-1 activity was quantified by the cleavage of the caspase-1 specific fluorogenic tetrapeptide substrate (WEHD-afc and the release of processed IL-18 and IL-1β.THP-1 cell lysates generated spontaneous activation of caspase-1 both by WEHD-afc cleavage and the generation of p20 caspase-1. A1AT added to this cell free system was unable to inhibit caspase-1 activity. Release of processed IL-18 by THP-1 cells was also unaffected by the addition of exogenous A1AT prior to stimulation with LPS/ATP, a standard caspase-1 activating signal. Importantly, the A1AT exhibited potent neutrophil elastase inhibitory capacity. Furthermore, A1AT complexed to NE (and hence conformationally modified also did not affect THP-1 cell caspase-1 activation. Finally, exogenous A1AT did not inhibit the ability of human whole blood samples to process and release IL-1β.A1AT does not inhibit human monocyte caspase-1.

  12. Lower-zone emphysema in young patients without α1-antitrypsin deficiency

    Science.gov (United States)

    Martelli, Nestor A.; Goldman, Ernesto; Roncoroni, Aquiles J.

    1974-01-01

    Martelli, N. A., Goldman, E., and Roncoroni, A. J. (1974).Thorax, 29, 237-244. Lowerzone emphysema in young patients without α1-antitrypsin deficiency. Three young patients with radiographic pulmonary emphysema predominantly in the lower zones are reported. The clinical and physiological features were those observed in severe pulmonary emphysema. Predominance of the main lesions in the lower zones was confirmed in two cases by selective pulmonary angiography. One of the patients died and extensive panlobular emphysema was found at necropsy. Although the similarities between our patients and those with emphysema and α1-antitrypsin deficiency were remarkable, the latter condition was ruled out. Images PMID:4545502

  13. 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.

  14. 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.

  15. alpha 1-Antitrypsin-levels and phenotypes in Crohn's disease in the Netherlands.

    Science.gov (United States)

    Klasen, E C; Biemond, I; Weterman, I T

    1980-01-01

    A group of 310 unrelated patients suffering from Crohn's disease has been screened for quantitative and electrophoretic variations of alpha 1-antitrypsin (alpha 1AT). A comparison was made betweeen patients and healthy controls. The distribution of electrophoretic alpha 1AT variants in the patients showed no significant deviation from the controls. The alpha 1AT quantities are significantly higher in the Crohn's disease population than in the controls. PMID:6969207

  16. How Is Alpha-1 Antitrypsin Deficiency Treated?

    Science.gov (United States)

    ... How the Lungs Work Lung Transplant Oxygen Therapy Pulmonary Function Tests Send a link to NHLBI to someone by E-MAIL | PRINT | SHARE this page from the ... a lung disease called COPD (chronic obstructive pulmonary disease). If you have symptoms related to AAT ...

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

    Science.gov (United States)

    ... of Genetic Tests Genomics and Health Disparities Genetic Discrimination Human Subjects Research Informed Consent for Genomics Research ... Smoking or exposure to tobacco smoke increases the appearance of symptoms and damage to the lungs. Other ...

  18. Living with Alpha-1 Antitrypsin Deficiency

    Science.gov (United States)

    ... secondhand smoke and other lung irritants, such as dust, fumes, or toxins. Check your living and working spaces for things that may irritate your lungs. Examples include flower and tree pollen, ash, allergens, air pollution, wood burning stoves, paint fumes, and fumes from cleaning ...

  19. 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...

  20. Sequestration of mutated alpha1-antitrypsin into inclusion bodies is a cell-protective mechanism to maintain endoplasmic reticulum function.

    Science.gov (United States)

    Granell, Susana; Baldini, Giovanna; Mohammad, Sameer; Nicolin, Vanessa; Narducci, Paola; Storrie, Brian; Baldini, Giulia

    2008-02-01

    A variant alpha1-antitrypsin with E342K mutation has a high tendency to form intracellular polymers, and it is associated with liver disease. In the hepatocytes of individuals carrying the mutation, alpha1-antitrypsin localizes both to the endoplasmic reticulum (ER) and to membrane-surrounded inclusion bodies (IBs). It is unclear whether the IBs contribute to cell toxicity or whether they are protective to the cell. We found that in hepatoma cells, mutated alpha1-antitrypsin exited the ER and accumulated in IBs that were negative for autophagosomal and lysosomal markers, and contained several ER components, but not calnexin. Mutated alpha1-antitrypsin induced IBs also in neuroendocrine cells, showing that formation of these organelles is not cell type specific. In the presence of IBs, ER function was largely maintained. Increased levels of calnexin, but not of protein disulfide isomerase, inhibited formation of IBs and lead to retention of mutated alpha1-antitrypsin in the ER. In hepatoma cells, shift of mutated alpha1-antitrypsin localization to the ER by calnexin overexpression lead to cell shrinkage, ER stress, and impairment of the secretory pathway at the ER level. We conclude that segregation of mutated alpha1-antitrypsin from the ER to the IBs is a protective cell response to maintain a functional secretory pathway.

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

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    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.

  2. alpha-1-antitrypsin in breast milk of healthy Nigerian mothers.

    Science.gov (United States)

    Omeme, J A; Lantos, J D; Ihongbe, J C

    1981-01-01

    Alpha-1-antitryspin (x-1-AT) may play a possible role as effector of immunological stasis. This study examines the levels of this glycoprotein in 73 breast milk samples from 60 healthy Nigerian mothers. Levels of x-1-AT were measured by single radial immunodiffusion according to the method of Mancini. Serum protein was measured by Lowry's method, albumin by Doumas' method. Highest mean levels of x-1-AT were found in colostrum (25 mg/dl). The level was significantly higher compared to transitional milk (14.2 mg/dl) or mature milk (165 mg/dl) (p0.001). Breast milk contains substantial amounts of x-1-AT which is not destroyed by pasturization at 56 degrees Centigrade. The immunological protective properties of breast milk are ideal for newborn babies, particularly those who are low birthweight and are thus most susceptible to neonatal necrotizing enterocolitis.

  3. Chitosan-genipin nanohydrogel as a vehicle for sustained delivery of alpha-1 antitrypsin.

    Science.gov (United States)

    Ghasemi, Ahmad; Mohtashami, Mahnaz; Sheijani, Samaneh Sotoudeh; Aliakbari, Kamelya

    2015-01-01

    Alpha-1antitrypsin (A1AT) deficiency, an inherited disorder, has been shown to be the cause of lung diseases such as emphysema and chronic obstructive pulmonary disease. One of the treatment strategies to provide appropriate and adequate concentrations of A1AT in the lungsis the application of nanoparticles (NPs) in pulmonary drug delivery. In the current study, biocompatible nanohydrogels were prepared using chemically cross-linked chitosan with ginepin, a natural cross linker reagent, and used as a carrier to deposit A1AT into the lung tissue. Colloidal and monodispersed NPs were synthesized through reverse microemulsion. Nanohydrogels were characterized with TEM, LLS, FTIR, ZTEA potential, UV spectrum, and swelling test. Encapsulation efficacy was determined at different concentrations of A1AT using Bradford assay. Effect of processing variables such as pH, loading efficiency, and release media components on drug release profile was determined in simulated lung fluids. To evaluate the inhibitory activity of the A1AT after release from NPs, trypsin inhibitory capacity assay was carried out. Results from FTIR and UV spectrum confirmed the development of chitosan cross linkage. Spherical chitosan-genipin NPs were sized from 30-100 nm. NPs exhibited the ability to release 49% of the drug within 12-dayperiodatpH 7. However, there were variations with the drug release profile due to pH variations and loading efficacy. Drug release was higher in pseudo alveolar fluid in comparison with saline solution. These data indicate that application of chitosan nanohydrogels can be a useful tool for sustained release of A1AT in the lung tissue.

  4. Alpha-1 antitrypsin Pi*Z gene frequency and Pi*ZZ genotype numbers worldwide: an update

    Directory of Open Access Journals (Sweden)

    Blanco I

    2017-02-01

    Full Text Available Ignacio Blanco,1 Patricia Bueno,2 Isidro Diego,3 Sergio Pérez-Holanda,4 Francisco Casas-Maldonado,5 Cristina Esquinas,6 Marc Miravitlles6,7 1Alpha1-Antitrypsin Deficiency Spanish Registry (REDAAT, Fundación Respira, Spanish Society of Pneumology and Thoracic Surgery (SEPAR, Barcelona, 2Internal Medicine Department, County Hospital of Jarrio, 3Materials and Energy Department, School of Mining Engineering, Oviedo University, 4Surgical Department, University Central Hospital of Asturias (HUCA, Oviedo, Principality of Asturias, 5Pneumology Department, Complejo Hospitalario Universitario de Granada, Granada, 6Pneumology Department, Hospital Universitari Vall d’Hebron, 7CIBER de Enfermedades Respiratorias (CIBERES, Barcelona, Spain Abstract: In alpha-1 antitrypsin deficiency (AATD, the Z allele is present in 98% of cases with severe disease, and knowledge of the frequency of this allele is essential from a public health perspective. However, there is a remarkable lack of epidemiological data on AATD worldwide, and many of the data currently used are outdated. Therefore, the objective of this study was to update the knowledge of the frequency of the Z allele to achieve accurate estimates of the prevalence and number of Pi*ZZ genotypes 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 measurements performed using a coefficient of variation calculated from the sample size and 95% confidence intervals. Studies fulfilling these criteria were used to develop maps with an inverse distance weighted (IDW-interpolation method, providing numerical and graphical information of Pi*Z distribution worldwide. A total of 224 cohorts from 65 countries were included in the study. With the data provided by these cohorts, a total of 253,404 Pi*ZZ were estimated worldwide: 119,594 in Europe, 91,490 in America and Caribbean, 3,824 in

  5. Alpha-1-antitrypsin phenotypes in Saudi Arabia: A study in the central province.

    Science.gov (United States)

    Warsy, A S; El-Hazmi, M A; Sedrani, S H; Kinhal, M

    1991-03-01

    This study was conducted on 204 plasma samples obtained from Saudis living in the central province of Saudi Arabia, to determine the prevalence of alpha-1-antitrypsin (alpha1AT) phenotypes. The alpha1AT phenotypes were separated by isoelectric focusing on ampholine gels (pH 4-5). The prevalences of PiMM, MS, MZ, SZ, and ZZ were 0.8676, 0.0931, 0.0245, 0.0098, and 0.0049, respectively. The gene frequencies of the alpha1AT variants, i.e.., PiM, PiS, and PiZ, were 0.9265, 0.0515, 0.022, respectively. We describe and compare our results in a Saudi population with those reported for other populations.

  6. 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.

  7. 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

    . 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......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......1AT is produced at all stages of myeloid maturation in the bone marrow. The production increases as neutrophils enter circulation and increases further upon migration to tissues as observed in skin windows and when blood neutrophils are incubated with granulocyte colony-stimulating factor...

  8. Production of human alpha-1-antitrypsin from transgenic rice cell culture in a membrane bioreactor.

    Science.gov (United States)

    McDonald, Karen A; Hong, Lo Ming; Trombly, David M; Xie, Qing; Jackman, Alan P

    2005-01-01

    Transgenic plant cell cultures offer a number of advantages over alternative host expression systems, but so far relatively low product concentrations have been achieved. In this study, transgenic rice cells are used in a two-compartment membrane bioreactor (CELLine 350, Integra Biosciences) for the production of recombinant alpha-1-antitrypsin (rAAT). Expression of rAAT is controlled by the rice alpha-amylase (RAmy3D) promoter, which is induced in the absence of sugar. The extracellular product is retained in the bioreactor's relatively small cell compartment, thereby increasing product concentration. Due to the packed nature of the cell aggregates in the cell compartment, a clarified product solution can be withdrawn from the bioreactor. Active rAAT reached levels of 100-247 mg/L (4-10% of the total extracellular protein) in the cell compartment at 5-6 days postinduction, and multiple inductions of the RAmy3D promoter were demonstrated.

  9. 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.

  10. Alpha-1 antitrypsin is markedly decreased following pulmonary F. tularensis challenge

    Directory of Open Access Journals (Sweden)

    James Patrick Chambers

    2011-12-01

    Full Text Available Alpha-1 antitrypsin, a small glycoprotein clade A serpine serine protease inhibitor of neutrophil elastase has been shown to increase in humans following bacterial and viral infection. However, we report here significant reduction of this major inhibitor of elastase in plasma of F. tularensis LVS and SCHU S4 (Type A strain following pulmonary challenge. Consistent with an imbalance of protease-antiprotease function at the alveolar level in lungs of infected animals, increased elastase activity was observed in lung lavage fluids accompanied by decrease lung function, i.e., loss of lung elastance with concomitant increase of pulmonary hysteresistivity. These data are suggestive of targeted tissue destruction via unchecked neutrophhil elastase activity in infected animals.

  11. Art, alpha-1-antitrypsin polymorphisms and intense creative energy: blessing or curse?

    Science.gov (United States)

    Schmechel, Donald Everett

    2007-09-01

    Persons heterozygous for Z, S and rare alpha-1-antitrypsin (AAT, SERPIN1A) polymorphisms (ca. 9% of population) are often considered 'silent' carriers with increased vulnerability to environmentally modulated liver and lung disease. They may have significantly more anxiety and bipolar spectrum disorders, nutritional compromise, and white matter disease [Schmechel DE, Browndyke J, Ghio A. Strategies for the dissection of genetic-environmental interactions in neurodegenerative disorders. Neurotoxicology 2006;27:637-57]. Given association of art and mood disorders, we examined occupation and artistic vocation from this same series. One thousand five hundred and thirty-seven consecutive persons aged 16-90 years old received comprehensive work-up including testing for AAT 'phenotype' and level, nutritional factors, and inflammatory, iron and copper indices. Occupations were grouped by Bureau of Labor Standards classification and information gathered on artistic activities. Proportion of reactive airway disease, obstructive pulmonary disease, and pre-existing anxiety disorder or bipolar disorder were significantly increased in persons carrying AAT non-M polymorphisms compared to normal MM genotype (respectively, 10, 20, 21, and 33% compared to 8, 12, 11, and 9%; contingency table, pulmonary: chi2 37, p=0.0001; affective disorder: chi2=171, p=0.0001). In persons with artistic avocation (n=189) or occupation (n=57), AAT non-M polymorphisms are significantly increased (respectively, proportions of 44 and 40% compared to background rate of 9%; contingency table, avocation: chi2=172, p=0.0001; occupation: chi2=57, p=0.0007). Artistic ability and 'anxiety/bipolar spectrum' mood disorders may represent phenotypic attributes that had selective advantage during recent human evolution, an 'intensive creative energy' (ICE) behavioral phenotype. Background proportion of ICE of 7% consists of 49 of 1312 persons with AAT MM genotype (4%), and 58 of 225 persons with non-MM genotypes

  12. 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.

  13. [Relationship between serum levels of C-reactive protein and alpha1-antitrypsin and insulin resistance in obese women].

    Science.gov (United States)

    Ramírez Alvarado, María Matilde; Sánchez Roitz, César

    2014-09-01

    Adipose tissue produces cytokines involved in insulin resistance (IR) such as IL-6, IL-8, TNF-alpha and proinflammatory molecules such as C reactive protein (CRP). alpha1-antitrypsin is an inflammation-sensitive plasma protein. The objective of this study is to determine the correlation between serum CRP high-sensitivity (CRPhs) and alpha1-antitrypsin levels with IR indices in obese Venezuelan women. The study population consisted of 15 normal weight women (BMI 21.8 +/- 1.9 kg/m2) and 15 obese women (BMI 35.3 +/- 5.3 kg/m2). Obese and lean women underwent a 2 h-75 g oral glucose tolerance test and the following indices were calculated: homeostatic model assessment of insulin resistance (HOMA-IR), homeostatic model assessment of beta cell function (HOMA-beta), Matsuda Index and Insulinogenic Index. The relationship between serum CRPhs and alpha1-antitrypsin levels and these indices were determined. Obese women had higher CRPhs levels (p = 0.001) compared with normal weight women. In obese women, serum CRPhs levels were positively correlated with HOMA-IR (r = 0.73, p = 0.0021), HOMA-beta (r = 0.53, p = 0.031) and negatively correlated with the Matsuda Index (r = -0.60, p = 0.017). No correlation between serum levels of alpha1-antitrypsin and IR indices in the obese group and the lean group was observed. There was a relation between serum CRPhs levels and insulin resistance, suggesting a role of subclinical inflammation in IR.

  14. 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.

  15. C-Terminal Alpha-1 Antitrypsin Peptide: A New Sepsis Biomarker with Immunomodulatory Function

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    Nancy Blaurock

    2016-01-01

    Full Text Available Systemic inflammatory response syndrome (SIRS is a life threatening condition and the leading cause of death in intensive care units. Although single aspects of pathophysiology have been described in detail, numerous unknown mediators contribute to the progression of this complex disease. The aim of this study was to elucidate the pathophysiological role of CAAP48, a C-terminal alpha-1 antitrypsin fragment, that we found to be elevated in septic patients and to apply this peptide as diagnostic marker for infectious and noninfectious etiologies of SIRS. Incubation of human polymorphonuclear neutrophils with synthetic CAAP48, the SNP-variant CAAP47, and several control peptides revealed intense neutrophil activation, induction of neutrophil chemotaxis, reduction of neutrophil viability, and release of cytokines. We determined the abundance of CAAP48 in patients with severe sepsis, severe SIRS of noninfectious origin, and viral infection. CAAP48 levels were 3-4-fold higher in patients with sepsis compared to SIRS of noninfectious origin and allowed discrimination of those patients with high sensitivity and specificity. Our results suggest that CAAP48 is a promising discriminatory sepsis biomarker with immunomodulatory functions, particularly on human neutrophils, supporting its important role in the host response and pathophysiology of sepsis.

  16. 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.

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

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    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.

  18. 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

  19. Deficient and Null Variants of SERPINA1 Are Proteotoxic in a Caenorhabditis elegans Model of α1-Antitrypsin Deficiency.

    Directory of Open Access Journals (Sweden)

    Erin E Cummings

    Full Text Available α1-antitrypsin deficiency (ATD predisposes patients to both loss-of-function (emphysema and gain-of-function (liver cirrhosis phenotypes depending on the type of mutation. Although the Z mutation (ATZ is the most prevalent cause of ATD, >120 mutant alleles have been identified. In general, these mutations are classified as deficient (<20% normal plasma levels or null (<1% normal levels alleles. The deficient alleles, like ATZ, misfold in the ER where they accumulate as toxic monomers, oligomers and aggregates. Thus, deficient alleles may predispose to both gain- and loss-of-function phenotypes. Null variants, if translated, typically yield truncated proteins that are efficiently degraded after being transiently retained in the ER. Clinically, null alleles are only associated with the loss-of-function phenotype. We recently developed a C. elegans model of ATD in order to further elucidate the mechanisms of proteotoxicity (gain-of-function phenotype induced by the aggregation-prone deficient allele, ATZ. The goal of this study was to use this C. elegans model to determine whether different types of deficient and null alleles, which differentially affect polymerization and secretion rates, correlated to any extent with proteotoxicity. Animals expressing the deficient alleles, Mmalton, Siiyama and S (ATS, showed overall toxicity comparable to that observed in patients. Interestingly, Siiyama expressing animals had smaller intracellular inclusions than ATZ yet appeared to have a greater negative effect on animal fitness. Surprisingly, the null mutants, although efficiently degraded, showed a relatively mild gain-of-function proteotoxic phenotype. However, since null variant proteins are degraded differently and do not appear to accumulate, their mechanism of proteotoxicity is likely to be different to that of polymerizing, deficient mutants. Taken together, these studies showed that C. elegans is an inexpensive tool to assess the proteotoxicity of

  20. Alpha-1 antitrypsin Pi*Z gene frequency and Pi*ZZ genotype numbers worldwide: an update

    Science.gov (United States)

    Blanco, Ignacio; Bueno, Patricia; Diego, Isidro; Pérez-Holanda, Sergio; Casas-Maldonado, Francisco; Esquinas, Cristina; Miravitlles, Marc

    2017-01-01

    In alpha-1 antitrypsin deficiency (AATD), the Z allele is present in 98% of cases with severe disease, and knowledge of the frequency of this allele is essential from a public health perspective. However, there is a remarkable lack of epidemiological data on AATD worldwide, and many of the data currently used are outdated. Therefore, the objective of this study was to update the knowledge of the frequency of the Z allele to achieve accurate estimates of the prevalence and number of Pi*ZZ genotypes 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) measurements performed using a coefficient of variation calculated from the sample size and 95% confidence intervals. Studies fulfilling these criteria were used to develop maps with an inverse distance weighted (IDW)-interpolation method, providing numerical and graphical information of Pi*Z distribution worldwide. A total of 224 cohorts from 65 countries were included in the study. With the data provided by these cohorts, a total of 253,404 Pi*ZZ were estimated worldwide: 119,594 in Europe, 91,490 in America and Caribbean, 3,824 in Africa, 32,154 in Asia, 4,126 in Australia, and 2,216 in New Zealand. In addition, the IDW-interpolation maps predicted Pi*Z frequencies throughout the world even in some areas that lack real data. In conclusion, the inclusion of new well-designed studies and the exclusion of the low-quality ones have significantly improved the reliability of results, which may be useful to plan strategies for future research and diagnosis and to rationalize the therapeutic resources available. PMID:28243076

  1. Deficient and Null Variants of SERPINA1 Are Proteotoxic in a Caenorhabditis elegans Model of α1-Antitrypsin Deficiency.

    Science.gov (United States)

    Cummings, Erin E; O'Reilly, Linda P; King, Dale E; Silverman, Richard M; Miedel, Mark T; Luke, Cliff J; Perlmutter, David H; Silverman, Gary A; Pak, Stephen C

    2015-01-01

    α1-antitrypsin deficiency (ATD) predisposes patients to both loss-of-function (emphysema) and gain-of-function (liver cirrhosis) phenotypes depending on the type of mutation. Although the Z mutation (ATZ) is the most prevalent cause of ATD, >120 mutant alleles have been identified. In general, these mutations are classified as deficient (null (Null variants, if translated, typically yield truncated proteins that are efficiently degraded after being transiently retained in the ER. Clinically, null alleles are only associated with the loss-of-function phenotype. We recently developed a C. elegans model of ATD in order to further elucidate the mechanisms of proteotoxicity (gain-of-function phenotype) induced by the aggregation-prone deficient allele, ATZ. The goal of this study was to use this C. elegans model to determine whether different types of deficient and null alleles, which differentially affect polymerization and secretion rates, correlated to any extent with proteotoxicity. Animals expressing the deficient alleles, Mmalton, Siiyama and S (ATS), showed overall toxicity comparable to that observed in patients. Interestingly, Siiyama expressing animals had smaller intracellular inclusions than ATZ yet appeared to have a greater negative effect on animal fitness. Surprisingly, the null mutants, although efficiently degraded, showed a relatively mild gain-of-function proteotoxic phenotype. However, since null variant proteins are degraded differently and do not appear to accumulate, their mechanism of proteotoxicity is likely to be different to that of polymerizing, deficient mutants. Taken together, these studies showed that C. elegans is an inexpensive tool to assess the proteotoxicity of different AT variants using a transgenic approach.

  2. Accumulation of mutant alpha1-antitrypsin Z in the endoplasmic reticulum activates caspases-4 and -12, NFkappaB, and BAP31 but not the unfolded protein response.

    Science.gov (United States)

    Hidvegi, Tunda; Schmidt, Bela Z; Hale, Pamela; Perlmutter, David H

    2005-11-25

    In alpha(1)-antitrypsin (alpha1AT) deficiency, a polymerogenic mutant form of the secretory glycoprotein alpha1AT, alpha1ATZ, is retained in the endoplasmic reticulum (ER) of liver cells. It is not yet known how this results in liver injury in a subgroup of deficient individuals and how the remainder of deficient individuals escapes liver disease. One possible explanation is that the "susceptible" subgroup is unable to mount the appropriate protective cellular responses. Here we examined the effect of mutant alpha1ATZ on several potential protective signaling pathways by using cell lines with inducible expression of mutant alpha1AT as well as liver from transgenic mice with liver-specific inducible expression of mutant alpha1AT. The results show that ER retention of polymerogenic mutant alpha1ATZ does not result in an unfolded protein response (UPR). The UPR can be induced in the presence of alpha1ATZ by tunicamycin excluding the possibility that the pathway has been disabled. In striking contrast, ER retention of nonpolymerogenic alpha1AT mutants does induce the UPR. These results indicate that the machinery responsible for activation of the UPR can distinguish the physical characteristics of proteins that accumulate in the ER in such a way that it can respond to misfolded but not relatively ordered polymeric structures. Accumulation of mutant alpha1ATZ does activate specific signaling pathways, including caspase-12 in mouse, caspase-4 in human, NFkappaB, and BAP31, a profile that was distinct from that activated by nonpolymerogenic alpha1AT mutants.

  3. Mixture-Based Combinatorial Libraries from Small Individual Peptide Libraries: A Case Study on α1-Antitrypsin Deficiency

    Directory of Open Access Journals (Sweden)

    Yi-Pin Chang

    2014-05-01

    Full Text Available The design, synthesis and screening of diversity-oriented peptide libraries using a “libraries from libraries” strategy for the development of inhibitors of α1-antitrypsin deficiency are described. The major buttress of the biochemical approach presented here is the use of well-established solid-phase split-and-mix method for the generation of mixture-based libraries. The combinatorial technique iterative deconvolution was employed for library screening. While molecular diversity is the general consideration of combinatorial libraries, exquisite design through systematic screening of small individual libraries is a prerequisite for effective library screening and can avoid potential problems in some cases. This review will also illustrate how large peptide libraries were designed, as well as how a conformation-sensitive assay was developed based on the mechanism of the conformational disease. Finally, the combinatorially selected peptide inhibitor capable of blocking abnormal protein aggregation will be characterized by biophysical, cellular and computational methods.

  4. Mixture-based combinatorial libraries from small individual peptide libraries: a case study on α1-antitrypsin deficiency.

    Science.gov (United States)

    Chang, Yi-Pin; Chu, Yen-Ho

    2014-05-16

    The design, synthesis and screening of diversity-oriented peptide libraries using a "libraries from libraries" strategy for the development of inhibitors of α1-antitrypsin deficiency are described. The major buttress of the biochemical approach presented here is the use of well-established solid-phase split-and-mix method for the generation of mixture-based libraries. The combinatorial technique iterative deconvolution was employed for library screening. While molecular diversity is the general consideration of combinatorial libraries, exquisite design through systematic screening of small individual libraries is a prerequisite for effective library screening and can avoid potential problems in some cases. This review will also illustrate how large peptide libraries were designed, as well as how a conformation-sensitive assay was developed based on the mechanism of the conformational disease. Finally, the combinatorially selected peptide inhibitor capable of blocking abnormal protein aggregation will be characterized by biophysical, cellular and computational methods.

  5. 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

    biomarkers are currently needed for identification of patients with mild or moderate disease activity. Using a commercially available platform, we aimed at identifying serum biomarkers that are able to grade the disease severity. METHODS: Serum samples from 65 patients with UC with varying disease activity......-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......BACKGROUND: Initial assessment of patients with ulcerative colitis (UC) is challenging and relies on apparent clinical symptoms and measurements of surrogate markers (e.g., C-reactive protein [CRP] or similar acute phase proteins). As CRP only reliably identifies patients with severe disease, novel...

  6. Proteome Profiling of Urinary Exosomes Identifies Alpha 1-Antitrypsin and H2B1K as Diagnostic and Prognostic Biomarkers for Urothelial Carcinoma

    Science.gov (United States)

    Lin, Shih-Yi; Chang, Chao-Hsiang; Wu, His-Chin; Lin, Ching-Chan; Chang, Kai-Po; Yang, Chi-Rei; Huang, Chi-Ping; Hsu, Wu-Huei; Chang, Chiz-Tzung; Chen, Chao-Jung

    2016-01-01

    MALDI-TOF spectrometry has not been used for urinary exosome analysis. We used it for determining UC biomarkers. From 2012 to 2015, we enrolled 129 consecutive patients with UC and 62 participants without UC. Exosomes from their urine were isolated, and analyzed through MALDI-TOF spectrometry. Immunohistochemical (IHC) analysis of another 122 UC and 26 non-UC tissues was conducted to verify the discovered biomarkers. Two peaks at m/z 5593 (fragmented peptide of alpha-1-antitrypsin; sensitivity, 50.4%; specificity, 96.9%) and m/z 5947 (fragmented peptide of histone H2B1K sensitivity, 62.0%; specificity, 92.3%) were identified as UC diagnosis exosome biomarkers. UC patients with detectable histone H2B1K showed 2.29- and 3.11-fold increased risks of recurrence and progression, respectively, compared with those with nondetectable histone H2B1K. Verification results of IHC staining revealed significantly higher expression of alpha 1-antitrypsin (p = 0.038) and H2B1K (p = 0.005) in UC tissues than in normal tissues. The expression of alpha 1-antitrypsin and H2B1K in UC tissues was significantly correlated with UC grades (p exosome proteins alpha 1-antitrypsin and histone H2B1K, which are identified through MALDI-TOF analysis, could facilitate rapid diagnosis and prognosis of UC. PMID:27686150

  7. RELEVANCE OF CLASSIC ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODY (C-ANCA)-MEDIATED INHIBITION OF PROTEINASE 3-ALPHA-1-ANTITRYPSIN COMPLEXATION TO DISEASE-ACTIVITY IN WEGENER-GRANULOMATOSIS

    NARCIS (Netherlands)

    DOLMAN, KM; STEGEMAN, CA; VANDEWIEL, BA; HACK, CE; BORNE, AEGKV; KALLENBERG, CGM; GOLDSCHMEDING, R

    1993-01-01

    In the sera of patients with Wegener's granulomatosis (WG), C-ANCA can be detected that are directed against proteinase 3 (PR3). We have previously observed that C-ANCA interfere with PR3 proteolytic activity and with complexation of PR3 with its major physiologic inhibitor, alpha1-antitrypsin (alph

  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 reg

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

    Institute of Scientific and Technical Information of China (English)

    Catherine; M; Greene; Noel; G; McElvaney

    2010-01-01

    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 def iciency 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 def iciency 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.

  10. Polymorphism of alpha 1 antitrypsin in North American species of Canis

    Science.gov (United States)

    Federoff, N.E.; Kueppers, F.

    2000-01-01

    a1-Antitrypsin (A1AT) is a major protease inhibitor present in all mammalian sera that have thus far been investigated. A1AT is also highly polymorphic and is therefore a useful genetic marker. Previously reported A1AT polymorphism in domestic dogs consisted of two alleles designated as PiM and PiS which exhibited frequencies of 0.72 and 0.28, respectively, in a group of randomly collected mongrel dogs. North American species of Canis, which included gray wolves (n=29), Mexican wolves (n=20), coyotes (n=24), wolfdog crosses (n=9), and red wolves (n=27) were tested for A1AT polymorphism. A1AT phenotypes were determined by isoelectric focusing, followed by direct immunoblotting using a specific antiserum. A1AT concentrations were determined by radial immunodiffusion. Concentrations of A1AT were similar to those found in domestic dogs (2.26 + 0.3 mg/ml SD) and tended to be higher in females than in males, possibly indicating that A1AT may be hormonally influenced in females. Three phenotypic band patterns were observed (M, MS, S). The allele frequencies for domestic dogs and gray wolves were very similar, 0.72 and 0.69 for PiM and 0.28 and 0.31 for PiS, respectively. The Mexican wolves had a significantly lower frequency of PiS= 0.10. Coyotes and red wolves were all found to be monomorphic for the PiS allele and were indistinguishable from each other in that respect.

  11. Understanding Lung Deposition of Alpha-1 Antitrypsin in Acute Experimental Mouse Lung Injury Model Using Fluorescence Microscopy

    Directory of Open Access Journals (Sweden)

    Mengmeng Wang

    2016-01-01

    Full Text Available Human plasma-derived α1-antitrypsin (AAT delivered by intravenous infusion is used as augmentation therapy in patients with emphysema who have a genetic mutation resulting in deficiency of AAT. Inhalation is an alternative route of administration that can potentially increase the efficacy and convenience of treatment. This study was conducted to determine whether delivery to the lungs, initially via the intratracheal (IT route of administration, would deliver efficacious levels of a recombinant AAT (rAAT to the site of action in the lungs in mice. 125I-radiolabeled rAAT, fluorophore-conjugated rAAT (rAAT-Alexa488, and NE680 (neutrophil elastase 680, a silent fluorescent substrate of neutrophil elastase which fluoresces in the near-infrared range upon activation by neutrophil elastase were used to characterize the pharmacokinetics and tissue distribution profile, distribution of rAAT within the lung, and efficacy of rAAT to inhibit neutrophil elastase at the site of action, respectively. The study has demonstrated that rAAT was able to gain access to locations where neutrophil elastase was localized. The histochemical quantification of rAAT activity relative to dose at the site of action provided here will improve confidence in predicting the human dose via the inhalation route.

  12. Prevalence of S and Z alpha 1-antitrypsin mutations in patients with pancreatic diseases in Serbian population

    Directory of Open Access Journals (Sweden)

    Nikolić Aleksandra

    2010-01-01

    Full Text Available One of the key points in research of pancreatic disease pathology is further elucidation of the role of proteases and antiproteases, since their imbalance can lead to pancreatic injury. Alpha 1-antitrypsin (AAT is one of the most important serum inhibitors of proteolytic enzymes, including pancreatic enzymes trypsin, chymotrypsin and elastase. It is speculated that mutations in the AAT gene may influence the onset and the development of pancreatic disease. The presence of the most common AAT mutations Z and S was analyzed in 160 patients with pancreatic diseases (50 patients with pancreatic cancer, 50 patients with chronic pancreatitis and 60 patients with type 2 diabetes mellitus and 129 healthy individuals by PCR-mediated site-directed mutagenesis (PSM method. One patient with pancreatic cancer was found to be a carrier of Z mutation, as well as one patient with type 2 diabetes mellitus. One patient with chronic pancreatitis was found to be a carrier of S mutation. The common AAT mutations were statistically significantly over-represented in patients with pancreatic diseases (3 of 160 patients, allelic frequency 0.9% than in the control group (1 of 129 individuals, allelic frequency 0.4%. The results of this study, requiring confirmation, suggest that common AAT mutations Z and S may be associated with a modest increase in susceptibility to the development of pancreatic disease.

  13. Validation and development of an immunonephelometric assay for the determination of alpha-1 antitrypsin levels in dried blood spots from patients with COPD

    Directory of Open Access Journals (Sweden)

    Laura Russo Zillmer

    2013-09-01

    Full Text Available OBJECTIVE: To validate and develop an immunonephelometric assay for the determination of alpha-1 antitrypsin (AAT levels in dried blood spots from COPD patients in Brazil. METHODS: We determined AAT levels in serum samples and dried blood spots from 192 COPD patients. For the preparation of dried blood spots, a disk (diameter, 6 mm was placed into a tube, eluted with 200 µL of PBS, and stored overnight at 4ºC. All of the samples were analyzed by immunonephelometry in duplicate. We used the bootstrap resampling method in order to determine a cut-off point for AAT levels in dried blood spots. RESULTS: The correlation coefficient between the AAT levels in serum samples and those in dried blood spots was r = 0.45. For dried blood spots, the cut-off value was 2.02 mg/dL (97% CI: 1.45-2.64 mg/dL, with a sensitivity, specificity, positive predictive value, and negative predictive value of 100%, 95.7%, 27.2%, and 100%, respectively. CONCLUSIONS: This method for the determination of AAT levels in dried blood spots appears to be a reliable screening tool for patients with AAT deficiency.

  14. 1H, 15N and 13C backbone resonance assignments of the archetypal serpin α1-antitrypsin.

    Science.gov (United States)

    Nyon, Mun Peak; Kirkpatrick, John; Cabrita, Lisa D; Christodoulou, John; Gooptu, Bibek

    2012-10-01

    Alpha(1)-antitrypsin is a 45-kDa (394-residue) serine protease inhibitor synthesized by hepatocytes, which is released into the circulatory system and protects the lung from the actions of neutrophil elastase via a conformational transition within a dynamic inhibitory mechanism. Relatively common point mutations subvert this transition, causing polymerisation of α(1)-antitrypsin and deficiency of the circulating protein, predisposing carriers to severe lung and liver disease. We have assigned the backbone resonances of α(1)-antitrypsin using multidimensional heteronuclear NMR spectroscopy. These assignments provide the starting point for a detailed solution state characterization of the structural properties of this highly dynamic protein via NMR methods.

  15. 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

  16. Causal and synthetic associations of variants in the SERPINA gene cluster with alpha1-antitrypsin serum levels.

    Directory of Open Access Journals (Sweden)

    Gian Andri Thun

    Full Text Available 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 onset chronic obstructive pulmonary disease (COPD. The role of more common SERPINA1 single nucleotide polymorphisms (SNPs in respiratory health remains poorly understood. We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS in 1392 individuals of the SAPALDIA cohort. Five common SNPs, defined by showing minor allele frequencies (MAFs >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of β = -0.068 g/L per minor allele (P = 1.20*10(-12. But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410, suggested that AAT serum level is causally determined at this locus by rare (MAF<1% and low-frequent (MAF 1-5% variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273 was successful (P<0.0001, as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57. Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397, associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene

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

    Science.gov (United States)

    Thun, Gian Andri; Kumar, Ashish; Obeidat, Ma'en; Zorzetto, Michele; Haun, Margot; Curjuric, Ivan; Couto Alves, Alexessander; Jackson, Victoria E.; Albrecht, Eva; Ried, Janina S.; Teumer, Alexander; Lopez, Lorna M.; Huffman, Jennifer E.; Enroth, Stefan; Bossé, Yohan; Hao, Ke; Timens, Wim; Gyllensten, Ulf; Polasek, Ozren; Wilson, James F.; Rudan, Igor; Hayward, Caroline; Sandford, Andrew J.; Deary, Ian J.; Koch, Beate; Reischl, Eva; Schulz, Holger; Hui, Jennie; James, Alan L.; Rochat, Thierry; Russi, Erich W.; Jarvelin, Marjo-Riitta; Strachan, David P.; Hall, Ian P.; Tobin, Martin D.; Dahl, Morten; Fallgaard Nielsen, Sune; Nordestgaard, Børge G.; Kronenberg, Florian; Luisetti, Maurizio; Probst-Hensch, Nicole M.

    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 onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood. We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort. Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of β = −0.068 g/L per minor allele (P = 1.20*10−12). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1–5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in

  18. Features of the milk whey protein partitioning in polyethyleneglycol-sodium citrate aqueous two-phase systems with the goal of isolating human alpha-1 antitrypsin expressed in bovine milk.

    Science.gov (United States)

    Boaglio, Andrea; Bassani, Georgina; Picó, Guillermo; Nerli, Bibiana

    2006-06-06

    Partitioning behaviour of the bovine whey proteins (bovine serum albumin, alpha-lactoalbumin and beta-lactoglobulin) and human alpha-1 antitrypsin in aqueous two-phase systems prepared with polyethyleneglycol (molecular masses: 1000, 1450 and 3350)-sodium citrate was analysed at pH 5.2, 6.2 and 8.2. Alpha lactoalbumin concentrated in the polyethyleneglycol rich-phase, while beta-lactoglobulin, bovine serum albumin and alpha-1 antitrypsin showed affinity for the citrate rich-phase. In aqueous two-phase systems of high medium pH and high polyethyleneglycol molecular mass the protein partitioning equilibrium is displaced to the citrate rich-phase. The polyethyleneglycol 1450-pH 5.2 system with a top/bottom phase-volume ratio of 3 showed to have the best capability of recovering the alpha-1 antitrypsin from a mixture prepared with natural milk whey and human alpha-1 antitrypsin. The recovery of this protein in the bottom phase was of 90% and the purity of the obtained product was of 98%. The method appears to be suitable as a starting point to isolate other human proteins expressed in transgenic bovine milk.

  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

    Two new nonradioactive polymerase chain reaction (PCR)-based assays for the Z and S mutations in the alpha 1-antitrypsin gene are presented. The assays take advantage of PCR-mediated mutagenesis, creating new diagnostic restriction enzyme sites for unambiguous discrimination between test samples...

  20. Evaluation of alpha 1-antitrypsin and the levels of mRNA expression of matrix metalloproteinase 7, urokinase type plasminogen activator receptor and COX-2 for the diagnosis of colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Luis Bujanda

    Full Text Available BACKGROUND: Colorectal cancer (CRC is the second most common cause of death from cancer in both men and women in the majority of developed countries. Molecular tests of blood could potentially provide this ideal screening tool. AIM: Our objective was to assess the usefulness of serum markers and mRNA expression levels in the diagnosis of CRC. METHODS: In a prospective study, we measured mRNA expression levels of 13 markers (carbonic anhydrase, guanylyl cyclase C, plasminogen activator inhibitor, matrix metalloproteinase 7 (MMP7, urokinase-type plasminogen activator receptor (uPAR, urokinase-type plasminogen activator, survivin, tetranectin, vascular endothelial growth factor (VEGF, cytokeratin 20, thymidylate synthase, cyclooxygenase 2 (COX-2, and CD44 and three proteins in serum (alpha 1 antitrypsin, carcinoembryonic antigen (CEA and activated C3 in 42 patients with CRC and 33 with normal colonoscopy results. RESULTS: Alpha 1-antitrypsin was the serum marker that was most useful for CRC diagnosis (1.79 ± 0.25 in the CRC group vs 1.27 ± 0.25 in the control group, P<0.0005. The area under the ROC curve for alpha 1-antitrypsin was 0.88 (0.79-0.96. The mRNA expression levels of five markers were statistically different between CRC cases and controls: those for which the ROC area was over 75% were MMP7 (0.81 and tetranectin (0.80, COX-2 (0.78, uPAR (0.78 and carbonic anhydrase (0.77. The markers which identified early stage CRC (Stages I and II were alpha 1-antitrypsin, uPAR, COX-2 and MMP7. CONCLUSIONS: Serum alpha 1-antitrypsin and the levels of mRNA expression of MMP7, COX-2 and uPAR have good diagnostic accuracy for CRC, even in the early stages.

  1. 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.

  2. The role and importance of glycosylation of acute phase proteins with focus on alpha-1 antitrypsin in acute and chronic inflammatory conditions.

    Science.gov (United States)

    McCarthy, Cormac; Saldova, Radka; Wormald, Mark R; Rudd, Pauline M; McElvaney, Noel G; Reeves, Emer P

    2014-07-03

    Acute phase proteins (APPs) are a group of circulating plasma proteins which undergo changes quantitatively or qualitatively at the time of inflammation. Many of these APPs are glycosylated, and it has been shown that alterations in glycosylation may occur in inflammatory and malignant conditions. Changes in glycosylation have been studied as potential biomarkers in cancer and also in chronic inflammatory conditions and have been shown to correlate with disease severity in certain conditions. Serine protease inhibitors (serpins), many of which are also APPs, are proteins involved in the control of proteases in numerous pathways. Alpha-1 Antitrypsin (AAT) is the most abundant serpin within the circulation and is an APP which has been shown to increase in response to inflammation. The primary role of AAT is maintaining the protease/antiprotease balance in the lung, but it also possesses important anti-inflammatory and immune-modulating properties. Several glycoforms of AAT exist, and they possess differing properties in regard to plasma half-life and stability. Glycosylation may also be important in determining the immune modulatory properties of AAT. The review will focus on the role and importance of glycosylation in acute phase proteins with particular attention to AAT and its use as a biomarker of disease. The review describes the processes involved in glycosylation, how glycosylation changes in differing disease states, and the alterations that occur to glycans of APPs with disease and inflammation. Finally, the review explores the importance of changes in glycosylation of AAT at times of inflammation and in malignant conditions and how this may impact upon the functions of AAT.

  3. Prevalence of the serpin peptidase inhibitor (alpha-1-antitrypsin PI*S and PI*Z alleles in Brazilian children with liver disease

    Directory of Open Access Journals (Sweden)

    Guilherme Baldo

    2008-01-01

    Full Text Available Serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin, member 1 (SERPINA1 deficiency is one of the main genetic causes related to liver disease in children. In SERPINA1 deficiency the most frequent SERPINA1 alleles found are the PI*S and PI*Z alleles. We used the polymerase chain reaction and the amplification created restriction site (ACRS technique to investigate the prevalence of the PI*S and PI*Z alleles in a group of Brazilian children (n = 200 with liver disease and established the general frequency of the PI*S allele in our population. We found a significant association of the PI*Z allele and liver disease, but no such relationship was found for the PI*S allele. Our results show that SERPINA1 deficiency due to the PI*Z allele, even when heterozygous, is a frequent cause of liver disease in our group of Brazilian children but that the PI*S allele does not confer an increased risk of hepatic disorders in our group of Brazilian children.

  4. Significance of correlation between levels of carcinoembryonic antigen and carbohydrate antigen 19-9, carcinoembryonic antigen and C-reactive protein, carcinoembryonic antigen and alpha-1 antitrypsin in gastric and colon cancer patients

    Directory of Open Access Journals (Sweden)

    Bhawna Bagaria

    2014-01-01

    Full Text Available Aim: Recent progress in proteomics studies profiled that serum proteins of cancer patients and those of normal individuals have altered cancer antigen and acute phase protein expression for distinct types and stages of cancer. In our study, correlation between carcinoembryonic antigen (CEA and carbohydrate antigen (CA 19-9, CEA and C-reactive protein (CRP, CEA and alpha-1 antitrypsin (A1AT were evaluated in gastric and colon cancer patients. Materials and Methods: CEA was estimated by solid phase, two-site sequential chemiluminescent immunometric assay, CA19-9 by solid phase enzyme-linked immunosorbent assay, CRP by latex turbidimetry method and A1AT by turbidimetry method. Results: A significant correlation was seen in levels of CEA and CA19-9 in gastric (r = 0.457, P < 0.001 and colon cancer (r = 0.451, P < 0.001 patients. Correlation between CEA and CRP was significant in gastric (r = 0.462, P < 0.001 and colon cancer (r = 0.759, P < 0.001 patients and between CEA and A1AT also, correlation was found to be significant in gastric (r = 0.631, P < 0.001 and colon cancer patients (r = 0.516, P ≤ 0.001. Conclusion: Serum acute-phase protein concentrations, when combined with CEA increases the sensitivity of CEA and provide substantial information concerning the diagnosis of gastrointestinal cancers. They have a definite role as a significant prognostic indicator which undoubtedly correlates with progression of cancer. Combined CEA and CA19-9 positivity reflected more biologic malignant properties and were significantly correlated with lymph node metastasis, hepatic metastasis and lower rates of curative resection. Surgical outcomes of patients who were CEA and CA19-9 positive were poorer than those of patients with normal CEA and CA19-9 levels.

  5. [Place of genotyping in addition to the phenotype and the assay of serum α-1 antitrypsin].

    Science.gov (United States)

    Joly, Philippe; Francina, Alain; Lacan, Philippe; Heraut, Jessica; Chapuis-Cellier, Colette

    2011-01-01

    The diagnosis of deficiency of alpha-1 antitrypsin (A1AT) is based on isoelectric focusing of serum proteins and the extent of serum. However, the focusing is technically difficult and a greatly reduced concentration in abnormal A1AT tapeless does not differentiate an unstable variant of a variant called 'null' (that is to say without any phenotypic expression) to 'heterozygous' state. In this study, we compared the results of the assay, the phenotype and genotype of A1AT in 50 patients. Normal A1AT alleles (Pi*M1 to Pi*M4) or loss of the most common (Pi*S and Pi*Z) were clearly identified in phenotyping. However, genotyping was necessary to characterize: (i) certain alleles rarer A1AT (S-Munich, X-Christchurch); (ii) a null allele and; (iii) two new alleles A1AT not yet described in the literature. In conclusion, although the A1AT genotyping is generally not necessary, it is necessary to resolve complex cases and to obtain witnesses validated for isoelectric focusing.

  6. Exploration of α1-Antitrypsin Treatment Protocol for Islet Transplantation: Dosing Plan and Route of Administration

    OpenAIRE

    Baranovski, Boris M.; Ozeri, Eyal; Shahaf, Galit; Ochayon, David E.; Schuster, Ronen; Bahar, Nofar; Kalay, Noa; Cal, Pablo; Mizrahi, Mark I.; Nisim, Omer; Strauss, Pnina; Schenker, Eran; Eli C Lewis

    2016-01-01

    Lifelong weekly infusions of human α1-antitrypsin (hAAT) are currently administered as augmentation therapy for patients with genetic AAT deficiency (AATD). Several recent clinical trials attempt to extend hAAT therapy to conditions outside AATD, including type 1 diabetes. Because the endpoint for AATD is primarily the reduction of risk for pulmonary emphysema, the present study explores hAAT dose protocols and routes of administration in attempt to optimize hAAT therapy for islet-related inj...

  7. Hypersensitivity Vasculitis with Leukocytoclastic Vasculitis Associated with Alpha-1-Proteinase Inhibitor

    Directory of Open Access Journals (Sweden)

    Nicola W. Mwirigi

    2009-01-01

    Full Text Available Prolastin is a commercially available form of alpha-1-antitrypsin (AAT that is derived from pooled human plasma and used for treatment of severe alpha-1-antitrypsin deficiency (AATD. We describe a patient with AATD who developed presumed hypersensitivity vasculitis (HV following a Prolastin infusion. Hypersensitivity vasculitis (HV, or cutaneous vasculitis, is characterized by inflammation of the small vessels of the skin with resultant ischemia to the distally supplied areas. To our knowledge, this is the first reported case of presumed hypersensitivity vasculitis following Prolastin infusion.

  8. Evaluación del efecto de la ingesta de una alta carga de ácidos grasos saturados sobre los niveles séricos de la proteína C reactiva, alfa1-antitripsina, fibrinógeno y alfa1-glicoproteína ácida en mujeres obesas Effect of a high saturated fatty acids load on serum concentrations of C-reactive protein, alpha1-antitrypsin, fibrinogen and alpha1-acid glycoprotein in obese women

    Directory of Open Access Journals (Sweden)

    M.ª M. Ramírez Alvarado

    2010-02-01

    en mujeres obesas. Los niveles séricos de PCR y fibrinógeno están incrementados en mujeres obesas y se correlacionan positivamente con el IMC.Obesity is associated with increased inflammation. Creactive protein (CRP and inflammation-sensitive plasma protein (ISPs are inflammatory markers. Proinflammatory process may be influenced by high saturated fatty acid intake. Objective: The aim of the present study was to evaluate the role of saturated fatty acids load on postprandial circulating levels of PCR and ISPs (alpha1-antitrypsin, alpha1-acid glucoprotein, and fibrinogen in obese women. Design: A total of 15 obese women (age = 31,7 ± 4,5 years, BMI = 37,9 ± 7,3 kg/m² and 15 lean controls women (age = 30,6 ± 4,6 years, BMI = 20,6 ± 2,6 kg/m² were recruited for this study. After and overnight fast subjects ate the fat load consisted of 75 g of fat (100% saturated fatty acid, 0% cholesterol, 5 g of carbohydrates, and 6 g of protein per m2 body surface area. Postprandial serum levels of CRP, alpha1-antitrypsin, alpha1-acid glucoprotein, and fibrinogen were measured. Anthropometry and blood biochemical parameters were measured in both groups. Results: The obese women had fasting serum PCR levels higher (p = 0,013 and fibrinogen (p = 0,04 than those of control women. Serum CRP and fibrinogen levels was positively related to body mass index (BMI in obese group. There weren't differences in fasting serum alpha1- antitrypsin levels (p = 0,40, and alpha1-acid glucoprotein (p = 0,28 levels in obese group in comparison to lean control group. Serum CRP, alpha1-antitrypsin, alpha1-acid glucoprotein, and fibrinogen did not change postprandially (p = > 0,05 difference to fasting levels. Conclusion: A high-saturated fatty acids load is not associated with serum CRP, alpha1-antitrypsin, alpha1-acid glucoprotein, and fibrinogen levels increase. Serum alpha1-antitripsin and alpha1-acid glucoprotein levels are not increased in obese women. Serum PCR and fibrinogen levels are

  9. 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...

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

    DEFF Research Database (Denmark)

    Gøtzsche, Peter C; Johansen, Helle Krogh

    2010-01-01

    trials were included with a total of 140 patients. The trials ran for two to three years. Mortality data were not reported. There was no information on harms in the first trial; in the second trial, serious adverse events were reported in ten of 38 patients in the drug group and in 18 of 39 patients...

  11. 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.

  12. Alpha-1-antitripsin deficiency: the need of a new diagnostic algorithm for improving the diagnostic ability of perinatologists and pediatricians

    Directory of Open Access Journals (Sweden)

    Gavino Faa

    2015-02-01

    Full Text Available Caution should be taken in considering immunoelectrofocusing (IEF as the best method for the diagnosis of alpha-1-antitrypsin (A1AT deficiency, particularly in some population, including Sardinians, in which a M-like variant represents the most frequent pathological A1AT variant. Regarding the future, my opinion is that the algorithm generally suggested for reaching a proper diagnosis of this disease should be completely changed. The cut-off of the A1AT serum values should be reconsidered, not to avoid the diagnosis of a number of heterozygous subjects who may be affected by liver and/or lung disease. Given that the two A1AT alleles are co-dominant, and since A1AT is a phase acute protein, in all heterozygous PiMZ or PiM/M-Cagliari subjects carrying an inflammation, the M allele is induced to produce high quantities of A1AT, whose serum levels may reach normal values. In these cases, PCR serum levels should be evaluated and, when increased, the diagnosis of A1AT deficiency should not be excluded even in the presence of serum A1AT levels within the normal range. Gene sequencing should be included, on the basis of our experience, in all neonates and pediatric patients with liver or lung disease of unknown origin, including asthma, avoiding IEF. Finally, for a screening in the perinatal period, I suggest the accurate examination of the electrophoresis of serum proteins. With a similar new approach, I think that we will transform A1AT deficiency from a rare disease into a previously rarely diagnosed disease, changing completely the epidemiology of this complex and fascinating metabolic disease.

  13. Associação entre deficiência de alfa-1-antitripsina e a gravidade da fibrose cística Association between alpha 1 antitrypsin deficiency and cystic fibrosis severity

    OpenAIRE

    2005-01-01

    OBJETIVO: Verificar a distribuição dos genótipos da alfa-1-antitripsina e correlacionar com a gravidade da doença pulmonar em pacientes fibrocísticos. MÉTODO: Estudo clínico-laboratorial de corte transversal, com 70 pacientes fibrocísticos do Hospital Universitário da UNICAMP. Os fibrocísticos tiveram diagnóstico confirmado clínica e laboratorialmente. A gravidade da fibrose cística foi avaliada pelo escore de Shwachman. Todos os pacientes foram analisados para os alelos S e Z de alfa-1-antit...

  14. 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

  15. Prolastin, a pharmaceutical preparation of purified human α1-antitrypsin, blocks endotoxin-mediated cytokine release

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    Westin Ulla

    2005-01-01

    Full Text Available Abstract Background α1-antitrypsin (AAT serves primarily as an inhibitor of the elastin degrading proteases, neutrophil elastase and proteinase 3. There is ample clinical evidence that inherited severe AAT deficiency predisposes to chronic obstructive pulmonary disease. Augmentation therapy for AAT deficiency has been available for many years, but to date no sufficient data exist to demonstrate its efficacy. There is increasing evidence that AAT is able to exert effects other than protease inhibition. We investigated whether Prolastin, a preparation of purified pooled human AAT used for augmentation therapy, exhibits anti-bacterial effects. Methods Human monocytes and neutrophils were isolated from buffy coats or whole peripheral blood by the Ficoll-Hypaque procedure. Cells were stimulated with lipopolysaccharide (LPS or zymosan, either alone or in combination with Prolastin, native AAT or polymerised AAT for 18 h, and analysed to determine the release of TNFα, IL-1β and IL-8. At 2-week intervals, seven subjects were submitted to a nasal challenge with sterile saline, LPS (25 μg and LPS-Prolastin combination. The concentration of IL-8 was analysed in nasal lavages performed before, and 2, 6 and 24 h after the challenge. Results In vitro, Prolastin showed a concentration-dependent (0.5 to 16 mg/ml inhibition of endotoxin-stimulated TNFα and IL-1β release from monocytes and IL-8 release from neutrophils. At 8 and 16 mg/ml the inhibitory effects of Prolastin appeared to be maximal for neutrophil IL-8 release (5.3-fold, p Conclusion Our data demonstrate for the first time that Prolastin inhibits bacterial endotoxin-induced pro-inflammatory responses in vitro and in vivo, and provide scientific bases to explore new Prolastin-based therapies for individuals with inherited AAT deficiency, but also for other clinical conditions.

  16. The Z Mutation Alters the Global Structural Dynamics of α1-Antitrypsin

    Science.gov (United States)

    Hughes, Victoria A.; Meklemburg, Robert; Bottomley, Stephen P.; Wintrode, Patrick L.

    2014-01-01

    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. PMID:25181470

  17. 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.

  18. Automated high-content live animal drug screening using C. elegans expressing the aggregation prone serpin α1-antitrypsin Z.

    Directory of Open Access Journals (Sweden)

    Sager J Gosai

    Full Text Available The development of preclinical models amenable to live animal bioactive compound screening is an attractive approach to discovering effective pharmacological therapies for disorders caused by misfolded and aggregation-prone proteins. In general, however, live animal drug screening is labor and resource intensive, and has been hampered by the lack of robust assay designs and high throughput work-flows. Based on their small size, tissue transparency and ease of cultivation, the use of C. elegans should obviate many of the technical impediments associated with live animal drug screening. Moreover, their genetic tractability and accomplished record for providing insights into the molecular and cellular basis of human disease, should make C. elegans an ideal model system for in vivo drug discovery campaigns. The goal of this study was to determine whether C. elegans could be adapted to high-throughput and high-content drug screening strategies analogous to those developed for cell-based systems. Using transgenic animals expressing fluorescently-tagged proteins, we first developed a high-quality, high-throughput work-flow utilizing an automated fluorescence microscopy platform with integrated image acquisition and data analysis modules to qualitatively assess different biological processes including, growth, tissue development, cell viability and autophagy. We next adapted this technology to conduct a small molecule screen and identified compounds that altered the intracellular accumulation of the human aggregation prone mutant that causes liver disease in α1-antitrypsin deficiency. This study provides powerful validation for advancement in preclinical drug discovery campaigns by screening live C. elegans modeling α1-antitrypsin deficiency and other complex disease phenotypes on high-content imaging platforms.

  19. α1-Antitrypsin Activates Protein Phosphatase 2A to Counter Lung Inflammatory Responses

    Science.gov (United States)

    Geraghty, Patrick; Eden, Edward; Pillai, Manju; Campos, Michael; McElvaney, Noel G.

    2014-01-01

    Rationale: α1-Antitrypsin (A1AT) was identified as a plasma protease inhibitor; however, it is now recognized as a multifunctional protein that modulates immunity, inflammation, proteostasis, apoptosis, and cellular senescence. Like A1AT, protein phosphatase 2A (PP2A), a major serine-threonine phosphatase, regulates similar biologic processes and plays a key role in chronic obstructive pulmonary disease. Objectives: Given their common effects, this study investigated whether A1AT acts via PP2A to alter tumor necrosis factor (TNF) signaling, inflammation, and proteolytic responses in this disease. Methods: PP2A activity was measured in peripheral blood neutrophils from A1AT-deficient (PiZZ) and healthy (PiMM) individuals and in alveolar macrophages from normal (60 mg/kg) and high-dose (120 mg/kg) A1AT-treated PiZZ subjects. PP2A activation was assessed in human neutrophils, airway epithelial cells, and peripheral blood monocytes treated with plasma purified A1AT protein. Similarly, lung PP2A activity was measured in mice administered intranasal A1AT. PP2A was silenced in lung epithelial cells treated with A1AT and matrix metalloproteinase and cytokine production was then measured following TNF-α stimulation. Measurements and Main Results: PP2A was significantly lower in neutrophils isolated from PiZZ compared with PiMM subjects. A1AT protein activated PP2A in human alveolar macrophages, monocytes, neutrophils, airway epithelial cells, and in mouse lungs. This activation required functionally active A1AT protein and protein tyrosine phosphatase 1B expression. A1AT treatment acted via PP2A to prevent p38 and IκBα phosphorylation and matrix metalloproteinase and cytokine induction in TNF-α–stimulated epithelial cells. Conclusions: Together, these data indicate that A1AT modulates PP2A to counter inflammatory and proteolytic responses induced by TNF signaling in the lung. PMID:25341065

  20. Exploration of α1-antitrypsin treatment protocol for islet transplantation: dosing plan and route of administration.

    Science.gov (United States)

    Baranovski, Boris M; Ozeri, Eyal; Shahaf, Galit; Ochayon, David E; Schuster, Ronen; Bahar, Nofar; Kalay, Noa; Cal, Pablo; Mizrahi, Mark I; Nisim, Omer; Strauss, Pnina; Schenker, Eran; Lewis, Eli C

    2016-11-07

    Life-long weekly infusions of human α1-antitrypsin (hAAT) are currently administered as augmentation therapy for patients with genetic AAT deficiency (AATD). Several recent clinical trials attempt to extend hAAT therapy to conditions outside AATD, including type 1 diabetes. Since the endpoint for AATD is primarily the reduction of risk for pulmonary emphysema, the present study explores hAAT dose protocols and routes of administration in attempt to optimize hAAT therapy for islet-related injury. Islet-grafted mice were treated with hAAT (Glassia™; i.p. or s.c.) under an array of clinically relevant dosing plans. Serum hAAT and immunocyte cell membrane association were examined, as well as parameters of islet survival. Results indicate that dividing the commonly prescribed 60 mg/kg i.p. dose to three 20 mg/kg injections is superior in affording islet graft survival; in addition, a short dynamic descending dose protocol (240→120→60→60 mg/kg i.p.) is comparable in outcomes to indefinite 60 mg/kg injections. While hAAT pharmacokinetics after i.p. administration in mice resembles exogenous hAAT treatment in humans, s.c. administration better imitated the physiological progressive rise of hAAT during acute phase responses; nonetheless, only the 60 mg/kg dose depicted an advantage using the s.c. route. Taken together, this study provides a platform for extrapolating an islet-relevant clinical protocol from animal models that use hAAT to protect islets. In addition, the study places emphasis on outcome-oriented analyses of drug efficacy, particularly important when considering that hAAT is presently at an era of drug-repurposing towards an extended list of clinical indications outside genetic AATD.

  1. α1-Antitrypsin Activates Protein Phosphatase 2A to Counter Lung Inflammatory Responses

    OpenAIRE

    Geraghty, Patrick; Eden, Edward; Pillai, Manju; Campos, Michael; McElvaney, Noel G; Foronjy, Robert F.

    2014-01-01

    Rationale: α1-Antitrypsin (A1AT) was identified as a plasma protease inhibitor; however, it is now recognized as a multifunctional protein that modulates immunity, inflammation, proteostasis, apoptosis, and cellular senescence. Like A1AT, protein phosphatase 2A (PP2A), a major serine-threonine phosphatase, regulates similar biologic processes and plays a key role in chronic obstructive pulmonary disease.

  2. 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.

  3. 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

  4. A single-chain variable fragment intrabody prevents intracellular polymerization of Z α1-antitrypsin while allowing its antiproteinase activity.

    Science.gov (United States)

    Ordóñez, Adriana; Pérez, Juan; Tan, Lu; Dickens, Jennifer A; Motamedi-Shad, Neda; Irving, James A; Haq, Imran; Ekeowa, Ugo; Marciniak, Stefan J; Miranda, Elena; Lomas, David A

    2015-06-01

    Mutant Z α1-antitrypsin (E342K) accumulates as polymers within the endoplasmic reticulum (ER) of hepatocytes predisposing to liver disease, whereas low levels of circulating Z α1-antitrypsin lead to emphysema by loss of inhibition of neutrophil elastase. The ideal therapy should prevent polymer formation while preserving inhibitory activity. Here we used mAb technology to identify interactors with Z α1-antitrypsin that comply with both requirements. We report the generation of an mAb (4B12) that blocked α1-antitrypsin polymerization in vitro at a 1:1 molar ratio, causing a small increase of the stoichiometry of inhibition for neutrophil elastase. A single-chain variable fragment (scFv) intrabody was generated based on the sequence of mAb4B12. The expression of scFv4B12 within the ER (scFv4B12KDEL) and along the secretory pathway (scFv4B12) reduced the intracellular polymerization of Z α1-antitrypsin by 60%. The scFv4B12 intrabody also increased the secretion of Z α1-antitrypsin that retained inhibitory activity against neutrophil elastase. MAb4B12 recognized a discontinuous epitope probably located in the region of helices A/C/G/H/I and seems to act by altering protein dynamics rather than binding preferentially to the native state. This novel approach could reveal new target sites for small-molecule intervention that may block the transition to aberrant polymers without compromising the inhibitory activity of Z α1-antitrypsin.

  5. Laminin alpha2 chain-deficient congenital muscular dystrophy: variable epitope expression in severe and mild cases

    DEFF Research Database (Denmark)

    Cohn, R D; Herrmann, R; Sorokin, L;

    1998-01-01

    To characterize the expression of distinct fragments of laminin alpha2 chain in patients with partial laminin alpha2 chain deficiency and variable clinical severity.......To characterize the expression of distinct fragments of laminin alpha2 chain in patients with partial laminin alpha2 chain deficiency and variable clinical severity....

  6. 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...

  7. Acute myocardial ischemia in a patient with heterozygous alpha-2-plasmin inhibitor deficiency

    NARCIS (Netherlands)

    Brands-Nijenhuis, Angelique V. M.; van Geel, Peter P.; Meijer, Karina

    2009-01-01

    In this brief report we present a patient with heterozygous alpha 2 plasmin inhibitor (alpha 2PI) deficiency who developed atherosclerosis and myocardial ischemia in the presence of multiple classical risk factors. Management was complicated by fear of bleeding complications with the use of antiplat

  8. Laminin alpha2 deficiency and muscular dystrophy; genotype-phenotype correlation in mutant mice

    DEFF Research Database (Denmark)

    Guo, L T; Zhang, X U; Kuang, W;

    2003-01-01

    Deficiency of laminin alpha2 is the cause of one of the most severe muscular dystrophies in humans and other species. It is not yet clear how particular mutations in the laminin alpha2 chain gene affect protein expression, and how abnormal levels or structure of the protein affect disease. Animal...... models may be valuable for such genotype-phenotype analysis and for determining mechanism of disease as well as function of laminin. Here, we have analyzed protein expression in three lines of mice with mutations in the laminin alpha2 chain gene and in two lines of transgenic mice overexpressing...... the human laminin alpha2 chain gene in skeletal muscle. The dy(3K)/dy(3K) experimental mutant mice are completely deficient in laminin alpha2; the dy/dy spontaneous mutant mice have small amounts of apparently normal laminin; and the dy(W)/dy(W) mice express even smaller amounts of a truncated laminin alpha...

  9. The roles of helix I and strand 5A in the folding, function and misfolding of α1-antitrypsin.

    Directory of Open Access Journals (Sweden)

    Anja S Knaupp

    Full Text Available α(1-Antitrypsin, the archetypal member of the serpin superfamily, is a metastable protein prone to polymerization when exposed to stressors such as elevated temperature, low denaturant concentrations or through the presence of deleterious mutations which, in a physiological context, are often associated with disease. Experimental evidence suggests that α(1-Antitrypsin can polymerize via several alternative mechanisms in vitro. In these polymerization mechanisms different parts of the molecule are proposed to undergo conformational change. Both strand 5 and helix I are proposed to adopt different conformations when forming the various polymers, and possess a number of highly conserved residues however their role in the folding and misfolding of α(1-Antitrypsin has never been examined. We have therefore created a range of α(1Antitypsin variants in order to explore the role of these conserved residues in serpin folding, misfolding, stability and function. Our data suggest that key residues in helix I mediate efficient folding from the folding intermediate and residues in strand 5A ensure native state stability in order to prevent misfolding. Additionally, our data indicate that helix I is involved in the inhibitory process and that both structural elements undergo differing conformational rearrangements during unfolding and misfolding. These findings suggest that the ability of α(1-Antitrypsin to adopt different types of polymers under different denaturing conditions may be due to subtle conformational differences in the transiently populated structures adopted prior to the I and M* states.

  10. 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

  11. Deficient attention modulation of lateralized alpha power in schizophrenia.

    Science.gov (United States)

    Kustermann, Thomas; Rockstroh, Brigitte; Kienle, Johanna; Miller, Gregory A; Popov, Tzvetan

    2016-06-01

    Modulation of 8-14 Hz (alpha) activity in posterior brain regions is associated with covert attention deployment in visuospatial tasks. Alpha power decrease contralateral to to-be-attended stimuli is believed to foster subsequent processing, such as retention of task-relevant input. Degradation of this alpha-regulation mechanism may reflect an early stage of disturbed attention regulation contributing to impaired attention and working memory commonly found in schizophrenia. The present study tested this hypothesis of early disturbed attention regulation by examining alpha power modulation in a lateralized cued delayed response task in 14 schizophrenia patients (SZ) and 25 healthy controls (HC). Participants were instructed to remember the location of a 100-ms saccade-target cue in the left or right visual hemifield in order to perform a delayed saccade to that location after a retention interval. As expected, alpha power decrease during the retention interval was larger in contralateral than ipsilateral posterior regions, and SZ showed less of this lateralization than did HC. In particular, SZ failed to show hemifield-specific alpha modulation in posterior right hemisphere. Results suggest less efficient modulation of alpha oscillations that are considered critical for attention deployment and item encoding and, hence, may affect subsequent spatial working memory performance.

  12. Neutron and Alpha Structure in Neutron Deficient Nuclei in Astrophysics

    Institute of Scientific and Technical Information of China (English)

    S. Kubono; T. Hashimoto; Y. Wakabayashi; N. Iwasa; S. Kato; T. Komatsubara; D. N. Binh; L. H. Khiem; N. N. Duy; T. Kawabata; C. Spitaleri; 何建军; G. G. Rapisarda; M. La Cognata; L. Lamia; R. G. Pizzone; S. Romano; A. Coc; N. de Sereville; F. Hammache; G. Kiss; S. Bishop; H. Yamaguchi; D. M. Kahl; S. Hayakawa; T. Teranishi; S. Cheribini; M. Gulino; Y. K. Kwon

    2016-01-01

    The paper includes discussions on the important role of neutron and alpha configurations in proton-rich nuclei in nuclear astrophysics in terms of nucleosynthesis under extremely high-temperature hydrogenburning conditions. The νp-process, which is supposed to take place at the very early epoch of type II supernovae, has considerable neutrons and alphas together with protons. The alpha-induced reactions on proton-rich unstable nuclei in the light mass regions is expected to play a crucial role, but very few of them were investigated well yet because of the experimental difficulties. Specifically, I report our recent experimental effort for the breakout process from the pp-chain region, 7Be(α,γ)11C(α,p)14N under the νp-process. The neutron-induced reactions on proton-rich nuclei, which is even more a challenging subject, were investigated previously for very few nuclei. One possible experimental method is the Trojan Horse Method (THM). We successfully have applied THM to the 18F(n,α)14N reaction study with an unstable beam of 18F.

  13. Fecal calprotectin and α1-antitrypsin dynamics in gastrointestinal GvHD.

    Science.gov (United States)

    O'Meara, A; Kapel, N; Xhaard, A; Sicre de Fontbrune, F; Manéné, D; Dhedin, N; de Latour, R P; Socié, G; Robin, M

    2015-08-01

    In a previous study, the fecal biomarkers calprotectin and α1-antitrypsin (α1-AT) at symptom onset were reported to be significantly associated with the response to steroids in gastrointestinal GvHD (GI-GvHD). The purpose of this trial was to evaluate the dynamics of the fecal biomarkers calprotectin and α1-AT throughout the course of GvHD. Patients who were refractory to steroids had initially higher biomarker levels and in the course of GvHD demonstrated a continuous increase in fecal biomarkers. In contrast, the dynamics of calprotectin and α1-AT demonstrated low and decreasing levels in cortico-sensitive GvHD. In steroid-refractory patients who received a second line of treatment, the biomarker levels at the beginning of second-line treatment did not predict the subsequent response. Nevertheless, calprotectin levels progressively decreased in subsequent responders, whereas non-responders demonstrated continuously high levels of calprotectin. α1-AT values correlated to a lesser extent with the response to second-line treatment and remained elevated in both non-responders and responders. In conclusion, calprotectin monitoring can be of use in the management of immunosuppressive treatment in GI-GvHD.

  14. Response to Stress in 17 alpha-hydroxylase Deficient Common Carp (Cyprinus carpio L.)

    NARCIS (Netherlands)

    Nematollahi, M.A.; Pelt, van H.; Komen, J.

    2013-01-01

    The aim of this study was to analyze the stress response during 3 hours net confinement stress and recovery period of 22 hours in normal (STD) and in 17 alpha-hydroxylase deficient common carp (E5). Fish were raised for 6 months and sampled at T-0 (control, unstressed), 5 minutes, 20 minutes, 1 hour

  15. Phytanic acid alpha-oxidase deficiency (Refsum disease) presenting in infancy.

    Science.gov (United States)

    Herbert, M A; Clayton, P T

    1994-01-01

    This report describes a patient with high serum phytanic acid concentration due to phytanic acid alpha-oxidase deficiency (classical Refsum disease). He presented unusually early, hypotonia and developmental delay being apparent by 7 months. A generalized peroxisomal disorder (so-called 'infantile Refsum disease') was excluded by analyses of pristanic acid, very long-chain fatty acids, bile acids and plasmalogen synthesis. The early presentation raises the possibility of in utero exposure to phytanate.

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

    Institute of Scientific and Technical Information of China (English)

    Hui Zhao; Hong Liu; Lin Chai; Ping Xu; Lu Hua; Xiao-Yuan Guan; Bing Duan

    2015-01-01

    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 [CO: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.

  17. 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.

  18. Quantitation of residual trypsin in cell-based therapeutics using immobilized α-1-antitrypsin or SBTI in an ELISA format.

    Science.gov (United States)

    Braatz, James A; Elias, Christopher; Finny, Joseph G; Tran, Huan; McCaman, Michael

    2015-02-01

    An Enzyme-Linked Immunosorbent Assay (ELISA) has been developed for the quantitation of porcine trypsin as a process residual in cell therapy products based on its capture by either of two immobilized anti-trypsins, α-1-antitrypsin (α1AT) or soybean trypsin inhibitor (SBTI) followed by detection with a polyclonal goat anti-porcine trypsin-IgG conjugated with peroxidase. It was demonstrated that an extended range of antigen quantitation could be achieved that covered nearly three orders of magnitude of trypsin concentration. The utility of the assay was demonstrated by its application to samples generated in a cell-based therapeutic manufacturing setting.

  19. TNF-{alpha} mediates the stimulation of sclerostin expression in an estrogen-deficient condition

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Beom-Jun [Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap2-Dong, Seoul (Korea, Republic of); Bae, Sung Jin [Health Promotion Center, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap2-Dong, Seoul (Korea, Republic of); Lee, Sun-Young; Lee, Young-Sun; Baek, Ji-Eun; Park, Sook-Young [Asan Institute for Life Sciences, 388-1 Poongnap2-Dong, Seoul (Korea, Republic of); Lee, Seung Hun [Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap2-Dong, Seoul (Korea, Republic of); Koh, Jung-Min, E-mail: jmkoh@amc.seoul.kr [Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap2-Dong, Seoul (Korea, Republic of); Kim, Ghi Su [Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap2-Dong, Seoul (Korea, Republic of)

    2012-07-20

    Highlights: Black-Right-Pointing-Pointer Estrogen deprivation stimulates the bony sclerostin levels with reversal by estrogen. Black-Right-Pointing-Pointer TNF-{alpha} increases the activity and expression of MEF2 in UMR-106 cells. Black-Right-Pointing-Pointer TNF-{alpha} blocker prevents the stimulation of bony sclerostin expression by ovariectomy. Black-Right-Pointing-Pointer No difference in bony sclerostin expression between sham-operated and ovariectomized nude mice. -- Abstract: Although recent clinical studies have suggested a possible role for sclerostin, a secreted Wnt antagonist, in the pathogenesis of postmenopausal osteoporosis, the detailed mechanisms how estrogen deficiency regulates sclerostin expression have not been well-elucidated. Bilateral ovariectomy or a sham operation in female C57BL/6 mice and BALB/c nude mice was performed when they were seven weeks of age. The C57BL/6 mice were intraperitoneally injected with phosphate-buffered serum (PBS), 5 {mu}g/kg {beta}-estradiol five times per week for three weeks, or 10 mg/kg TNF-{alpha} blocker three times per week for three weeks. Bony sclerostin expression was assessed by immunohistochemistry staining in their femurs. The activity and expression of myocyte enhancer factors 2 (MEF2), which is essential for the transcriptional activation of sclerostin, in rat UMR-106 osteosarcoma cells were determined by luciferase reporter assay and western blot analysis, respectively. Bony sclerostin expression was stimulated by estrogen deficiency and it was reversed by estradiol supplementation. When the UMR-106 cells were treated with well-known, estrogen-regulated cytokines, only TNF-{alpha}, but not IL-1 and IL-6, increased the MEF2 activity. Consistently, TNF-{alpha} also increased the nuclear MEF2 expression. Furthermore, the TNF-{alpha} blocker prevented the stimulation of bony sclerostin expression by ovariectomy. We also found that there was no difference in sclerostin expression between ovariectomized

  20. α-1-Antitrypsin detected by MALDI imaging in the study of glomerulonephritis: Its relevance in chronic kidney disease progression.

    Science.gov (United States)

    Smith, Andrew; L'Imperio, Vincenzo; De Sio, Gabriele; Ferrario, Franco; Scalia, Carla; Dell'Antonio, Giacomo; Pieruzzi, Federico; Pontillo, Claudia; Filip, Szymon; Markoska, Katerina; Granata, Antonio; Spasovski, Goce; Jankowski, Joachim; Capasso, Giovambattista; Pagni, Fabio; Magni, Fulvio

    2016-06-01

    Idiopathic glomerulonephritis (GN), such as membranous glomerulonephritis, focal segmental glomerulosclerosis (FSGS), and IgA nephropathy (IgAN), represent the most frequent primary glomerular kidney diseases (GKDs) worldwide. Although the renal biopsy currently remains the gold standard for the routine diagnosis of idiopathic GN, the invasiveness and diagnostic difficulty related with this procedure highlight the strong need for new diagnostic and prognostic biomarkers to be translated into less invasive diagnostic tools. MALDI-MS imaging MALDI-MSI was applied to fresh-frozen bioptic renal tissue from patients with a histological diagnosis of FSGS (n = 6), IgAN, (n = 6) and membranous glomerulonephritis (n = 7), and from controls (n = 4) in order to detect specific molecular signatures of primary glomerulonephritis. MALDI-MSI was able to generate molecular signatures capable to distinguish between normal kidney and pathological GN, with specific signals (m/z 4025, 4048, and 4963) representing potential indicators of chronic kidney disease development. Moreover, specific disease-related signatures (m/z 4025 and 4048 for FSGS, m/z 4963 and 5072 for IgAN) were detected. Of these signals, m/z 4048 was identified as α-1-antitrypsin and was shown to be localized to the podocytes within sclerotic glomeruli by immunohistochemistry. α-1-Antitrypsin could be one of the markers of podocyte stress that is correlated with the development of FSGS due to both an excessive loss and a hypertrophy of podocytes.

  1. 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

  2. Alpha decay as a probe for the structure of neutron-deficient nuclei

    CERN Document Server

    Qi, Chong

    2016-01-01

    The advent of radioactive ion beam facilities and new detector technologies have opened up new possibilities to investigate the radioactive decays of highly unstable nuclei, in particular the proton emission, $\\alpha$ decay and heavy cluster decays from neutron-deficient (or proton-rich) nuclei around the proton drip line. It turns out that these decay measurements can serve as a unique probe for studying the structure of the nuclei involved. On the theoretical side, the development in nuclear many-body theories and supercomputing facilities have also made it possible to simulate the nuclear clusterization and decays from a microscopic and consistent perspective. In this article we would like to review the current status of these structure and decay studies in heavy nuclei, regarding both experimental and theoretical opportunities. We then discuss in detail the recent progress in our understanding of the nuclear $\\alpha$ formation probabilities in heavy nuclei and their indication on the underlying nuclear st...

  3. Identification of the novel autoantigen candidate Rab GDP dissociation inhibitor alpha in isolated adrenocorticotropin deficiency.

    Science.gov (United States)

    Kiyota, Atsushi; Iwama, Shintaro; Sugimura, Yoshihisa; Takeuchi, Seiji; Takagi, Hiroshi; Iwata, Naoko; Nakashima, Kohtaro; Suzuki, Haruyuki; Nishioka, Tomoki; Kato, Takuya; Enomoto, Atsushi; Arima, Hiroshi; Kaibuchi, Kozo; Oiso, Yutaka

    2015-01-01

    Isolated adrenocorticotropin deficiency (IAD) is characterized by low or absent adrenocorticotropic hormone (ACTH) production. IAD is presumed to be caused in part by an autoimmune mechanism, and several lines of evidence have suggested the presence of anti-pituitary antibodies in IAD. However, the exact autoantigens remain unknown. The present study was designed to identify the autoantigen(s) in IAD using chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Rat anterior pituitary lysate was subjected to SDS-PAGE, and immunoblotting was performed using the sera from two patients with IAD and from a healthy subject. The bands detected by the patient serum samples, but not by the healthy subject sample, were excised, in-gel digested using trypsin, and subjected to LC-MS/MS analysis. On immunoblots, a 51-kDa band in the insoluble pellet was detected by the sera from the IAD patients but not from the healthy subject. Mass spectrometric analysis revealed the 51-kDa band contained Rab guanine nucleotide dissociation inhibitor (GDI) alpha. Consistent with the mass spectrometric analysis, a recombinant full-length human Rab GDI alpha was recognized by the two IAD patient samples but not by the healthy subject sample using immunoblotting. In total, anti-Rab GDI alpha antibodies were detected in serum samples from three of five patients with IAD (60%) but were absent in 5 healthy subjects. In addition, Rab GDI alpha was expressed in the anterior pituitary. In conclusion, it appears that Rab GDI alpha is a candidate autoantigen involved in IAD, and that anti-Rab GDI alpha antibodies are present predominantly in patients with IAD.

  4. Globotriaosylsphingosine accumulation and not alpha-galactosidase-A deficiency causes endothelial dysfunction in Fabry disease.

    Directory of Open Access Journals (Sweden)

    Mehdi Namdar

    Full Text Available BACKGROUND: Fabry disease (FD is caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (GLA resulting in the accumulation of globotriaosylsphingosine (Gb3 in a variety of tissues. While GLA deficiency was always considered as the fulcrum of the disease, recent attention shifted towards studying the mechanisms through which Gb3 accumulation in vascular cells leads to endothelial dysfunction and eventually multiorgan failure. In addition to the well-described macrovascular disease, FD is also characterized by abnormalities of microvascular function, which have been demonstrated by measurements of myocardial blood flow and coronary flow reserve. To date, the relative importance of Gb3 accumulation versus GLA deficiency in causing endothelial dysfunction is not fully understood; furthermore, its differential effects on cardiac micro- and macrovascular endothelial cells are not known. METHODS AND RESULTS: In order to assess the effects of Gb3 accumulation versus GLA deficiency, human macro- and microvascular cardiac endothelial cells (ECs were incubated with Gb3 or silenced by siRNA to GLA. Gb3 loading caused deregulation of several key endothelial pathways such as eNOS, iNOS, COX-1 and COX-2, while GLA silencing showed no effects. Cardiac microvascular ECs showed a greater susceptibility to Gb3 loading as compared to macrovascular ECs. CONCLUSIONS: Deregulation of key endothelial pathways as observed in FD vasculopathy is likely caused by intracellular Gb3 accumulation rather than deficiency of GLA. Human microvascular ECs, as opposed to macrovascular ECs, seem to be affected earlier and more severely by Gb3 accumulation and this notion may prove fundamental for future progresses in early diagnosis and management of FD patients.

  5. 17-Alpha Hydroxylase Deficiency: A Rare Case of Primary Amenorrhea and Hypertension

    Directory of Open Access Journals (Sweden)

    Yasin Şimşek

    2014-12-01

    Full Text Available 17-alpha hydroxylase deficiency (17OHD is an uncommon cause of congenital adrenal hyperplasia (CAH resulting from mutation in the CYP17 gene. It is an autosomal recessive disease leading to the deficiency of enzyme activity which results in impaired synthesis of cortisol, androgen and sex steroids. A 35-year-old woman was admitted to the hospital with hypokalemia, weakness, and fatigue. Medical history revealed two attempts of in vitro fertilization (IVF without achieving pregnancy. Laboratory evaluation showed hypokalemia, hypocortisolemia, hypergonadotropic hypogonadism and increased levels of 11-deoxycorticosterone. Her karyotype was 46XX. The patient had no history of menarche. She had Tanner stage 2 breast development. Genotyping showed homozygous mutation located in exon 7 which abolishes both 17-alpha hydroxylase and 17,20 lyase activities of the CYP17A1 protein. After starting dexamethasone 0.5 mg/day, her potassium level was normalized, and blood pressure improved. In conclusion, a comprehensive evaluation should be performed before using assisted reproductive techniques, such as in vitro fertilization in hypertensive women with sexual infantilism, primary amenorrhea, and hypokalemia.

  6. The effects of weight gain after smoking cessation on atherogenic α1-antitrypsin-low-density lipoprotein.

    Science.gov (United States)

    Komiyama, Maki; Wada, Hiromichi; Ura, Shuichi; Yamakage, Hajime; Satoh-Asahara, Noriko; Shimada, Sayaka; Akao, Masaharu; Koyama, Hiroshi; Kono, Koichi; Shimatsu, Akira; Takahashi, Yuko; Hasegawa, Koji

    2015-11-01

    Although cardiovascular risks decrease after quitting smoking, body weight often increases in the early period after smoking cessation. We have previously reported that the serum level of the α1-antitrypsin-low-density lipoprotein complex (AT-LDL)-an oxidatively modified low-density lipoprotein that accelerates atherosclerosis-is high in current smokers, and that the level rapidly decreases after smoking cessation. However, the effects of weight gain after smoking cessation on this cardiovascular marker are unknown. In 183 outpatients (134 males, 49 females) who had successfully quit smoking, serum AT-LDL levels were measured using an enzyme-linked immunosorbent assay. For all persons who had successfully quit smoking, body mass index (BMI) significantly increased 12 weeks after the first examination (p smoking is influenced by weight gain after smoking cessation.

  7. Analysis of SM22alpha-deficient mice reveals unanticipated insights into smooth muscle cell differentiation and function.

    Science.gov (United States)

    Zhang, J C; Kim, S; Helmke, B P; Yu, W W; Du, K L; Lu, M M; Strobeck, M; Yu, Q; Parmacek, M S

    2001-02-01

    SM22alpha is a 22-kDa smooth muscle cell (SMC) lineage-restricted protein that physically associates with cytoskeletal actin filament bundles in contractile SMCs. To examine the function of SM22alpha, gene targeting was used to generate SM22alpha-deficient (SM22(-/-LacZ)) mice. The gene targeting strategy employed resulted in insertion of the bacterial lacZ reporter gene at the SM22alpha initiation codon, permitting precise analysis of the temporal and spatial pattern of SM22alpha transcriptional activation in the developing mouse. Northern and Western blot analyses confirmed that the gene targeting strategy resulted in a null mutation. Histological analysis of SM22(+/-LacZ) embryos revealed detectable beta-galactosidase activity in the unturned embryonic day 8.0 embryo in the layer of cells surrounding the paired dorsal aortae concomitant with its expression in the primitive heart tube, cephalic mesenchyme, and yolk sac vasculature. Subsequently, during postnatal development, beta-galactosidase activity was observed exclusively in arterial, venous, and visceral SMCs. SM22alpha-deficient mice are viable and fertile. Their blood pressure and heart rate do not differ significantly from their control SM22alpha(+/-) and SM22alpha(+/+) littermates. The vasculature and SMC-containing tissues of SM22alpha-deficient mice develop normally and appear to be histologically and ultrastructurally similar to those of their control littermates. Taken together, these data demonstrate that SM22alpha is not required for basal homeostatic functions mediated by vascular and visceral SMCs in the developing mouse. These data also suggest that signaling pathways that regulate SMC specification and differentiation from local mesenchyme are activated earlier in the angiogenic program than previously recognized.

  8. 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

    a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort. Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated...

  9. High dose androgen therapy in male pseudohermaphroditism due to 5 alpha-reductase deficiency and disorders of the androgen receptor.

    OpenAIRE

    Price, P; Wass, J. A.; Griffin, J E; Leshin, M; Savage, M O; Large, D. M.; Bu'Lock, D E; Anderson, D. C.; Wilson, J. D.; Besser, G M

    1984-01-01

    We describe the clinical and biochemical features of six men with male pseudohermaphroditism due to androgen resistance. Each of the subjects had male-gender behavior but incomplete virilization. The underlying defects in androgen metabolism were defined by studies of the 5 alpha-reductase enzyme and the androgen receptor in fibroblasts cultured from biopsies of genital skin. Four of the six have 5 alpha-reductase deficiency, and two have defects of the androgen receptor (the Reifenstein synd...

  10. Bleeding diathesis and gastro-duodenal ulcers in inherited cytosolic phospholipase-A2 alpha deficiency.

    Science.gov (United States)

    Faioni, E M; Razzari, C; Zulueta, A; Femia, E A; Fenu, L; Trinchera, M; Podda, G M; Pugliano, M; Marongiu, F; Cattaneo, M

    2014-12-01

    Arachidonic acid (AA), when cleaved from phospholipids by cytosolic phospholipase A2 alpha (cPLA2a), generates eicosanoids, with pro-hemostatic, pro-inflammatory, vasoactive and gastro-protective functions. We describe a patient (27-year-old man) and his twin-sister with early-onset bleeding diathesis and recurrent gastro-intestinal (GI) ulcers. Platelet aggregation/δ-granules secretion by collagen was impaired, but normal by AA; serum levels of thromboxane (Tx) B2 and 12-hydroxyeicosatetraenoic acid, and urinary levels of 11-dehydro-TxB2 were extremely low. Patients were homozygous for 1723G>C transition in PLA2G4A gene, which changed the codon for Asp575 to His. GI ulcers affected 5/14 heterozygous ( 60 years) family members; none had bleeding diathesis. The proband, his sister and mother also had mildly reduced factor XI levels. Platelet messenger RNA expression did not differ among subjects with different PLA2G4A genotypes. Conversely, platelet cPLA2a was undetectable by Western Blotting in the proband and his sister, and decreased in 1723G>C heterozygous subjects, suggesting that the variant is transcribed, but not translated or translated into an unstable protein. We described a syndromic form of deficiency of cPLA2a , characterised by recurrent GI ulcers and bleeding diathesis, associated with mild inherited deficiency of factor XI. Unlike other reported patients with cPLA2a deficiency, these patients had extremely low levels of platelet TxA2 biosynthesis.

  11. Conformational properties of the disease-causing Z variant of α1-antitrypsin revealed by theory and experiment.

    Science.gov (United States)

    Kass, Itamar; Knaupp, Anja S; Bottomley, Stephen P; Buckle, Ashley M

    2012-06-20

    The human serine protease inhibitor (serpin) α-1 antitrypsin (α1-AT) protects tissues from proteases of inflammatory cells. The most common disease-causing mutation in α1-AT is the Z-mutation (E342K) that results in an increased propensity of α1-AT to polymerize in the ER of hepatocytes, leading to a lack of secretion into the circulation. The structural consequences of this mutation, however, remain elusive. We report a comparative molecular dynamics investigation of the native states of wild-type and Z α1-AT, revealing a striking contrast between their structures and dynamics in the breach region at the top of β-sheet A, which is closed in the wild-type simulations but open in the Z form. Our findings are consistent with experimental observations, notably the increased solvent exposure of buried residues in the breach region in Z, as well as polymerization via domain swapping, whereby the reactive center loop is rapidly inserted into an open A-sheet before proper folding of the C-terminal β-strands, allowing C-terminal domain swapping with a neighboring molecule. Taken together, our experimental and simulation data imply that mutations at residue 342 that either stabilize an open form of the top of β-sheet A or increase the local flexibility in this region, may favor polymerization and hence aggregation.

  12. Omigapil ameliorates the pathology of muscle dystrophy caused by laminin-alpha2 deficiency.

    Science.gov (United States)

    Erb, Michael; Meinen, Sarina; Barzaghi, Patrizia; Sumanovski, Lazar T; Courdier-Früh, Isabelle; Rüegg, Markus A; Meier, Thomas

    2009-12-01

    Laminin alpha2-deficient congenital muscular dystrophy, called MDC1A, is a rare, devastating genetic disease characterized by severe neonatal hypotonia ("floppy infant syndrome"), peripheral neuropathy, inability to stand or walk, respiratory distress, and premature death in early life. Transgenic overexpression of the apoptosis inhibitor protein BCL-2, or deletion of the proapoptotic Bax gene in a mouse model for MDC1A prolongs survival and mitigates pathology, indicating that apoptotic events are involved in the pathology. Here we demonstrate that the proapoptotic glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-Siah1-CBP/p300-p53 pathway is activated in a mouse model for MDC1A. Moreover, we show that omigapil, which inhibits GAPDH-Siah1-mediated apoptosis, ameliorates several pathological hallmarks in the MDC1A mouse model. Specifically, we demonstrate that treatment with omigapil inhibits apoptosis in muscle, reduces body weight loss and skeletal deformation, increases locomotive activity, and protects from early mortality. These data qualify omigapil, which is in late phase of clinical development for human use, as a drug candidate for the treatment of MDC1A.

  13. Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response

    OpenAIRE

    1996-01-01

    To investigate the role of TNF alpha in the development of in vivo immune response we have generated TNF alpha-deficient mice by gene targeting. Homozygous mutant mice are viable and fertile, develop lymph nodes and Peyer's patches and show no apparent phenotypic abnormalities, indicating that TNF alpha is not required for normal mouse development. In the absence of TNF alpha mice readily succumb to L. monocytogenes infections and show reduced contact hypersensitivity responses. Furthermore, ...

  14. Induction of experimental autoimmune encephalomyelitis in C57BL/6 mice deficient in either the chemokine macrophage inflammatory protein-1alpha or its CCR5 receptor

    DEFF Research Database (Denmark)

    Tran, E H; Kuziel, W A; Owens, T

    2000-01-01

    Macrophage inflammatory protein (MIP)-1alpha is a chemokine that is associated with Th1 cytokine responses. Expression and antibody blocking studies have implicated MIP-1alpha in multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis (EAE). We examined the role of MIP-1alpha...... and its CCR5 receptor in the induction of EAE by immunizing C57BL / 6 mice deficient in either MIP-1alpha or CCR5 with myelin oligodendrocyte glycoprotein (MOG). We found that MIP-1alpha-deficient mice were fully susceptible to MOG-induced EAE. These knockout animals were indistinguishable from wild...... chemoattractant protein-1, MIP-1beta, MIP-2, lymphotactin and T cell activation gene-3 during the course of the disease. CCR5-deficient mice were also susceptible to disease induction by MOG. The dispensability of MIP-1alpha and CCR5 for MOG-induced EAE in C57BL / 6 mice supports the idea that differential...

  15. Deficiencies

    Data.gov (United States)

    U.S. Department of Health & Human Services — A list of all deficiencies currently listed on Nursing Home Compare, including the nursing home that received the deficiency, the associated inspection date,...

  16. Correlation Between Arteriosclerosis and Periodontal Condition Assessed by Lactoferrin and α1-Antitrypsin Levels in Gingival Crevicular Fluid.

    Science.gov (United States)

    Hayashi, Shuji; Yamada, Hirotsugu; Fukui, Makoto; Ito, Hiro-o; Sata, Masataka

    2015-01-01

    Patients with periodontal disease exhibit exacerbated atherosclerosis, aortic stiffness, or vascular endothelial dysfunction. However, in a recent scientific statement, the American Heart Association noted that neither has periodontal disease been proven to cause atherosclerotic vascular disease nor has the treatment of periodontal disease been proven to prevent atherosclerotic vascular disease. Therefore, the aim of the present study was to examine the correlation between periodontal condition and arteriosclerosis in patients with coronary artery disease (CAD), which is usually accompanied by systemic arteriosclerosis.We measured levels of gingival crevicular fluid lactoferrin (GCF-Lf) and α1-antitrypsin (GCF-AT) in 72 patients (67 ± 8 years, 56 men) with CAD. Furthermore, we evaluated the maximum intima-media thickness (max IMT) and plaque score of the carotid arteries as well as brachial-ankle pulse wave velocity (baPWV) and flow-mediated dilation (FMD) of the brachial artery, each of which is a parameter for determining arteriosclerosis status. The average level of GCF-Lf was 0.29 ± 0.36 µg/mL and that of GCF-AT was 0.31 ± 0.66 µg/mL, with significant correlation between the two (r = 0.701, P arteriosclerosis parameters (ie, max IMT, plaque score, baPWV, and FMD) and GCF-Lf or GCF-AT.No correlation between the GCF biomarkers and the severity of arteriosclerosis was detected. This result may suggest that worsening of the periodontal condition assessed by GCF biomarkers is not a major potential risk factor for arteriosclerosis.

  17. Possible Role of α1-Antitrypsin in Endometriosis-Like Grafts From a Mouse Model of Endometriosis.

    Science.gov (United States)

    Tamura, Kazuhiro; Takashima, Haruka; Fumoto, Keiko; Kajihara, Takeshi; Uchino, Satomi; Ishihara, Osamu; Yoshie, Mikihiro; Kusama, Kazuya; Tachikawa, Eiichi

    2015-09-01

    Previous study indicated that bleeding into the peritoneum may accelerate inflammatory response in endometriosis-like grafts in mice. To identify changes in protein levels in the grafts from mice that underwent unilateral ovariectomy (uOVX), which causes bleeding from ovarian arteries and vein, the grafts were generated by injecting a suspension of human endometrial cells in BALB/c nude female mice, and protein profile changes were compared with non-uOVX control mice. The level of α1-antitrypsin (α1-AT) decreased in grafts from nude mice that underwent uOVX. The levels of phosphorylated Akt, mammalian target of rapamycin, S6K, regulatory factors for cell survival, and of phosphorylated nuclear factor κB, an inflammatory mediator, were higher in endometriosis-like grafts from the uOVX group than from the control. The grafts were mostly comprised of stromal cells. The bioactivity of α1-AT was assessed by investigating cytokine expression in protease-activated receptor (PAR) 1/2 agonists-stimulated stromal cells. The PARs promoted the expression of interleukin 8 (IL-8), but treatment with α1-AT blocked IL-8 expression dose dependently. Knocking down α1-AT expression increased the constitutive IL-6, IL-8, and cyclooxygenase 2 expression as well as PAR1 agonist-stimulated IL-6 expression. These findings support the notion that decreased α1-AT protein in the grafts constituted with human endometrial cells in mice may have exacerbated inflammation in endometriosis-like grafts, suggesting the possible involvement of α1-AT in the pathophysiology of endometriosis.

  18. Acute-phase protein α1-antitrypsin--a novel regulator of angiopoietin-like protein 4 transcription and secretion.

    Science.gov (United States)

    Frenzel, Eileen; Wrenger, Sabine; Immenschuh, Stephan; Koczulla, Rembert; Mahadeva, Ravi; Deeg, H Joachim; Dinarello, Charles A; Welte, Tobias; Marcondes, A Mario Q; Janciauskiene, Sabina

    2014-06-01

    The angiopoietin-like protein 4 (angptl4, also known as peroxisome proliferator-activated receptor [PPAR]γ-induced angiopoietin-related protein) is a multifunctional protein associated with acute-phase response. The mechanisms accounting for the increase in angptl4 expression are largely unknown. This study shows that human α1-antitrypsin (A1AT) upregulates expression and release of angplt4 in human blood adherent mononuclear cells and in primary human lung microvascular endothelial cells in a concentration- and time-dependent manner. Mononuclear cells treated for 1 h with A1AT (from 0.1 to 4 mg/ml) increased mRNA of angptl4 from 2- to 174-fold, respectively, relative to controls. In endothelial cells, the maximal effect on angptl4 expression was achieved at 8 h with 2 mg/ml A1AT (11-fold induction versus controls). In 10 emphysema patients receiving A1AT therapy (Prolastin), plasma angptl4 levels were higher relative to patients without therapy (nanograms per milliliter, mean [95% confidence interval] 127.1 [99.5-154.6] versus 76.8 [54.8-98.8], respectively, p = 0.045) and correlated with A1AT levels. The effect of A1AT on angptl4 expression was significantly diminished in cells pretreated with a specific inhibitor of ERK1/2 activation (UO126), irreversible and selective PPARγ antagonist (GW9662), or genistein, a ligand for PPARγ. GW9662 did not alter the ability of A1AT to induce ERK1/2 phosphorylation, suggesting that PPARγ is a critical mediator in the A1AT-driven angptl4 expression. In contrast, the forced accumulation of HIF-1α, an upregulator of angptl4 expression, enhanced the effect of A1AT. Thus, acute-phase protein A1AT is a physiological regulator of angptl4, another acute-phase protein.

  19. Uniparental disomy of chromosome 2 resulting in lethal trifunctional protein deficiency due to homozygous alpha-subunit mutations.

    Science.gov (United States)

    Spiekerkoetter, Ute; Eeds, Angela; Yue, Zou; Haines, Jonathan; Strauss, Arnold W; Summar, Marshall

    2002-12-01

    The mitochondrial trifunctional protein (TFP) is an enzyme complex of the fatty acid beta-oxidation cycle composed of an alpha- and a beta-subunit. The two encoding genes are located in the same region on chromosome 2 (2p23). TFP deficiency due to either alpha- or beta-subunit mutations is characterized by mutational and phenotypic heterogeneity with severe, early-onset, cardiac forms and milder, later-onset, myopathic phenotypes. In two unrelated patients with lethal TFP deficiency, we delineated apparently homozygous alpha-subunit mutations that were present in heterozygous form in both mothers, but not in either biological father. We performed a microsatellite repeat analysis of both patients and their parents using seven chromosome 2-specific polymorphic DNA markers and four nonchromosome 2 markers. In both patients, two chromosome 2-specific markers demonstrated maternal isodisomy of chromosome 2. The other five chromosome 2-specific markers were noninformative in each patient. Inheritance of alleles from chromosomes 4, 5, and 7 was consistent with paternity. These results explain the apparently anomalous pattern of transmission. Six of our 12 known TFP-deficient patients with alpha-subunit mutations have disease due to homozygous changes and two of them via the mechanism of uniparental disomy (UPD) (16.7%). For very rare autosomal recessive diseases, UPD may represent a common mechanism. This study emphasizes the need to confirm mutations in parents whenever possible. TFP deficiency is another disorder that has become manifest due to isodisomy of chromosome 2. This information will impact genetic counseling for these families, reducing greatly the 25% risk normally used for recessive disorders.

  20. Alpha Thalassemia

    Science.gov (United States)

    Alpha Thalassemia Physicians often mistake alpha thalassemia trait for iron deficiency anemia and incorrectly prescribe iron supplements that have no effect 1 on the anemia. αα αα Normal alpha ...

  1. Point mutation of Arg440 to his in cytochrome P450c17 causes severe 17{alpha}-hydroxylase deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Fardella, C.E.; Hum, D.W.; Miller, W.L. [Univ. of California, San Francisco, CA (United States); Homoki, J. [Univ. of Ulm (Germany)

    1994-07-01

    Genetic disorders in the gene encoding P450c17 cause 17{alpha}-hydroxylase deficiency. The consequent defects in the synthesis of cortisol and sex steroids cause sexual infantilism and a female phenotype in both genetic sexes as well as mineralorcorticoid excess and hypertension. A 15-yr-old patient from Germany was seen for absent pubertal development and mild hypertension with hypokalemia, high concentrations of 17-deoxysteroids, and hypergonadotropic hypogonadism. Analysis of her P450c17 gene by polymerase chain reaction amplification and direct sequencing showed mutation of codon 440 from CGC (Arg) to CAC (His). Expression of a vector encoding this mutated form of P450c17 in transfected nonsteroidogenic COS-1 cells showed that the mutant P450c17 protein was produced, but it lacked both 17{alpha}-hydroxylase and 17,20-lyase activities. To date, 15 different P450c17 mutations have been described in 23 patients with 17{alpha}-hydroxylase deficiency, indicating that mutations in this gene are due to random events. 36 refs., 3 figs., 2 tabs.

  2. ADAM12 overexpression does not improve outcome in mice with laminin alpha2-deficient muscular dystrophy

    DEFF Research Database (Denmark)

    Guo, Ling T; Shelton, G Diane; Wewer, Ulla M;

    2005-01-01

    We have recently shown that overexpression of ADAM12 results in increased muscle regeneration and significantly reduced pathology in mdx, dystrophin deficient mice. In the present study, we tested the effect of overexpressing ADAM12 in dy(W) laminin-deficient mice. dy mice have a very severe...

  3. [Male pseudohermaphroditism caused by enzymatic deficiency of 17-alpha-hydroxylase. 1st case reported in Puerto Rico].

    Science.gov (United States)

    Rosado, A; Alegre, M; Colón, G

    1997-01-01

    A 36 year old white female came to our service after having been evaluated on repetitive occasions in the past for a workup of gigantism and acromegalic features. Since childhood she had developed tall stature, frontal bossing, prominence of zygomatic bones, separated teeth, large hands and size 14 shoes. Human growth hormone and somatomedin serum levels had been normal on all occasions tested. Her past history was significant for primary amenorrhea and a 12 year history of hypertension. On physical examination BP was 140/100, height 6' 2", weight 2571 bs. Her phenotype was truly acromegalic. There was absence of axillary and pubic hair with no breast development. External genitalia was of female appearance. Laboratory evaluation showed increased FSH of 88 mlU/ml, increase LH of 65.6 mlU/ml and decreased E2 of 12.6 pg/ml. Other findings were low serum cortisol of 0.2 mg/dl, high ACTH of 344 pg/ml, low 17-Ketosteroids, high pregnenolone levels of 595 mg/dl, low 17-hydroxypregnenolone less than 10 ng/dl, very high aldosterone of 31 ng/dl and suppressed PRA of less than 0.1 ng/ml. A pelvic sonogram showed a right ovoid structure which could represent a gonad and failed to identify the uterus and left gonad. A bone densitometry showed a decrease bone mineral density compatible with osteoporosis. Chromosome study showed a karyotype of 46-XY. A diagnosis was made of congenital adrenal hyperplasia secondary to 17-alpha-hydroxylase deficiency in a genotypic male. Our patient was referred to the department of gynecology for surgical removal of the gonads. It is amazing how a patient with severe adrenal insufficiency can withstand 36 years of her life undiagnosed without going into an adrenal crisis. Her tall stature and acromegalic features were the striking signs confusing all physicians and delaying the correct diagnosis and appropriate treatment. There has been reported worldwide, nearly 120 cases with documented severe 17-alpha-hydroxylase deficiency. To our knowledge

  4. Modeling the influence of vitamin D deficiency on cigarette smoke-induced emphysema.

    Directory of Open Access Journals (Sweden)

    Mardi A. Crane-Godreau

    2013-06-01

    Full Text Available Chronic obstructive pulmonary disease (COPD is a major cause of morbidity and mortality worldwide. While the primary risk factor for COPD is cigarette smoke exposure, vitamin D deficiency has been epidemiologically implicated as a factor in the progressive development of COPD-associated emphysema. Because of difficulties inherent to studies involving multiple risk factors in the progression of COPD in humans, we developed a murine model in which to study the separate and combined effects of vitamin D deficiency and cigarette smoke exposure. During a 16 week period, mice were exposed to one of four conditions, control diet breathing room air (CD-NS, control diet with cigarette smoke exposure (CD-CSE, vitamin D deficient diet breathing room air (VDD-NS or vitamin D deficient diet with cigarette smoke exposure (VDD-CSE. At the end of the exposure period, the lungs were examined by a pathologist and separately by morphometric analysis. In parallel experiments, mice were anesthetized for pulmonary function testing followed by sacrifice and analysis. Emphysema (determined by an increase in alveolar mean linear intercept length was more severe in the VDD-CSE mice compared to control animals and animals exposed to VDD or CSE alone. The VDD-CSE and the CD-CSE mice had increased total lung capacity and increased static lung compliance. There was also a significant increase in the matrix metalloproteinase-9: tissue inhibitor of metalloproteinases-1 ratio in VDD-CSE mice compared with all controls. Alpha-1 antitrypsin expression was reduced in VDD-CSE mice as well. In summary, vitamin D deficiency, when combined with cigarette smoke exposure, seemed to accelerate the appearance of emphysemas, perhaps by virtue of an increased protease-antiprotease ratio in the combined VDD-CSE animals. These results support the value of our mouse model in the study of COPD.

  5. Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders

    Directory of Open Access Journals (Sweden)

    Yamasaki Nobuyuki

    2008-09-01

    Full Text Available Abstract Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here we report that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/- have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG. The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed. Strikingly, among the 20 most downregulated genes, 5 had highly selective expression in the DG. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neurons in the DG was dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Moreover, c-Fos expression in the DG after electric footshock was almost completely and selectively abolished in the mutants. Statistical clustering of human post-mortem brains using 10 genes differentially-expressed in the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophrenia-enriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose that an "immature DG" in adulthood might induce alterations in behavior and

  6. In vivo multiplex quantitative analysis of 3 forms of alpha melanocyte stimulating hormone in pituitary of prolyl endopeptidase deficient mice

    Directory of Open Access Journals (Sweden)

    Perroud Bertrand

    2009-06-01

    Full Text Available Abstract Background In vitro reactions are useful to identify putative enzyme substrates, but in vivo validation is required to identify actual enzyme substrates that have biological meaning. To investigate in vivo effects of prolyl endopeptidase (PREP, a serine protease, on alpha melanocyte stimulating hormone (α-MSH, we developed a new mass spectrometry based technique to quantitate, in multiplex, the various forms of α-MSH. Methods Using Multiple Reaction Monitoring (MRM, we analyzed peptide transitions to quantify three different forms of α-MSH. Transitions were first confirmed using standard peptides. Samples were then analyzed by mass spectrometry using a triple quadrupole mass spectrometer, after elution from a reverse phase C18 column by a gradient of acetonitrile. Results We first demonstrate in vitro that PREP digests biological active alpha melanocyte stimulating hormone (α-MSH1–13, by cleaving the terminal amidated valine and releasing a truncated alpha melanocyte stimulating hormone (α-MSH1–12 product – the 12 residues α-MSH form. We then use the technique in vivo to analyze the MRM transitions of the three different forms of α-MSH: the deacetylated α-MSH1–13, the acetylated α-MSH1–13 and the truncated form α-MSH1–12. For this experiment, we used a mouse model (PREP-GT in which the serine protease, prolyl endopeptidase, is deficient due to a genetrap insertion. Here we report that the ratio between acetylated α-MSH1–13 and α-MSH1–12 is significantly increased (P-value = 0.015, N = 6 in the pituitaries of PREP-GT mice when compared to wild type littermates. In addition no significant changes were revealed in the relative level of α-MSH1–13 versus the deacetylated α-MSH1–13. These results combined with the demonstration that PREP digests α-MSH1–13 in vitro, strongly suggest that α-MSH1–13 is an in vivo substrate of PREP. Conclusion The multiplex targeted quantitative peptidomics technique we

  7. α1-antitrypsin and its C-terminal fragment attenuate effects of degranulated neutrophil-conditioned medium on lung cancer HCC cells, in vitro

    Directory of Open Access Journals (Sweden)

    Westin Ulla

    2004-11-01

    Full Text Available Abstract Background Tumor microenvironment, which is largely affected by inflammatory cells, is a crucial participant in the neoplastic process through promotion of cell proliferation, survival and migration. We measured the effects of polymorphonuclear neutrophil (PMN conditioned medium alone, and supplemented with serine proteinase inhibitor α-1 antitrypsin (AAT or its C-terminal fragment (C-36 peptide, on cultured lung cancer cells. Methods Lung cancer HCC cells were grown in a regular medium or in a PMN-conditioned medium in the presence or absence of AAT (0.5 mg/ml or its C-36 peptide (0.06 mg/ml for 24 h. Cell proliferation, invasiveness and release of IL-8 and VEGF were analyzed by [3H]-thymidine incorporation, Matrigel invasion and ELISA methods, respectively. Results Cells exposed to PMN-conditioned medium show decreased proliferation and IL-8 release by 3.9-fold, p Conclusions Our data provide evidence that neutrophil derived factors decrease lung cancer HCC cell proliferation and IL-8 release, but increase cell invasiveness. These effects were found to be modulated by exogenously present serine proteinase inhibitor, AAT, and its C-terminal fragment, which points to a complexity of the relationships between tumor cell biological activities and local microenvironment.

  8. Duodenal active transport of calcium and phosphate in vitamin D-deficient rats: effects of nephrectomy, Cestrum diurnum, and 1alpha,25-dihydroxyvitamin D3.

    Science.gov (United States)

    Walling, M W; Kimberg, D V; Wasserman, R H; Feinberg, R R

    1976-05-01

    Both the methanol:chloroform extractable material from the leaves of the Solanaceous plant, Cestrum diurnum (C.d.), and a 270 ng dose of 1alpha, 25-dihydroxyvitamin D3 (1alpha,25-(OH)2D3) increased the active absorption of calcium and phosphate across the proximal duodenum, studied in vitro, from sham-operated and nephrectomized (NPX) vitamin D-deficient rats. In these studies, conducted 24 h after surgery, the uremic state in the NPX animals markedly diminished the intestinal transport response to 1alpha,25-(OH)2D3 and also lowered baseline transport values across duodenum from the NPX vitamin D-deficient controls. Both C.d. and 1alpha, 25-(OH)2D3 elevated plasma Ca levels equally well in the sham-operated and NPX groups. The stimulation of intestinal Ca absorption in NPX animals indicates that, like the leaves of the South American plant, Solanum glaucophyllum, C.d. contains materials which can function in an analogous manner to compounds in the vitamin D group that have either a 1alpha hydroxyl group or its steric equivalent.

  9. A recombinant DNA vaccine protects mice deficient in the alpha/beta interferon receptor against lethal challenge with Usutu virus.

    Science.gov (United States)

    Martín-Acebes, Miguel A; Blázquez, Ana-Belén; Cañas-Arranz, Rodrigo; Vázquez-Calvo, Ángela; Merino-Ramos, Teresa; Escribano-Romero, Estela; Sobrino, Francisco; Saiz, Juan-Carlos

    2016-04-19

    Usutu virus (USUV) is a mosquito-borne flavivirus whose circulation had been confined to Africa since it was first detected in 1959. However, in the last decade USUV has emerged in Europe causing episodes of avian mortality and sporadic severe neuroinvasive infections in humans. Remarkably, adult laboratory mice exhibit limited susceptibility to USUV infection, which has impaired the analysis of the immune responses, thus complicating the evaluation of virus-host interactions and of vaccine candidates against this pathogen. In this work, we showed that mice deficient in the alpha/beta interferon receptor (IFNAR (-/-) mice) were highly susceptible to USUV infection and provided a lethal challenge model for vaccine testing. To validate this infection model, a plasmid DNA vaccine candidate encoding the precursor of membrane (prM) and envelope (E) proteins of USUV was engineered. Transfection of cultured cells with this plasmid resulted in expression of USUV antigens and the assembly and secretion of small virus-like particles also known as recombinant subviral particles (RSPs). A single intramuscular immunization with this plasmid was sufficient to elicit a significant level of protection against challenge with USUV in IFNAR (-/-) mice. The characterization of the humoral response induced revealed that DNA vaccination primed anti-USUV antibodies, including neutralizing antibodies. Overall, these results probe the suitability of IFNAR (-/-) mice as an amenable small animal model for the study of USUV host virus interactions and vaccine testing, as well as the feasibility of DNA-based vaccine strategies for the control of this pathogen.

  10. Sesamin attenuates intercellular cell adhesion molecule-1 expression in vitro in TNF-alpha-treated human aortic endothelial cells and in vivo in apolipoprotein-E-deficient mice.

    Science.gov (United States)

    Wu, Wen-Huey; Wang, Shu-Huei; Kuan, I-I; Kao, Ya-Shi; Wu, Pei-Jhen; Liang, Chan-Jung; Chien, Hsiung-Fei; Kao, Chiu-Hua; Huang, Ching-Jang; Chen, Yuh-Lien

    2010-09-01

    Sesame lignans have antioxidative and anti-inflammatory properties. We focused on the effects of the lignans sesamin and sesamol on the expression of endothelial-leukocyte adhesion molecules in tumor necrosis factor-alpha (TNF-alpha)-treated human aortic endothelial cells (HAECs). When HAECs were pretreated with sesamin (10 or 100 microM), the TNF-alpha-induced expression of intercellular cell adhesion molecule-1 (ICAM-1) was significantly reduced (35 or 70% decrease, respectively) by Western blotting. Sesamol was less effective at inhibiting ICAM-1 expression (30% decrease at 100 microM). Sesamin and sesamol reduced the marked TNF-alpha-induced increase in human antigen R (HuR) translocation and the interaction between HuR and the 3'UTR of ICAM-1 mRNA. Both significantly reduced the binding of monocytes to TNF-alpha-stimulated HAECs. Sesamin significantly attenuated TNF-alpha-induced ICAM-1 expression and cell adhesion by downregulation of extracellular signal-regulated kinase 1/2 and p38. Furthermore, in vivo, sesamin attenuated intimal thickening and ICAM-1 expression seen in aortas of apolipoprotein-E-deficient mice. Taken together, these data suggest that sesamin inhibits TNF-alpha-induced extracellular signal-regulated kinase/p38 phosphorylation, nuclear translocation of NF-kappaB p65, cytoplasmic translocalization of HuR and thereby suppresses ICAM-1 expression, resulting in reduced adhesion of leukocytes. These results also suggest that sesamin may prevent the development of atherosclerosis and inflammatory responses.

  11. Compensation for dystrophin-deficiency: ADAM12 overexpression in skeletal muscle results in increased alpha 7 integrin, utrophin and associated glycoproteins

    DEFF Research Database (Denmark)

    Moghadaszadeh, Behzad; Albrechtsen, Reidar; Guo, Ling T;

    2003-01-01

    , and suggested that significant changes in mdx/ADAM12 muscle might occur post-transcriptionally. Indeed, by immunostaining and immunoblotting we found an approximately 2-fold increase in expression, and distinct extrasynaptic localization, of alpha 7B integrin and utrophin, the functional homolog of dystrophin....... The expression of the dystrophin-associated glycoproteins was also increased. In conclusion, these results demonstrate a novel way to alleviate dystrophin deficiency in mice, and may stimulate the development of new approaches to compensate for dystrophin deficiency in animals and humans....

  12. PPAR{alpha} deficiency augments a ketogenic diet-induced circadian PAI-1 expression possibly through PPAR{gamma} activation in the liver

    Energy Technology Data Exchange (ETDEWEB)

    Oishi, Katsutaka, E-mail: k-ooishi@aist.go.jp [Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki (Japan); Uchida, Daisuke [Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki (Japan); Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki (Japan); Ohkura, Naoki [Department of Clinical Molecular Biology, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamihara, Kanagawa (Japan); Horie, Shuichi [Department of Clinical Biochemistry, Kagawa Nutrition University, Sakado, Saitama (Japan)

    2010-10-15

    Research highlights: {yields} PPAR{alpha} deficiency augments a ketogenic diet-induced circadian PAI-1 expression. {yields} Hepatic expressions of PPAR{gamma} and PCG-1{alpha} are induced by a ketogenic diet. {yields} PPAR{gamma} antagonist attenuates a ketogenic diet-induced PAI-1 expression. {yields} Ketogenic diet advances the phase of circadian clock in a PPAR{alpha}-independent manner. -- Abstract: An increased level of plasminogen activator inhibitor-1 (PAI-1) is considered a risk factor for cardiovascular diseases, and PAI-1 gene expression is under the control of molecular circadian clocks in mammals. We recently showed that PAI-1 expression is augmented in a phase-advanced circadian manner in mice fed with a ketogenic diet (KD). To determine whether peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) is involved in hypofibrinolytic status induced by a KD, we examined the expression profiles of PAI-1 and circadian clock genes in PPAR{alpha}-null KD mice. Chronic administration of bezafibrate induced the PAI-1 gene expression in a PPAR{alpha}-dependent manner. Feeding with a KD augmented the circadian expression of PAI-1 mRNA in the hearts and livers of wild-type (WT) mice as previously described. The KD-induced mRNA expression of typical PPAR{alpha} target genes such as Cyp4A10 and FGF21 was damped in PPAR{alpha}-null mice. However, plasma PAI-1 concentrations were significantly more elevated in PPAR{alpha}-null KD mice in accordance with hepatic mRNA levels. These observations suggest that PPAR{alpha} activation is dispensable for KD-induced PAI-1 expression. We also found that hyperlipidemia, fatty liver, and the hepatic expressions of PPAR{gamma} and its coactivator PCG-1{alpha} were more effectively induced in PPAR{alpha}-null, than in WT mice on a KD. Furthermore, KD-induced hepatic PAI-1 expression was significantly suppressed by supplementation with bisphenol A diglycidyl ether, a PPAR{gamma} antagonist, in both WT and PPAR{alpha

  13. Normal bone density in male pseudohermaphroditism due to 5alpha- reductase 2 deficiency Pseudohermafroditas masculinos por deficiência de 5alfa-redutase 2 apresentam densidade óssea normal

    Directory of Open Access Journals (Sweden)

    Elaine Maria Frade Costa

    2001-10-01

    Full Text Available Bone is an androgen-dependent tissue, but it is not clear whether the androgen action in bone depends on testosterone or on dihydrotestosterone. Patients with 5alpha-reductase 2 deficiency present normal levels of testosterone and low levels of dihydrotestosterone, providing an in vivo human model for the analysis of the effect of testosterone on bone. OBJECTIVE: To analyze bone mineral density in 4 adult patients with male pseudohermaphroditism due to 5alpha-reductase 2 deficiency. RESULTS: Three patients presented normal bone mineral density of the lumbar column (L1-L4 and femur neck, and the other patient presented a slight osteopenia in the lumbar column. CONCLUSION: Patients with dihydrotestosterone deficiency present normal bone mineral density, suggesting that dihydrotestosterone is not the main androgen acting in bone.O tecido ósseo é um tecido andrógeno-dependente porém não está claro se a ação androgênica depende da testosterona ou da diidrotestosterona. Os pacientes portadores de deficiência de 5alfa-redutase tipo 2, constituem um modelo natural para avaliar o efeito isolado da testosterona sobre a massa óssea. OBJETIVO: Avaliar a densidade mineral óssea em quatro pacientes adultos portadores de pseudohermafroditismo masculino por deficiência da 5alfa-redutase tipo 2. RESULTADOS: Três pacientes apresentaram densidade mineral óssea normal na coluna lombar e fêmur e o quarto paciente apresentou osteopenia leve em coluna lombar. CONCLUSÃO: Pacientes com deficiência de diidrotestosterona apresentam densidade mineral óssea normal sugerindo que a diidrotestosterona não é o andrógeno que age sobre o osso.

  14. PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis.

    Directory of Open Access Journals (Sweden)

    Teresa C Leone

    2005-04-01

    Full Text Available The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha was targeted in mice. PGC-1alpha null (PGC-1alpha(-/- mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1alpha(-/- mice. With age, the PGC-1alpha(-/- mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1alpha(-/- mice, leading to reduced muscle performance and exercise capacity. PGC-1alpha(-/- mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1alpha(-/- mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1alpha(-/- mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1alpha(-/- mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1alpha(-/- mice. These results demonstrate that PGC-1alpha is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.

  15. PGC-1alpha Deficiency Causes Multi-System Energy Metabolic Derangements: Muscle Dysfunction, Abnormal Weight Control and Hepatic Steatosis

    Directory of Open Access Journals (Sweden)

    Leone Teresa C

    2005-01-01

    Full Text Available The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha was targeted in mice. PGC-1alpha null (PGC-1alpha-/- mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1alpha-/- mice. With age, the PGC-1alpha-/- mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1alpha-/- mice, leading to reduced muscle performance and exercise capacity. PGC-1alpha-/- mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1alpha-/- mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1alpha-/- mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1alpha-/- mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1alpha-/- mice. These results demonstrate that PGC-1alpha is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.

  16. Female mice deficient in alpha-fetoprotein show female-typical neural responses to conspecific-derived pheromones.

    Directory of Open Access Journals (Sweden)

    Olivier Brock

    Full Text Available The neural mechanisms controlling sexual behavior are sexually differentiated by the perinatal actions of sex steroid hormones. We recently observed using female mice deficient in alpha-fetoprotein (AFP-KO and which lack the protective actions of AFP against maternal estradiol, that exposure to prenatal estradiol completely defeminized the potential to show lordosis behavior in adulthood. Furthermore, AFP-KO females failed to show any male-directed mate preferences following treatment with estradiol and progesterone, indicating a reduced sexual motivation to seek out the male. In the present study, we asked whether neural responses to male- and female-derived odors are also affected in AFP-KO female mice. Therefore, we compared patterns of Fos, the protein product of the immediate early gene, c-fos, commonly used as a marker of neuronal activation, between wild-type (WT and AFP-KO female mice following exposure to male or estrous female urine. We also tested WT males to confirm the previously observed sex differences in neural responses to male urinary odors. Interestingly, AFP-KO females showed normal, female-like Fos responses, i.e. exposure to urinary odors from male but not estrous female mice induced equivalent levels of Fos protein in the accessory olfactory pathways (e.g. the medial part of the preoptic nucleus, the bed nucleus of the stria terminalis, the amygdala, and the lateral part of the ventromedial hypothalamic nucleus as well as in the main olfactory pathways (e.g. the piriform cortex and the anterior cortical amygdaloid nucleus, as WT females. By contrast, WT males did not show any significant induction of Fos protein in these brain areas upon exposure to either male or estrous female urinary odors. These results thus suggest that prenatal estradiol is not involved in the sexual differentiation of neural Fos responses to male-derived odors.

  17. Integrins (alpha7beta1) in muscle function and survival. Disrupted expression in merosin-deficient congenital muscular dystrophy

    DEFF Research Database (Denmark)

    Vachon, P H; Xu, H; Liu, L;

    1997-01-01

    isoforms in myofibers of merosin-deficient human patients and mice, but not in dystrophin-deficient or sarcoglycan-deficient humans and animals. It was shown previously that skeletal muscle fibers require merosin for survival and function (Vachon, P.H., F. Loechel, H. Xu, U.M. Wewer, and E. Engvall. 1996...

  18. The measurement of urinary Delta(1)-piperideine-6-carboxylate, the alter ego of alpha-aminoadipic semialdehyde, in Antiquitin deficiency.

    NARCIS (Netherlands)

    Struys, E.A.; Bok, L.A.; Emal, D.; Houterman, S.; Willemsen, M.A.A.P.; Jakobs, C.

    2012-01-01

    The assessment of urinary alpha-aminoadipic semialdehyde (alpha-AASA) has become the diagnostic laboratory test for pyridoxine dependent seizures (PDS). alpha-AASA is in spontaneous equilibrium with its cyclic form Delta(1)-piperideine-6-carboxylate (P6C); a molecule with a heterocyclic ring structu

  19. 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.

  20. α1-Antitrypsin modifies general NK cell interactions with dendritic cells and specific interactions with islet β-cells in favor of protection from autoimmune diabetes.

    Science.gov (United States)

    Guttman, Ofer; Yossef, Rami; Freixo-Lima, Gabriella; Rider, Peleg; Porgador, Angel; Lewis, Eli C

    2014-10-13

    The autoimmune destruction of pancreatic β-cells is the hallmark of type 1 diabetes (T1D). Failure of anti-CD3 antibodies to provide long-lasting reversal of T1D and the expression of an NK cell ligand on β-cells suggest that NK cells play a role in disease pathogenesis. Indeed, killing of β-cells by NK cells has been shown to occur, mediated by activation of the NK cell activating receptor, NKp46. α1-antitrypsin (AAT), an anti-inflammatory and immunomodulatory glycoprotein, protects β-cells from injurious immune responses and is currently evaluated as a therapeutic for recent onset T1D. While isolated T lymphocytes are not inhibited by AAT, dendritic cells (DCs) become tolerogenic in its presence and other innate immune cells become less inflammatory. Yet a comprehensive profile of NK cell responses in the presence of AAT has yet to be described. In the present study, we demonstrate that AAT significantly reduces NK cell degranulation against β-cells, albeit in the whole animal and not in isolated NK cell cultures. AAT-treated mice, and not isolated cultured β-cells, exhibited a marked reduction in NKp46 ligand levels on β-cells. In related experiments, AAT-treated DCs exhibited reduced inducible DC-expressed IL-15 levels and evoked a weaker NK cell response. NK cell depletion in a T1D mouse model resulted in improved β-cell function and survival, similar to the effects observed by AAT treatment alone; nonetheless, the two approaches were non-synergistic. Our data suggest that AAT is a selective immunomodulator that retains pivotal NK cell responses, while diverting their activities away from islet β-cells. This article is protected by copyright. All rights reserved.

  1. Direct bone formation during distraction osteogenesis does not require TNF alpha receptors and elevated serum TNF alpha fails to inhibit bone formation in TNFR1 deficient mice

    Science.gov (United States)

    Distraction osteogenesis (DO) is a process which induces direct new bone formation as a result of mechanical distraction. Tumor necrosis factor-alpha (TNF) is a cytokine that can modulate osteoblastogenesis. The direct effects of TNF on direct bone formation in rodents are hypothetically mediated th...

  2. Pyridoxine-dependent seizures caused by alpha amino adipic semialdehyde dehydrogenase deficiency: the first polish case with confirmed biochemical and molecular pathology.

    Science.gov (United States)

    Kaczorowska, Magdalena; Kmiec, Tomasz; Jakobs, Cornelis; Kacinski, Marek; Kroczka, Slawomir; Salomons, Gajja S; Struys, Eduard A; Jozwiak, Sergiusz

    2008-12-01

    Pyridoxine-dependent seizures are a rare condition recognized when numerous seizures respond to pyridoxine treatment and recur on pyridoxine withdrawal. For decades the diagnosis was confirmed only with pyridoxine treatment withdrawal trial. Recently described biochemical and molecular pathology improved the diagnostic process for those cases in which seizures are caused by alpha amino adipic semialdehyde dehydrogenase deficiency. This article presents a girl with recurrent status epilepticus episodes resistant to phenobarbital and phenytoin and partly responding to midazolam. Eventually the seizures were completely controlled with pyridoxine; however, due to the severe condition of this child when seizing, no trial of withdrawal has been performed. The diagnosis of pyridoxine-dependent seizures was confirmed with biochemical and molecular testing revealing elevated alpha-AASA excretion and the presence of 2 different mutations in the antiquitin ( ALDH7A1) gene. Due to the availability of reliable laboratory testing, confirmation of the diagnosis was made without the life-threatening trial of pyridoxine withdrawal.

  3. Hyperresponsive febrile reactions to interleukin (IL) 1alpha and IL-1beta, and altered brain cytokine mRNA and serum cytokine levels, in IL-1beta-deficient mice.

    Science.gov (United States)

    Alheim, K; Chai, Z; Fantuzzi, G; Hasanvan, H; Malinowsky, D; Di Santo, E; Ghezzi, P; Dinarello, C A; Bartfai, T

    1997-03-18

    IL-1beta is an endogenous pyrogen that is induced during systemic lipopolysaccharide (LPS)- or IL-1-induced fever. We have examined the fever and cytokine responses following i.p. injection of IL-1 agonists, IL-1alpha and IL-1beta, and compared these with response to LPS (i.p.) in wild-type and IL-1beta-deficient mice. The IL-1beta deficient mice appear to have elevated body temperature but exhibit a normal circadian temperature cycle. Exogenously injected IL-1beta, IL-1alpha, or LPS induced hyperresponsive fevers in the IL-1beta-deficient mice. We also observed phenotypic differences between wild-type and IL-1beta-deficient mice in hypothalamic basal mRNA levels for IL-1alpha and IL-6, but not for IL-1beta-converting enzyme or IL-1 receptor type I or type II. The IL-1alpha mRNA levels were down-regulated, whereas the IL-6 mRNA levels were up-regulated in the hypothalamus of IL-1beta-deficient mice as compared with wild-type mice. The IL-1beta-deficient mice also responded to LPS challenge with significantly higher serum corticosterone and with lower serum tumor necrosis factor type alpha levels than the wild-type mice. The data suggest that, in the redundant cascade of proinflammatory cytokines, IL-1beta plays an important but not obligatory role in fever induction by LPS or IL-1alpha, as well as in the induction of serum tumor necrosis factor type alpha and corticosterone responses either by LPS or by IL-1alpha or IL-1beta.

  4. Profile of follitropin alpha/lutropin alpha combination for the stimulation of follicular development in women with severe luteinizing hormone and follicle-stimulating hormone deficiency.

    Science.gov (United States)

    Rinaldi, Leonardo; Selman, Helmy

    2016-01-01

    A severe gonadotropin deficiency together with chronic estradiol deficiency leading to amenorrhea characterizes patients suffering from hypogonadotropic hypogonadism. Administration of both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) to these patients has been shown to be essential in achieving successful stimulation of follicular development, ovulation, and rescue of fertility. In recent years, the availability of both recombinant FSH (rFSH) and recombinant LH (rLH) has provided a new therapeutic option for the stimulation of follicular growth in hypopituitary-hypogonadotropic women (World Health Organization Group I). In this article, we review the data reported in the literature to highlight the role and the efficacy of using recombinant gonadotropins, rFSH and rLH, in the treatment of women with severe LH/FSH deficiency. Although the studies on this issue are limited and the experiences available in the literature are few due to the small number of such patients, it is clearly evident that the recombinant gonadotropins rFSH and rLH are efficient in treating patients affected by hypogonadotropic hypogonadism. The results observed in the studies reported in this review suggest that recombinant gonadotropins are able to induce proper follicular growth, oocyte maturation, and eventually pregnancy in this group of women. Moreover, the clinical use of recombinant gonadotropins in this type of patients has given more insight into some endocrinological aspects of ovarian function that have not yet been fully understood.

  5. Leptin stimulates fibroblast growth factor 23 expression in bone and suppresses renal 1alpha,25-dihydroxyvitamin D3 synthesis in leptin-deficient mice.

    Science.gov (United States)

    Tsuji, Kiyomi; Maeda, Toyonobu; Kawane, Tetsuya; Matsunuma, Ayako; Horiuchi, Noboru

    2010-08-01

    Leptin is the LEP (ob) gene product secreted by adipocytes. We previously reported that leptin decreases renal expression of the 25-hydroxyvitamin D(3) 1alpha-hydroxylase (CYP27B1) gene through the leptin receptor (ObRb) by indirectly acting on the proximal tubules. This study focused on bone-derived fibroblast growth factor 23 (FGF-23) as a mediator of the influence of leptin on renal 1alpha-hydroxylase mRNA expression in leptin-deficient ob/ob mice. Exposure to leptin (200 ng/mL) for 24 hours stimulated FGF-23 expression by primary cultured rat osteoblasts. Administration of leptin (4 mg/kg i.p. at 12-hour intervals for 2 days) to ob/ob mice markedly increased the serum FGF-23 concentration while significantly reducing the serum levels of calcium, phosphate, and 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. Administration of FGF-23 (5 microg i.p. at 12-hour intervals for 2 days) to ob/ob mice suppressed renal 1alpha-hydroxylase mRNA expression. The main site of FGF-23 mRNA expression was the bone, and leptin markedly increased the FGF-23 mRNA level in ob/ob mice. In addition, leptin significantly reduced 1alpha-hydroxylase and sodium-phosphate cotransporters (NaP(i)-IIa and NaP(i)-IIc) mRNA levels but did not affect Klotho mRNA expression in the kidneys of ob/ob mice. Furthermore, the serum FGF-23 level and renal expression of 1alpha-hydroxylase mRNA were not influenced by administration of leptin to leptin receptor-deficient (db/db) mice. These results indicate that leptin directly stimulates FGF-23 synthesis by bone cells in ob/ob mice, suggesting that inhibition of renal 1,25(OH)(2)D(3) synthesis in these mice is at least partly due to elevated bone production of FGF-23.

  6. Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism.

    NARCIS (Netherlands)

    Steinfeld, R.; Grapp, M.; Kraetzner, R.; Dreha-Kulaczewski, S.; Helms, G.; Dechent, P.; Wevers, R.A.; Grosso, S.; Gartner, J.

    2009-01-01

    Sufficient folate supplementation is essential for a multitude of biological processes and diverse organ systems. At least five distinct inherited disorders of folate transport and metabolism are presently known, all of which cause systemic folate deficiency. We identified an inherited brain-specifi

  7. Linker molecules between laminins and dystroglycan ameliorate laminin-alpha2-deficient muscular dystrophy at all disease stages.

    Science.gov (United States)

    Meinen, Sarina; Barzaghi, Patrizia; Lin, Shuo; Lochmüller, Hanns; Ruegg, Markus A

    2007-03-26

    Mutations in laminin-alpha2 cause a severe congenital muscular dystrophy, called MDC1A. The two main receptors that interact with laminin-alpha2 are dystroglycan and alpha7beta1 integrin. We have previously shown in mouse models for MDC1A that muscle-specific overexpression of a miniaturized form of agrin (mini-agrin), which binds to dystroglycan but not to alpha7beta1 integrin, substantially ameliorates the disease (Moll, J., P. Barzaghi, S. Lin, G. Bezakova, H. Lochmuller, E. Engvall, U. Muller, and M.A. Ruegg. 2001. Nature. 413:302-307; Bentzinger, C.F., P. Barzaghi, S. Lin, and M.A. Ruegg. 2005. Matrix Biol. 24:326-332.). Now we show that late-onset expression of mini-agrin still prolongs life span and improves overall health, although not to the same extent as early expression. Furthermore, a chimeric protein containing the dystroglycan-binding domain of perlecan has the same activities as mini-agrin in ameliorating the disease. Finally, expression of full-length agrin also slows down the disease. These experiments are conceptual proof that linking the basement membrane to dystroglycan by specifically designed molecules or by endogenous ligands, could be a means to counteract MDC1A at a progressed stage of the disease, and thus opens new possibilities for the development of treatment options for this muscular dystrophy.

  8. The role of proteases, endoplasmic reticulum stress and SERPINA1 heterozygosity in lung disease and alpha-1 anti-trypsin deficiency.

    LENUS (Irish Health Repository)

    Greene, Catherine M

    2012-02-01

    The serine proteinase inhibitor alpha-1 anti-trypsin (AAT) provides an antiprotease protective screen throughout the body. Mutations in the AAT gene (SERPINA1) that lead to deficiency in AAT are associated with chronic obstructive pulmonary diseases. The Z mutation encodes a misfolded variant of AAT that is not secreted effectively and accumulates intracellularly in the endoplasmic reticulum of hepatocytes and other AAT-producing cells. Until recently, it was thought that loss of antiprotease function was the major cause of ZAAT-related lung disease. However, the contribution of gain-of-function effects is now being recognized. Here we describe how both loss- and gain-of-function effects can contribute to ZAAT-related lung disease. In addition, we explore how SERPINA1 heterozygosity could contribute to smoking-induced chronic obstructive pulmonary diseases and consider the consequences.

  9. A new sickle cell disease phenotype associating Hb S trait, severe pyruvate kinase deficiency (PK Conakry), and an alpha2 globin gene variant (Hb Conakry).

    Science.gov (United States)

    Cohen-Solal, M; Préhu, C; Wajcman, H; Poyart, C; Bardakdjian-Michau, J; Kister, J; Promé, D; Valentin, C; Bachir, D; Galactéros, F

    1998-12-01

    A Guinean woman, heterozygous for haemoglobin (Hb) S, was studied because of episodes of marked anaemia, repeated typical metaphyseal painful crises and haemosiderosis. Her sickling syndrome resulted from the association of Hb S trait with a severe pyruvate kinase deficiency leading to a 2,3-DPG concentration of twice normal levels. Sequence of the PK-R gene revealed an undescribed mutation in the homozygous or hemizygous state within exon 5 (nucleotide 2670 C-->A), leading to the interchange of Ser 130 into Tyr (PK Conakry). In addition, the patient carried a new haemoglobin variant, Hb Conakry [alpha80(F1) Leu-->Val], which seemed to have a mild effect. The high intraerythrocytic 2,3-DPG concentration induced by the PK deficiency resulted in a decreased oxygen affinity which favoured sickling to a level almost similar to that of Hb S/C compound heterozygous patients. This was confirmed by oxygen binding measurements of Hb A/Hb S erythrocytes in which 2,3-DPG content was modified in vitro. Hysteresis between deoxy- and reoxygenation curves, as well as increase in the n(max) value, demonstrated that the extent of HbS polymerization in the propositus was almost the same as that of RBCs from a homozygous sickle cell patient or those of an A/S heterozygous patient with an artificial in vitro increase of 2,3-DPG concentration.

  10. Alpha 1,3-Galactosyltransferase Deficiency in Pigs Increases Sialyltransferase Activities That Potentially Raise Non-Gal Xenoantigenicity

    Directory of Open Access Journals (Sweden)

    Jong-Yi Park

    2011-01-01

    Full Text Available We examined whether deficiency of the GGTA1 gene in pigs altered the expression of several glycosyltransferase genes. Real-time RT-PCR and glycosyltransferase activity showed that 2 sialyltransferases [α2,3-sialyltransferase (α2,3ST and α2,6-sialyltransferase (α2,6ST] in the heterozygote GalT KO liver have higher expression levels and activities compared to controls. Enzyme-linked lectin assays indicated that there were also more sialic acid-containing glycoconjugate epitopes in GalT KO livers than in controls. The elevated level of sialic-acid-containing glycoconjugate epitopes was due to the low level of α-Gal in heterozygote GalT KO livers. Furthermore, proteomics analysis showed that heterozygote GalT KO pigs had a higher expression of NAD+-isocitrate dehydrogenase (IDH, which is related to the CMP-N-acetylneuraminic acid hydroxylase (CMAH enzyme reaction. These findings suggest the deficiency of GGTA1 gene in pigs results in increased production of N-glycolylneuraminic acid (Neu5Gc due to an increase of α2,6-sialyltransferase and a CMAH cofactor, NAD+-IDH. This indicates that Neu5Gc may be a critical xenoantigen. The deletion of the CMAH gene in the GalT KO background is expected to further prolong xenograft survival.

  11. Biogenesis of lysosomal enzymes in the alpha-glucosidase II-deficient modA mutant of Dictyostelium discoideum: retention of alpha-1,3-linked glucose on N-linked oligosaccharides delays intracellular transport but does not alter sorting of alpha-mannosidase or beta-glucosidase.

    Science.gov (United States)

    Ebert, D L; Bush, J M; Dimond, R L; Cardelli, J A

    1989-09-01

    The endoplasmic reticulum-localized enzyme alpha-glucosidase II is responsible for removing the two alpha-1,3-linked glucose residues from N-linked oligosaccharides of glycoproteins. This activity is missing in the modA mutant strain, M31, of Dictyostelium discoideum. Results from both radiolabeled pulse-chase and subcellular fractionation experiments indicate that this deficiency did not prevent intracellular transport and proteolytic processing of the lysosomal enzymes, alpha-mannosidase and beta-glucosidase. However, the rate at which the glucosylated precursors left the rough endoplasmic reticulum was several-fold slower than the rate at which the wild-type precursors left this compartment. Retention of glucose residues did not disrupt the binding of the precursor forms of the enzymes with intracellular membranes, indicating that the delay in movement of proteins from the ER did not result from lack of association with membranes. However, the mutant alpha-mannosidase precursor contained more trypsin-sensitive sites than did the wild-type precursor, suggesting that improper folding of precursor molecules might account for the slow rate of transport to the Golgi complex. Percoll density gradient fractionation of extracts prepared from M31 cells indicated that the proteolytically processed mature forms of alpha-mannosidase and beta-glucosidase were localized to lysosomes. Finally, the mutation in M31 may have other, more dramatic, effects on the lysosomal system since two enzymes, N-acetylglucosaminidase and acid phosphatase, were secreted much less efficiently from lysosomal compartments by the mutant strain.

  12. alpha,omega-Dicarboxylic acid accumulation by acyl-CoA oxidase deficient mutants of Yarrowia lipolytica.

    Science.gov (United States)

    Smit, Martha S; Mokgoro, Masego M; Setati, Evodia; Nicaud, Jean-Marc

    2005-06-01

    alpha,omega-Dicarboxylic acid accumulation from alkanes and alkane degradation intermediates was investigated using Yarrowia lipolytica wild type strain W29 as well as a double, a triple and a quadruple POX-deleted strains. Six genes, POX1 through POX6, encode six acyl-CoA oxidase isozymes in Y. lipolytica. All the strains accumulated dodecanedioic acid (5-20 mg ml(-1)) from the diterminal functionalised 1,12-dodecane diol and 12-hydroxdodecanoic acid. The quadruple-deleted strain was the only strain that was able to accumulate dioic acids from C16 alkanol and monocarboxylic acid as well as from C12, C14 and C16 alkanes (maximum 8 mg ml(-1) from dodecane).

  13. Establishment of a bluetongue virus infection model in mice that are deficient in the alpha/beta interferon receptor.

    Directory of Open Access Journals (Sweden)

    Eva Calvo-Pinilla

    Full Text Available Bluetongue (BT is a noncontagious, insect-transmitted disease of ruminants caused by the bluetongue virus (BTV. A laboratory animal model would greatly facilitate the studies of pathogenesis, immune response and vaccination against BTV. Herein, we show that adult mice deficient in type I IFN receptor (IFNAR((-/- are highly susceptible to BTV-4 and BTV-8 infection when the virus is administered intravenously. Disease was characterized by ocular discharges and apathy, starting at 48 hours post-infection and quickly leading to animal death within 60 hours of inoculation. Infectious virus was recovered from the spleen, lung, thymus, and lymph nodes indicating a systemic infection. In addition, a lymphoid depletion in spleen, and severe pneumonia were observed in the infected mice. Furthermore, IFNAR((-/- adult mice immunized with a BTV-4 inactivated vaccine showed the induction of neutralizing antibodies against BTV-4 and complete protection against challenge with a lethal dose of this virus. The data indicate that this mouse model may facilitate the study of BTV pathogenesis, and the development of new effective vaccines for BTV.

  14. Alpha-1,3-galactosyltransferase-deficient miniature pigs produced by serial cloning using neonatal skin fibroblasts with loss of heterozygosity

    Science.gov (United States)

    Kim, Young June; Ahn, Kwang Sung; Kim, Minjeong; Kim, Min Ju; Ahn, Jin Seop; Ryu, Junghyun; Heo, Soon Young; Park, Sang-Min; Kang, Jee Hyun; Choi, You Jung; Shim, Hosup

    2017-01-01

    Objective Production of alpha-1,3-galactosyltransferase (αGT)-deficient pigs is essential to overcome xenograft rejection in pig-to-human xenotransplantation. However, the production of such pigs requires a great deal of cost, time, and labor. Heterozygous αGT knockout pigs should be bred at least for two generations to ultimately obtain homozygote progenies. The present study was conducted to produce αGT-deficient miniature pigs in much reduced time using mitotic recombination in neonatal ear skin fibroblasts. Methods Miniature pig fibroblasts were transfected with αGT gene-targeting vector. Resulting gene-targeted fibroblasts were used for nuclear transfer (NT) to produce heterozygous αGT gene-targeted piglets. Fibroblasts isolated from ear skin biopsies of these piglets were cultured for 6 to 8 passages to induce loss of heterozygosity (LOH) and treated with biotin-conjugated IB4 that binds to galactose-α-1,3-galactose, an epitope produced by αGT. Using magnetic activated cell sorting, cells with monoallelic disruption of αGT were removed. Remaining cells with LOH carrying biallelic disruption of αGT were used for the second round NT to produce homozygous αGT gene-targeted piglets. Results Monoallelic mutation of αGT gene was confirmed by polymerase chain reaction in fibroblasts. Using these cells as nuclear donors, three heterozygous αGT gene-targeted piglets were produced by NT. Fibroblasts were collected from ear skin biopsies of these piglets, and homozygosity was induced by LOH. The second round NT using these fibroblasts resulted in production of three homozygous αGT knockout piglets. Conclusion The present study demonstrates that the time required for the production of αGT-deficient miniature pigs could be reduced significantly by postnatal skin biopsies and subsequent selection of mitotic recombinants. Such procedure may be beneficial for the production of homozygote knockout animals, especially in species, such as pigs, that require a

  15. Brain histaminergic system in mast cell-deficient (Ws/Ws) rats: histamine content, histidine decarboxylase activity, and effects of (S) alpha-fluoromethylhistidine.

    Science.gov (United States)

    Sugimoto, K; Maeyama, K; Alam, K; Sakurai, E; Onoue, H; Kasugai, T; Kitamura, Y; Watanabe, T

    1995-08-01

    The mast cell-deficient [Ws/Ws (White spotting in the skin)] rat was investigated with regard to the origin of histamine in the brain. No mast cells were detected in the pia mater and the perivascular region of the thalamus of Ws/Ws rats by Alcian Blue staining. The histamine contents and histidine decarboxylase (HDC) activities of various brain regions of Ws/Ws rats were similar to those of +/+ rats except the histamine contents of the cerebral cortex and cerebellum. As the cerebral cortex and cerebellum have meninges that are difficult to remove completely, the histamine contents of these two regions may be different between Ws/Ws and +/+ rats. We assume that the histamine content of whole brain with meninges in Ws/Ws rats is < 60% of that in +/+ rats. So we conclude that approximately half of the histamine content of rat brain is derived from mast cells. Next, the effects of (S) alpha-fluoromethylhistidine (FMH), a specific inhibitor of HDC, on the histamine contents and HDC activities of various regions of the brain were examined in Ws/Ws rats. In the whole brain of Ws/Ws rats, 51 and 37% of the histamine content of the control group remained 2 and 6 h, respectively, after FMH administration (100 mg/kg of body weight). Therefore, we suggest that there might be other histamine pools including histaminergic neurons in rat brain.

  16. Introduction of the human pro. cap alpha. 1(I) collagen gene into pro. cap alpha. 1(I)-deficient Mov-13 mouse cells leads to formation of functional mouse-human hybrid type I collagen

    Energy Technology Data Exchange (ETDEWEB)

    Schnieke, A.; Dziadek, M.; Bateman, J.; Mascara, T.; Harbers, K.; Gelinas, R.; Jaenisch, R.

    1987-02-01

    The Mov-13 mouse strain carries a retroviral insertion in the pro..cap alpha..1(I) collagen gene that prevents transcription of the gene. Cell lines derived from homozygous embryos do not express type I collagen although normal amounts of pro..cap alpha..2 mRNA are synthesized. The authors have introduced genomic clones of either the human or mouse pro..cap alpha..1(I) collagen gene into homozygous cell lines to assess whether the human or mouse pro..cap alpha..1(I) chains can associate with the endogenous mouse pro..cap alpha..2(I) chain to form stable type I collagen. The human gene under control of the simian virus 40 promoter was efficiently transcribed in the transfected cells. Protein analyses revealed that stable heterotrimers consisting of two human ..cap alpha..1 chains and one mouse ..cap alpha..2 chain were formed and that type I collagen was secreted by the transfected cells at normal rates. However, the electrophoretic migration of both ..cap alpha..1(I) and ..cap alpha..2(I) chains in the human-mouse hybrid molecules were retarded, compared to the ..cap alpha..(I) chains in control mouse cells. Inhibition of the posttranslational hydroxylation of lysine and proline resulted in comigration of human and mouse ..cap alpha..1 and ..cap alpha..2 chains, suggesting that increased posttranslational modification caused the altered electrophoretic migration in the human-mouse hybrid molecules. Amino acid sequence differences between the mouse and human ..cap alpha.. chains may interfere with the normal rate of helix formation and increase the degree of posttranslational modifications similar to those observed in patients with lethal perinatal osteogenesis imperfecta. The Mov-13 mouse system should allow the authors to study the effect specific mutations introduced in transfected pro..cap alpha..1(I) genes have on the synthesis, assembly, and function of collagen I.

  17. Value of Mentzer index in differentiation between alpha thalassemia carriers and iron deficiency anemia%Mentzer指数在鉴别轻型α地中海贫血与缺铁性贫血中的价值

    Institute of Scientific and Technical Information of China (English)

    梅敏; 帅虎; 朱甫津; 谭尚华

    2011-01-01

    Objective To evaluates the value of Mentzer index ( MI ) in differentiating alpha thalassemia carriers from iron deficiency anemia.Methods The data on alpha thalassemia gene,blood cell count,and serum levels of iron and ferritin were retrospectively analyzed in 151 patients with reduced hemoglobin A2( HbA2 )levels on hemoglobin electrophoresis.Based on α -globin gene analysis and levels of iron and ferritin,the patients were assigned to alpha thalassemia carriers group ( n =90 ),or iron deficiency anemia group ( n =61 ).Results MI differed significantly between iron deficiency anemia group and alpha thalassemia carriers with normal iron group ( P < 0.01 ),iron deficiency anemia group and alpha thalassemia carriers with iron deficiency group ( P< 0.01 ),iron deficiency anemia group and alpha thalassemia carriers group ( P < 0.01 ); but did not differ significantly between alpha thalassemia carriers with normal iron group and alpha thalassemia carriers with iron deficiency group ( P> 0.05 ).The area under the curve ( AUC ) for MI of receiver operating characteristic curve ( ROC ) was 0.849 between iron deficiency anemia group and alpha thalassemia carriers group,and the cut-off point was 13.1.As MI was -- 13.1,the sensitivity for detecting iron deficiency anemia was 96.7%,specificity 61.1%,and Youden index 0.58.If MI combined with RDW,the sensitivity was 100%.Conclusions Mentzer index has certain accuracy in differentiating alpha thalassemia carriers with reduced HbA2 levels from iron deficiency anemia.Both MI and RDW under the cut-off point can exclude the possibility of iron deficiency anemia.%目的 评估Mentzer指数(Mentzer index,MI)在鉴别HbA2减低中轻型α地中海贫血与缺铁性贫血中的价值.方法 回顾本院3年来血红蛋白电泳中HbA2减低的151例人群的α地贫基因、血常规、铁蛋白、血清铁数据,根据地贫基因分析和铁蛋白、血清铁水平将其分成2组:轻型α地中海贫血组(n=90),

  18. A polymorphic variant in the human electron transfer flavoprotein alpha-chain (alpha-T171) displays decreased thermal stability and is overrepresented in very-long-chain acyl-CoA dehydrogenase-deficient patients with mild childhood presentation

    DEFF Research Database (Denmark)

    Bross, P; Pedersen, P; Nyholm, M;

    1999-01-01

    The consequences of two amino acid polymorphisms of human electron transfer flavoprotein (alpha-T/I171 in the alpha-subunit and beta-M/T154 in the beta-subunit) on the thermal stability of the enzyme are described. The alpha-T171 variant displayed a significantly decreased thermal stability...... thermal stability) was significantly overrepresented. Subgrouping of the VLCAD patients into three phenotypic classes (severe childhood, mild childhood, and adult presentation) revealed that the overrepresentation of the alpha-T171 variant was significant only in patients with mild childhood presentation...

  19. Low Serum Levels of Alpha1 Anti-trypsin (α1-AT) and Risk of Airflow Obstruction in Non-Primary α1-AT-Deficient Patients with Compensated Chronic Liver Disease

    Science.gov (United States)

    Rodríguez-Romero, Elizabeth; Suárez-Cuenca, Juan Antonio; Elizalde-Barrera, César Iván; Mondragón-Terán, Paul; Martínez-Hernández, José Enrique; Gómez-Cortés, Eduardo; de Vaca, Rebeca Pérez-Cabeza; Hernández-Muñoz, Rolando E.; Melchor-López, Alberto; Jiménez-Saab, Nayeli Gabriela

    2015-01-01

    Background Alpha1 anti-trypsin (α1-AT), a serine protease inhibitor synthesized in the liver, is a major circulating antiprotease that provides defense against proteolytic damage in several tissues. Its deficiency is associated with airflow obstruction. The present study aimed to explore the role of α1-AT as a biomarker of airflow performance in chronic liver disease (CLD). Material/Methods Serum α1-AT levels and lung function (spirometry) were evaluated in non-primary α1-AT-deficient, alcoholic CLD patients without evident respiratory limitations. Results Thirty-four patients with airflow obstruction (n=11), airflow restriction (n=12), and normal airflow (n=11, age-matched controls) were eligible. α1-AT was decreased in the airflow obstruction group. ROC-cutoff α1-AT=24 mg/dL effectively discriminated airflow obstruction (AUC=0.687) and was associated with a 10-fold higher risk (p=0.0007). Conclusions Lower α1-AT increased the risk of airflow obstruction in CLD patients without primary α1-AT deficiency. PMID:25913248

  20. Evaluación del efecto de la ingesta de una sobrecarga de glucosa sobre los niveles séricos de la proteína C reactiva y de la α1-antitripsina en mujeres obesas Effect of a high glucose load on serum concentrations of C-reactive protein and α1-antitrypsin in obese women

    Directory of Open Access Journals (Sweden)

    M.ª M. Ramírez A.

    2008-08-01

    Full Text Available La obesidad está asociada con un estado inflamatorio. La proteína C reactiva (PCR es una molécula proinflamatoria y la α1-antitripsina es una proteína plasmática sensible a inflamación. El proceso proinflamatorio puede ser influenciado por la hiperglicemia postprandial. Objetivo: Evaluar el efecto de la ingesta de una sobrecarga de glucosa sobre los niveles séricos de PCR y de α1-antitripsina en mujeres obesas con tolerancia normal a la glucosa. Metodología: La población estuvo conformada por 15 mujeres obesas (edad = 34,4 ± 4,3 años, IMC = 35,3 ± 5,3 kg/m² y 15 mujeres normopeso (edad = 33,9 ± 2,9 años, IMC = 21,8 ± 1,9 kg/m². Los sujetos en ayuno se sometieron a una prueba de tolerancia oral a la glucosa (75 g y 2 h. Se midió los niveles pre y postprandiales de PCR y de α1-antitripsina. Los parámetros antropométricos y bioquímicos se midieron en ambos grupos. Resultados: Las mujeres obesas presentaron mayores niveles de PCR en ayuno (P = 0,05 diferencia con el nivel preprandial. Los niveles séricos de PCR se correlacionaron positivamente con el índice de masa corporal (IMC en el grupo obeso. Los niveles séricos de α1-antitripsina no se correlacionaron con el IMC en ninguno de los dos grupos estudio. Conclusión: La ingesta de una sobrecarga de glucosa no tiene ningún efecto sobre los niveles séricos de PCR y α1-antitripsina. Los niveles séricos de α1-antitripsina no están incrementados en mujeres obesas. Los niveles séricos de PCR están incrementados en mujeres obesas y se correlacionan positivamente con el IMC.Obesity is associated with increased inflammation. C-reactive protein (CRP is a proinflammatory molecule, and α1-antitrypsin is an inflammation-sensitive plasma protein. Proinflammatory process may be influenced by postprandial hyperglycemia. Objective: The aim of the present study was to evaluate the role of high-glucose load on postprandial circulating levels of PCR and α1-antitrypsin in obese

  1. Novel ATRX gene damaging missense mutation c.6740A>C segregates with profound to severe intellectual deficiency without alpha thalassaemia

    Directory of Open Access Journals (Sweden)

    Habib Bouazzi

    2016-01-01

    Interpretation & conclusions: The novel mutation c.6740A>C was identified within the ATRX gene helicase domain and confirmed by Sanger sequencing in the three affected males as well as in the mother and her two daughters. This mutation was predicted to be damaging and deleterious. The novel mutation segregated with the phenotype without alpha-thalassaemia and with non-skewed X chromosome.

  2. A neonate with Coombs-negative hemolytic jaundice with spherocytes but normal erythrocyte indices: a rare case of autosomal-recessive hereditary spherocytosis due to alpha-spectrin deficiency.

    Science.gov (United States)

    Yaish, H M; Christensen, R D; Agarwal, A

    2013-05-01

    The diagnosis of hereditary spherocytosis (HS) in a newborn infant is generally made on the basis of a positive family history, spherocytes on blood film and Coombs-negative hemolytic jaundice of variable severity with an elevated mean corpuscular hemoglobin concentration (MCHC) and a low mean corpuscular volume (MCV). In general, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) quantification of erythrocyte membrane proteins is not needed to make the clinical diagnosis of HS. However, we observed that a neonate with no family history of HS, but with abundant spherocytosis on repeated blood films, Coombs-negative hemolytic jaundice and normal MCHC and MCV measurements, where SDS-PAGE revealed alpha-spectrin deficiency, a rare autosomal-recessive variety of HS that generally has a severe clinical phenotype.

  3. Omega-3 fatty acid deficient male rats exhibit abnormal behavioral activation in the forced swim test following chronic fluoxetine treatment: association with altered 5-HT1A and alpha2A adrenergic receptor expression.

    Science.gov (United States)

    Able, Jessica A; Liu, Yanhong; Jandacek, Ronald; Rider, Therese; Tso, Patrick; McNamara, Robert K

    2014-03-01

    Omega-3 fatty acid deficiency during development leads to enduing alterations in central monoamine neurotransmission in rat brain. Here we investigated the effects of omega-3 fatty acid deficiency on behavioral and neurochemical responses to chronic fluoxetine (FLX) treatment. Male rats were fed diets with (CON, n = 34) or without (DEF, n = 30) the omega-3 fatty acid precursor alpha-linolenic acid (ALA) during peri-adolescent development (P21-P90). A subset of CON (n = 14) and DEF (n = 12) rats were administered FLX (10 mg/kg/d) through their drinking water for 30 d beginning on P60. The forced swimming test (FST) was initiated on P90, and regional brain mRNA markers of serotonin and noradrenaline neurotransmission were determined. Dietary ALA depletion led to significant reductions in frontal cortex docosahexaenoic acid (DHA, 22:6n-3) composition in DEF (-26%, p = 0.0001) and DEF + FLX (-32%, p = 0.0001) rats. Plasma FLX and norfluoxetine concentrations did not different between FLX-treated DEF and CON rats. During the 15-min FST pretest, DEF + FLX rats exhibited significantly greater climbing behavior compared with CON + FLX rats. During the 5-min test trial, FLX treatment reduced immobility and increased swimming in CON and DEF rats, and only DEF + FLX rats exhibited significant elevations in climbing behavior. DEF + FLX rats exhibited greater midbrain, and lower frontal cortex, 5-HT1A mRNA expression compared with all groups including CON + FLX rats. DEF + FLX rats also exhibited greater midbrain alpha2A adrenergic receptor mRNA expression which was positively correlated with climbing behavior in the FST. These preclinical data demonstrate that low omega-3 fatty acid status leads to abnormal behavioral and neurochemical responses to chronic FLX treatment in male rats.

  4. 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....

  5. The fibrinogen cleavage product Aα-Val360, a specific marker of neutrophil elastase activity in vivo

    DEFF Research Database (Denmark)

    Carter, Richard I; Mumford, Richard A; Treonze, Kelly M

    2011-01-01

    Alpha-1-antitrypsin (A1AT) deficiency is the only recognised genetic risk factor for chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality worldwide. Since A1AT is the major inhibitor of neutrophil elastase (NE), this enzyme has become widely implicated in the p...

  6. Alpha2 macroglobulin elevation without an acute phase response in depressed adults with Down's syndrome: implications.

    Science.gov (United States)

    Tsiouris, J A; Mehta, P D; Patti, P J; Madrid, R E; Raguthu, S; Barshatzky, M R; Cohen, I L; Sersen, E

    2000-12-01

    Studies of immune function during depression in persons without intellectual disability (ID) have revealed elevated levels of alpha2 macroglobulin (alpha2M) and an acute phase protein (APP) response. Clinical observation suggests that people with Down's syndrome (DS) may have associated genetic abnormalities in their immune systems. The APP response and alpha2M changes in depressed versus non-depressed adults with DS was the subject of the present study. The serum pan-proteinase inhibitor alpha2M, and the AP proteins c-reactive protein (CRP), alpha1 antitrypsin (alpha1AT), ceruloplasmin (Cp), beta2 Macroglobulin (beta2M), transthyretin (Trans), serum amyloid protein (SAP), and albumin (Alb) were measured in 38 adults with DS, 19 of whom were diagnosed with and 19 without depression using a sandwich enzyme-linked immunosorbent assay (ELISA). The DSM-IV criteria were used for diagnoses. Medical and neurological examinations excluded medical disorders associated with APP response. Only alpha2M and CRP were significantly different in the depressed versus non-depressed groups. The alpha2M was higher, a response similar to one observed in depressed people without ID, but the CRP was lower in the depressed group, especially in those subjects not on psychotropic medications, contrary to the expected APP response to depression. The results suggest that alpha2M elevation in depressed adults with DS is independent of the APP response. An alternative explanation for its elevation is proposed linking the core symptom of depression with the mammalian dormancy/hibernation process. Further studies are needed to confirm that alpha2M elevation is specific to depression and that it might provide a helpful marker for the diagnosis of depression in people with ID.

  7. Safety and tolerability of an intravenously administered alpha1-proteinase inhibitor at an increased infusion rate: a novel, randomized, placebo-masked, infusion rate-controlled, crossover study in healthy adults

    Directory of Open Access Journals (Sweden)

    Ngo LY

    2014-06-01

    Full Text Available Leock Y Ngo,1 Adam Haeberle,1 Jacqueline Dyck-Jones,1 David Gelmont,1 Leman Yel11Baxter Healthcare Corporation, Westlake Village, CA, USAPurpose: Alpha1-proteinase inhibitor (A1PI is indicated for chronic augmentation therapy in adults with emphysema due to congenital deficiency of A1PI. An intravenous infusion rate of 0.04 mL/kg/minute is currently recommended for the A1PI product, Glassia®. This randomized, placebo-masked, rate-controlled, crossover study was designed to evaluate the safety and tolerability of A1PI administration at an increased infusion rate.Patients and methods: A total of 30 healthy male and female subjects aged 19–61 years were enrolled. Each subject received simultaneous intravenous infusions of A1PI (Glassia® and placebo (human albumin 2.5% administered through a single infusion site on two separate treatment periods. Subjects were randomized in a 1:1 ratio to receive either test treatment (A1PI 0.2 mL/kg/minute + placebo 0.04 mL/kg/minute, or reference treatment (A1PI 0.04 mL/kg/minute + placebo 0.2 mL/kg/minute on Day 1. On Day 15, subjects received the other treatment regimen in a crossover sequence.Results: A total of 36 adverse events (AEs, regardless of causality, were reported; all were non-serious and of mild intensity, with headaches and dizziness occurring most frequently (12 [33.3%] and three [8.3%] of 36 AEs, respectively. Only seven AEs in six subjects were assessed as related to study treatment: with two AEs reported in two subjects treated with the 0.2 mL/kg/minute rate compared with five AEs in four subjects treated with the 0.04 mL/kg/minute rate.Conclusions: This study demonstrated the safety and tolerability of an A1PI product at an increased infusion rate (0.2 mL/kg/minute resulting in a shorter infusion duration in healthy subjects.Keywords: A1PI, Glassia, administration rate, Alpha-1 antitrypsin, ATT

  8. Iodine Deficiency

    Science.gov (United States)

    ... 2017 By ATA | Featured , Iodine Deficiency , News Releases , Potassium Iodide (KI) | No Comments IDD NEWSLETTER – February 2017 VOLUME ... 2016 By ATA | Featured , Iodine Deficiency , News Releases , Potassium Iodide (KI) | No Comments IDD NEWSLETTER – November 2015 (PDF ...

  9. [Vitamin deficiencies and hypervitaminosis].

    Science.gov (United States)

    Mino, M

    1999-10-01

    There have recently been very few deficiencies with respect to fat soluble and water soluble vitamins in Japan All-trans-retinoic acid as induction or maintenance treatment improves disease free and overall survival against acute promyelocytic leukemia. In the isolated vitamin E deficiencies gene mutation has been cleared for alpha-tocopherol transferprotein. Recently, a relation of nutritional vitamin K intake and senile osteoporosis in women was epidemiologically demonstrated on a prospective study. Thiamin was yet noticed as development of deficiency in alcoholism, while the importance of supplemental folic acid during pregnancy has become especially clear in light of studies showing that folic acid supplements reduce the risk of neural tube defects in the fetus. With respect to hypervitaminosis, the Council for Responsible Nutrition (CRN), USA, has established safe intakes by identifying the NOAEL (No Observed Adverse Effect Level) and LOAEL (Lowest Observed Adverse Effect Level). Summaries of NOAEL and LOAEL for individual vitamins were shown.

  10. α₁-Antitrypsin protease inhibitor MZ heterozygosity is associated with airflow obstruction in two large cohorts

    DEFF Research Database (Denmark)

    Sørheim, Inga-Cecilie; Bakke, Per; Gulsvik, Amund

    2010-01-01

    Severe a1-antitrypsin deficiency is a known genetic risk factor for COPD. Heterozygous (protease inhibitor [PI] MZ) individuals have moderately reduced serum levels of a1-antitrypsin, but whether they have an increased risk of COPD is uncertain....

  11. Disaccharidase deficiency.

    Science.gov (United States)

    Bayless, T M; Christopher, N L

    1969-02-01

    This review of the literature and current knowledge concerning a nutritional disorder of disaccharidase deficiency discusses the following topics: 1) a description of disorders of disaccharide digestion; 2) some historical perspective on the laboratory and bedside advances in the past 10 years that have helped define a group of these digestive disorders; 3) a classification of conditions causing disaccharide intolerance; and 4) a discussion of some of the specific clinical syndromes emphasizing nutritional consequences of these syndromes. The syndromes described include congenital lactase deficiency, acquired lactase deficiency in teenagers and adults, acquired generalized disaccharidase deficiency secondary to diffuse mucosal damage, acquired lactose intolerance secondary to alterations in the intestinal transit, sucrase-isomaltase deficiencies, and other disease associations connected with lactase deficiency such as colitis.

  12. Iodine Deficiency

    NARCIS (Netherlands)

    Zimmermann, M.B.

    2009-01-01

    Iodine deficiency has multiple adverse effects in humans, termed iodine deficiency disorders, due to inadequate thyroid hormone production. Globally, it is estimated that 2 billion individuals have an insufficient iodine intake, and South Asia and sub-Saharan Africa are particularly affected. Howeve

  13. Differential inhibition of 17alpha-hydroxylase and 17,20-lyase activities by three novel missense CYP17 mutations identified in patients with P450c17 deficiency

    NARCIS (Netherlands)

    E.L.T. van den Akker (Erica); J.W. Koper (Jan); A.L.M. Boehmer (Annemie); A.P.N. Themmen (Axel); M. Verhoef-Post (Miriam); M.A. Timmerman (Marianna); B.J. Otten (Barto); S.L.S. Drop (Stenvert); F.H. de Jong (Frank)

    2002-01-01

    textabstractThe microsomal enzyme cytochrome P450c17 is an important regulator of steroidogenesis. The enzyme has two functions: 17alpha-hydroxylase and 17,20-lyase activities. These functions determine the ability of adrenal glands and gonads to synthesize 17alpha-hydroxylated glu

  14. Iron deficiency.

    Science.gov (United States)

    Scrimshaw, N S

    1991-10-01

    The world's leading nutritional problem is iron deficiency. 66% of children and women aged 15-44 years in developing countries have it. Further, 10-20% of women of childbearing age in developed countries are anemic. Iron deficiency is identified with often irreversible impairment of a child's learning ability. It is also associated with low capacity for adults to work which reduces productivity. In addition, it impairs the immune system which reduces the body's ability to fight infection. Iron deficiency also lowers the metabolic rate and the body temperature when exposed to cold. Hemoglobin contains nearly 73% of the body's iron. This iron is always being recycled as more red blood cells are made. The rest of the needed iron does important tasks for the body, such as binds to molecules that are reservoirs of oxygen for muscle cells. This iron comes from our diet, especially meat. Even though some plants, such as spinach, are high in iron, the body can only absorb 1.4-7% of the iron in plants whereas it can absorb 20% of the iron in red meat. In many developing countries, the common vegetarian diets contribute to high rates of iron deficiency. Parasitic diseases and abnormal uterine bleeding also promote iron deficiency. Iron therapy in anemic children can often, but not always, improve behavior and cognitive performance. Iron deficiency during pregnancy often contributes to maternal and perinatal mortality. Yet treatment, if given to a child in time, can lead to normal growth and hinder infections. However, excess iron can be damaging. Too much supplemental iron in a malnourished child promotes fatal infections since the excess iron is available for the pathogens use. Many countries do not have an effective system for diagnosing, treating, and preventing iron deficiency. Therefore a concerted international effort is needed to eliminate iron deficiency in the world.

  15. Alpha fetoprotein

    Science.gov (United States)

    Fetal alpha globulin; AFP ... Greater than normal levels of AFP may be due to: Cancer in testes , ovaries, biliary (liver secretion) tract, stomach, or pancreas Cirrhosis of the liver Liver cancer ...

  16. 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

  17. Alpha-mannosidosis - a review of genetic, clinical findings and options of treatment

    DEFF Research Database (Denmark)

    Borgwardt, Line; Lund, Allan Meldgaard; Dali, Christine I.

    2014-01-01

    Alpha-mannosidosis (OMIM 248500) is a rare, autosomal recessive, multisystemic, progressive lysosomal storage disorder caused by a deficiency of alpha-mannosidase. It has been described in humans, cattle, domestic cats, mice and guinea pigs. In humans, alpha-mannosidosis results in progressive...... for alpha-mannosidosis. The pathology, genetics and clinical pictures, including impairments in the activity of daily living are discussed....

  18. Role of macrophage inflammatory protein-1alpha in T-cell-mediated immunity to viral infection

    DEFF Research Database (Denmark)

    Madsen, Andreas N; Nansen, Anneline; Christensen, Jan P

    2003-01-01

    The immune response to lymphocytic choriomeningitis virus in mice lacking macrophage inflammatory protein-1alpha (MIP-1alpha) was evaluated. Generation of virus-specific effector T cells is unimpaired in MIP-1alpha-deficient mice. Furthermore, MIP-1alpha is not required for T-cell-mediated virus...

  19. $\\alpha_s$ review (2016)

    CERN Document Server

    d'Enterria, David

    2016-01-01

    The current world-average of the strong coupling at the Z pole mass, $\\alpha_s(m^2_{Z}) = 0.1181 \\pm 0.0013$, is obtained from a comparison of perturbative QCD calculations computed, at least, at next-to-next-to-leading-order accuracy, to a set of 6 groups of experimental observables: (i) lattice QCD "data", (ii) $\\tau$ hadronic decays, (iii) proton structure functions, (iv) event shapes and jet rates in $e^+e^-$ collisions, (v) Z boson hadronic decays, and (vi) top-quark cross sections in p-p collisions. In addition, at least 8 other $\\alpha_s$ extractions, usually with a lower level of theoretical and/or experimental precision today, have been proposed: pion, $\\Upsilon$, W hadronic decays; soft and hard fragmentation functions; jets cross sections in pp, e-p and $\\gamma$-p collisions; and photon F$_2$ structure function in $\\gamma\\,\\gamma$ collisions. These 14 $\\alpha_s$ determinations are reviewed, and the perspectives of reduction of their present uncertainties are discussed.

  20. Iron deficiency

    DEFF Research Database (Denmark)

    Schou, Morten; Bosselmann, Helle; Gaborit, Freja

    2015-01-01

    BACKGROUND: Both iron deficiency (ID) and cardiovascular biomarkers are associated with a poor outcome in heart failure (HF). The relationship between different cardiovascular biomarkers and ID is unknown, and the true prevalence of ID in an outpatient HF clinic is probably overlooked. OBJECTIVES.......043). CONCLUSION: ID is frequent in an outpatient HF clinic. ID is not associated with cardiovascular biomarkers after adjustment for traditional confounders. Inflammation, but not neurohormonal activation is associated with ID in systolic HF. Further studies are needed to understand iron metabolism in elderly HF...

  1. Views of Discrimination among Individuals Confronting Genetic Disease

    OpenAIRE

    Klitzman, Robert

    2010-01-01

    Though the US passed the Genetic Information Non-Discrimination Act, many questions remain of how individuals confronting genetic disease view and experience possible discrimination. We interviewed, for 2 hours each, 64 individuals who had, or were at risk for, Huntington’s Disease, breast cancer, or Alpha-1 antitrypsin deficiency. Discrimination can be implicit, indirect and subtle, rather than explicit, direct and overt; and be hard to prove. Patients may be treated “differently” and unfair...

  2. Electron transfer flavoprotein deficiency: Functional and molecular aspects

    DEFF Research Database (Denmark)

    Schiff, M; Froissart, R; Olsen, Rikke Katrine Jentoft

    2006-01-01

    Multiple acyl-CoA dehydrogenase deficiency (MADD) is a recessively inherited metabolic disorder that can be due to a deficiency of electron transfer flavoprotein (ETF) or its dehydrogenase (ETF-ubiquinone oxidoreductase). ETF is a mitochondrial matrix protein consisting of alpha- (30kDa) and beta...

  3. Merosin-deficient congenital muscular dystrophy. Partial genetic correction in two mouse models

    DEFF Research Database (Denmark)

    Kuang, W; Xu, H; Vachon, P H;

    1998-01-01

    Humans and mice with deficiency of the alpha2 subunit of the basement membrane protein laminin-2/merosin suffer from merosin-deficient congenital muscular dystrophy (MCMD). We have expressed a human laminin alpha2 chain transgene under the regulation of a muscle-specific creatine kinase promoter ...

  4. VLCAD deficiency

    DEFF Research Database (Denmark)

    Boneh, A; Andresen, B S; Gregersen, N

    2006-01-01

    -negative diagnoses of VLCADD in asymptomatic newborn babies. In view of the emerging genotype-phenotype correlation in this disorder, the information derived from mutational analysis can be helpful in designing the appropriate follow-up and therapeutic regime for these patients.......We diagnosed six newborn babies with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) through newborn screening in three years in Victoria (prevalence rate: 1:31,500). We identified seven known and two new mutations in our patients (2/6 homozygotes; 4/6 compound heterozygotes). Blood...... samples taken at age 48-72 h were diagnostic whereas repeat samples at an older age were normal in 4/6 babies. Urine analysis was normal in 5/5. We conclude that the timing of blood sampling for newborn screening is important and that it is important to perform mutation analysis to avoid false...

  5. 发色底物法在酶促反应初速度内测定α1抗胰蛋白酶的活性%Detection ofα1 antitrypsin activity by chromogenic substrate assay with initial veloci-ty of enzymatic reaction

    Institute of Scientific and Technical Information of China (English)

    张晋超; 赵雄; 吕茂民; 尹惠琼; 王延琳; 章金刚

    2015-01-01

    Objective To detect the activity of α1 antitrypsin(AAT) with initial velocity of enzymatic reaction in order to detect the activity of samples in the process of separating and purifying plasma protein ,chromogenic substrate assay was optimized.Methods The effect of trypsin concentration and reaction time on enzymatic reaction was acquired by the kinetic monitoring mode of the microplate reader .Initial velocity was calculated to confirm the largest concentration of trypsin which was saturated by substrate .AAT was incubated with trypsin and absorbance produced by enzymatic reaction of remaining trypsin and substrate could reflect the activity of AAT .A standard curve was established with △D fitting with the activity of AAT standard.The activity of related samples was detected and the precision and accuracy of the method were evaluated . Results Trypsin concentration was 0.0625 mg/ml.Within 20 minutes, enzymatic reaction was with initial velocity .The range of the standard curve was 200-1200 IU/ml.Correlation coefficient was more than 0.99.The activity of Cohn Ⅳ, samples of pre-processing and elution were (720.59 ±18.63), (601.84 ±19.18),and (568.09 ±24.83)IU/ml, respec-tively.The relative standard deviation was less than 10%. Sample recovery rate was 90%-110%.Conclusion The optimized chromogenic substrate assay greatly improves accuracy and precision .The method can be used for the detec-tion of AAT activity of samples in laboratories and workshops .%目的:优化发色底物法,使其在酶促反应初速度内测定α1抗胰蛋白酶( AAT)的活性并用于血浆蛋白纯化过程中各样品活性的检测。方法采用酶标仪动态监测模式观察酶浓度和反应时间对酶促反应的影响;计算初速度并确定被底物饱和的最大酶浓度。将AAT与胰蛋白酶孵育,剩余靶酶和底物作用产生的光密度可反映AAT的活性。通过△D与AAT标准品活性进行拟合建立标准曲线,测定相关样品的活

  6. Role of G{alpha}12 and G{alpha}13 as Novel Switches for the Activity of Nrf2, a Key Antioxidative Transcription Factor

    OpenAIRE

    2007-01-01

    G{alpha}12 and G{alpha}13 function as molecular regulators responding to extracellular stimuli. NF-E2-related factor 2 (Nrf2) is involved in a protective adaptive response to oxidative stress. This study investigated the regulation of Nrf2 by G{alpha}12 and G{alpha}13. A deficiency of G{alpha}12, but not of G{alpha}13, enhanced Nrf2 activity and target gene transactivation in embryo fibroblasts. In mice, G{alpha}12 knockout activated Nrf2 and thereby facilitated heme catabolism to bilirubin a...

  7. Vitamin Deficiency Anemia

    Science.gov (United States)

    Vitamin deficiency anemia Overview By Mayo Clinic Staff Vitamin deficiency anemia is a lack of healthy red ... you have lower than normal amounts of certain vitamins. Vitamins linked to vitamin deficiency anemia include folate, ...

  8. Genetic, host, and environmental interactions in a 19 year old with severe chronic obstructive lung disease; observations regarding the pathophysiology of airflow obstruction

    Directory of Open Access Journals (Sweden)

    Grosu HB

    2012-06-01

    Full Text Available Horiana B Grosu,1 Jonathan Killam,2 Elvina Khusainova,3 James Lozada,1 Andrew Needelman,4 Edward Eden11Division of Pulmonary Critical Care and Sleep Medicine, 2Department of Radiology, 3Department of Medicine, St Luke's Roosevelt Hospital Center, New York, 4Mid Hudson Medical Group, Poughkeepsie, New York, USAAbstract: A case of a 19-year-old with severe chronic obstructive pulmonary disease is presented. This case illustrates genetic (severe alpha-1 antitrypsin deficiency and host factors (such as developmental diaphragmatic hernia and the innate response to injury, and environmental (high oxidative stress and lung injury interactions that lead to severe chronic obstructive lung disease. The development of chronic lung disease was caused by lung injury under high oxidative and inflammatory conditions in the setting of a diaphragmatic hernia. In the absence of normal alpha-1 antitrypsin levels, a pro-elastolytic environment in the early period of lung growth enhanced the development of severe hyperinflation and precocious airflow obstruction.Keywords: Swyer James Macleod syndrome, alpha-1 antitrypsin deficiency, bronchopulmonary dysplasia, chronic obstructive pulmonary disease

  9. Glucose-6-phosphatase deficiency

    Directory of Open Access Journals (Sweden)

    Labrune Philippe

    2011-05-01

    Full Text Available Abstract Glucose-6-phosphatase deficiency (G6P deficiency, or glycogen storage disease type I (GSDI, is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, between the ages of 3 to 4 months by symptoms of hypoglycemia (tremors, seizures, cyanosis, apnea. Patients have poor tolerance to fasting, marked hepatomegaly, growth retardation (small stature and delayed puberty, generally improved by an appropriate diet, osteopenia and sometimes osteoporosis, full-cheeked round face, enlarged kydneys and platelet dysfunctions leading to frequent epistaxis. In addition, in GSDIb, neutropenia and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphtous gingivostomatitis, and inflammatory bowel disease. Late complications are hepatic (adenomas with rare but possible transformation into hepatocarcinoma and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal insufficiency. GSDI is caused by a dysfunction in the G6P system, a key step in the regulation of glycemia. The deficit concerns the catalytic subunit G6P-alpha (type Ia which is restricted to expression in the liver, kidney and intestine, or the ubiquitously expressed G6P transporter (type Ib. Mutations in the genes G6PC (17q21 and SLC37A4 (11q23 respectively cause GSDIa and Ib. Many mutations have been identified in both genes,. Transmission is autosomal recessive. Diagnosis is based on clinical presentation, on abnormal basal values and absence of hyperglycemic response to glucagon. It can be confirmed by demonstrating a deficient activity of a G6P system component in a liver biopsy. To date, the diagnosis is most

  10. Glucose-6-phosphatase deficiency.

    Science.gov (United States)

    Froissart, Roseline; Piraud, Monique; Boudjemline, Alix Mollet; Vianey-Saban, Christine; Petit, François; Hubert-Buron, Aurélie; Eberschweiler, Pascale Trioche; Gajdos, Vincent; Labrune, Philippe

    2011-05-20

    Glucose-6-phosphatase deficiency (G6P deficiency), or glycogen storage disease type I (GSDI), is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, between the ages of 3 to 4 months by symptoms of hypoglycemia (tremors, seizures, cyanosis, apnea). Patients have poor tolerance to fasting, marked hepatomegaly, growth retardation (small stature and delayed puberty), generally improved by an appropriate diet, osteopenia and sometimes osteoporosis, full-cheeked round face, enlarged kydneys and platelet dysfunctions leading to frequent epistaxis. In addition, in GSDIb, neutropenia and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphtous gingivostomatitis, and inflammatory bowel disease. Late complications are hepatic (adenomas with rare but possible transformation into hepatocarcinoma) and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal insufficiency). GSDI is caused by a dysfunction in the G6P system, a key step in the regulation of glycemia. The deficit concerns the catalytic subunit G6P-alpha (type Ia) which is restricted to expression in the liver, kidney and intestine, or the ubiquitously expressed G6P transporter (type Ib). Mutations in the genes G6PC (17q21) and SLC37A4 (11q23) respectively cause GSDIa and Ib. Many mutations have been identified in both genes,. Transmission is autosomal recessive. Diagnosis is based on clinical presentation, on abnormal basal values and absence of hyperglycemic response to glucagon. It can be confirmed by demonstrating a deficient activity of a G6P system component in a liver biopsy. To date, the diagnosis is most commonly confirmed

  11. Carnitine Deficiency and Pregnancy

    OpenAIRE

    Anouk de Bruyn; Yves Jacquemyn; Kristof Kinget; François Eyskens

    2015-01-01

    We present two cases of carnitine deficiency in pregnancy. In our first case, systematic screening revealed L-carnitine deficiency in the first born of an asymptomatic mother. In the course of her second pregnancy, maternal carnitine levels showed a deficiency as well. In a second case, a mother known with carnitine deficiency under supplementation was followed throughout her pregnancy. Both pregnancies had an uneventful outcome. Because carnitine deficiency can have serious complications, su...

  12. Lyman alpha emission in starburst galaxies

    Science.gov (United States)

    Kunth, Daniel

    1999-07-01

    We propose to perform a deep study of Ly-alpha emission and destruction in 3 star-forming galaxies. These objects have been already observed with the GHRS and exhibit a variety of situations, with Ly-alpha showing P Cyg profiles, secondary emissions or even a deep damped absorption line with no emission. They also span a range of intrinsic properties: IZW18 is a gas-rich, metal deficient dust free dwarf galaxy, Haro 2 has a simple morphology while IRAS 08339+6517 is a luminous IRAS starburst galaxy with more dust and complex Ly- alpha profile. The use of STIS will allow for the first time to study the geometrical/kinematical configuration of the ionized and neutral gas across the galaxies nuclear regions and pin point the effects of porosity and the kinematical structure of the ISM, that may play the key roles {in addition to dust} in the detectability of the line. This study will have important impact for cosmology since Ly-alpha emitters are nowaday found at high-re dshift. We strongly emphasize that since Ly-alpha is primarely a diagnostic of the ISM, a full understanding of how the ISM and Ly-alpha are related is a necessary step before we can hope to correlate Ly-alpha to the cosmic star-formation rate. Our results will be interpreted against the model of superbubble evolution developed with G. Tenorio Tagle.

  13. Ab initio alpha-alpha scattering

    CERN Document Server

    Elhatisari, Serdar; Rupak, Gautam; Epelbaum, Evgeny; Krebs, Hermann; Lähde, Timo A; Luu, Thomas; Meißner, Ulf-G

    2015-01-01

    Processes involving alpha particles and alpha-like nuclei comprise a major part of stellar nucleosynthesis and hypothesized mechanisms for thermonuclear supernovae. In an effort towards understanding alpha processes from first principles, we describe in this letter the first ab initio calculation of alpha-alpha scattering. We use lattice effective field theory to describe the low-energy interactions of nucleons and apply a technique called the adiabatic projection method to reduce the eight-body system to an effective two-cluster system. We find good agreement between lattice results and experimental phase shifts for S-wave and D-wave scattering. The computational scaling with particle number suggests that alpha processes involving heavier nuclei are also within reach in the near future.

  14. Folate-deficiency anemia

    Science.gov (United States)

    ... medlineplus.gov/ency/article/000551.htm Folate-deficiency anemia To use the sharing features on this page, please enable JavaScript. Folate-deficiency anemia is a decrease in red blood cells (anemia) ...

  15. Anemia - B12 deficiency

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/000574.htm Vitamin B12 deficiency anemia To use the sharing features on ... tissues. There are many types of anemia. Vitamin B12 deficiency anemia is a low red blood cell ...

  16. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... or an inability to absorb enough iron from food. Overview Iron-deficiency anemia is a common type ... of the condition. Treatments may include dietary changes, medicines, and surgery. Severe iron-deficiency anemia may require ...

  17. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... the NHLBI on Twitter. What Is Iron-Deficiency Anemia? Español Iron-deficiency anemia is a common, easily ... Featured Video Living With and Managing Iron-Deficiency Anemia 05/18/2011 This video—presented by the ...

  18. Iron-Deficiency Anemia

    Science.gov (United States)

    ... the NHLBI on Twitter. What Is Iron-Deficiency Anemia? Español Iron-deficiency anemia is a common, easily ... Featured Video Living With and Managing Iron-Deficiency Anemia 05/18/2011 This video—presented by the ...

  19. Iron-Deficiency Anemia

    Science.gov (United States)

    ... page from the NHLBI on Twitter. What Is Iron-Deficiency Anemia? Español Iron-deficiency anemia is a common, ... Content: NEXT >> Featured Video Living With and Managing Iron-Deficiency Anemia 05/18/2011 This video—presented by ...

  20. Carnitine Deficiency and Pregnancy

    Directory of Open Access Journals (Sweden)

    Anouk de Bruyn

    2015-01-01

    Full Text Available We present two cases of carnitine deficiency in pregnancy. In our first case, systematic screening revealed L-carnitine deficiency in the first born of an asymptomatic mother. In the course of her second pregnancy, maternal carnitine levels showed a deficiency as well. In a second case, a mother known with carnitine deficiency under supplementation was followed throughout her pregnancy. Both pregnancies had an uneventful outcome. Because carnitine deficiency can have serious complications, supplementation with carnitine is advised. This supplementation should be continued throughout pregnancy according to plasma concentrations.

  1. Faddeev calculation of 3 alpha and alpha alpha Lambda systems using alpha alpha resonating-group method kernel

    CERN Document Server

    Fujiwara, Y; Kohno, M; Suzuki, Y; Baye, D; Sparenberg, J M

    2004-01-01

    We carry out Faddeev calculations of three-alpha (3 alpha) and two-alpha plus Lambda (alpha alpha Lambda) systems, using two-cluster resonating-group method kernels. The input includes an effective two-nucleon force for the alpha alpha resonating-group method and a new effective Lambda N force for the Lambda alpha interaction. The latter force is a simple two-range Gaussian potential for each spin-singlet and triplet state, generated from the phase-shift behavior of the quark-model hyperon-nucleon interaction, fss2, by using an inversion method based on supersymmetric quantum mechanics. Owing to the exact treatment of the Pauli-forbidden states between the clusters, the present three-cluster Faddeev formalism can describe the mutually related, alpha alpha, 3 alpha and alpha alpha Lambda systems, in terms of a unique set of the baryon-baryon interactions. For the three-range Minnesota force which describes the alpha alpha phase shifts quite accurately, the ground-state and excitation energies of 9Be Lambda are...

  2. Acquired color vision deficiency.

    Science.gov (United States)

    Simunovic, Matthew P

    2016-01-01

    Acquired color vision deficiency occurs as the result of ocular, neurologic, or systemic disease. A wide array of conditions may affect color vision, ranging from diseases of the ocular media through to pathology of the visual cortex. Traditionally, acquired color vision deficiency is considered a separate entity from congenital color vision deficiency, although emerging clinical and molecular genetic data would suggest a degree of overlap. We review the pathophysiology of acquired color vision deficiency, the data on its prevalence, theories for the preponderance of acquired S-mechanism (or tritan) deficiency, and discuss tests of color vision. We also briefly review the types of color vision deficiencies encountered in ocular disease, with an emphasis placed on larger or more detailed clinical investigations.

  3. Radiochemical studies of neutron deficient actinide isotopes

    Energy Technology Data Exchange (ETDEWEB)

    Williams, K.E.

    1978-04-01

    The production of neutron deficient actinide isotopes in heavy ion reactions was studied using alpha, gamma, x-ray, and spontaneous fission detection systems. A new isotope of berkelium, /sup 242/Bk, was produced with a cross-section of approximately 10 ..mu..b in reactions of boron on uranium and nitrogen on thorium. It decays by electron capture with a half-life of 7.0 +- 1.3 minutes. The alpha-branching ratio for this isotope is less than 1% and the spontaneous fission ratio is less than 0.03%. Studies of (Heavy Ion, pxn) and (Heavy Ion, ..cap alpha..xn) transfer reactions in comparison with (Heavy ion, xn) compound nucleus reactions revealed transfer reaction cross-sections equal to or greater than the compound nucleus yields. The data show that in some cases the yield of an isotope produced via a (H.I.,pxn) or (H.I.,..cap alpha..xn) reaction may be higher than its production via an xn compound nucleus reaction. These results have dire consequences for proponents of the ''Z/sub 1/ + Z/sub 2/ = Z/sub 1+2/'' philosophy. It is no longer acceptable to assume that (H.I.,pxn) and (H.I.,..cap alpha..xn) product yields are of no consequence when studying compound nucleus reactions. No evidence for spontaneous fission decay of /sup 228/Pu, /sup 230/Pu, /sup 232/Cm, or /sup 238/Cf was observed indicating that strictly empirical extrapolations of spontaneous fission half-life data is inadequate for predictions of half-lives for unknown neutron deficient actinide isotopes.

  4. 1,25-Vitamin D3 Deficiency Induces Albuminuria

    NARCIS (Netherlands)

    Sonneveld, R.; Hoenderop, J.G.; Stavenuiter, A.W.; Ferrantelli, E.; Baltissen, M.P.A.; Dijkman, H.B.; Florquin, S.; Rops, A.; Wetzels, J.F.M.; Berden, J.H.M.; Vlag, J. van der; Nijenhuis, T.

    2016-01-01

    Vitamin D plays an important role in renal (patho)physiology. Patients with glomerular diseases have an injured renal filtration barrier, leading to proteinuria and reduced renal function. An impaired renal function also leads to 1,25-vitamin D3 deficiency as a result of reduced renal 1alpha-hydroxy

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

    CERN Document Server

    Bruno, Mattia; Fritzsch, Patrick; Korzec, Tomasz; Ramos, Alberto; Schaefer, Stefan; Simma, Hubert; Sint, Stefan; Sommer, Rainer

    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 $0.0002$.

  6. Phosphatidylinositol transfer protein alpha and its role in neurodegeneration

    NARCIS (Netherlands)

    Bunte, H.

    2007-01-01

    Selective neuronal loss is a prominent feature in neurodegenerative disorders. Recently, a link between neurodegeneration and a deficiency in the protein phosphatidylinositol transfer protein alpha (PI-TPalpha) has been demonstrated. In this context it is of importance that fibroblasts overexpressin

  7. Deficiently Extremal Gorenstein Algebras

    Indian Academy of Sciences (India)

    Pavinder Singh

    2011-08-01

    The aim of this article is to study the homological properties of deficiently extremal Gorenstein algebras. We prove that if / is an odd deficiently extremal Gorenstein algebra with pure minimal free resolution, then the codimension of / must be odd. As an application, the structure of pure minimal free resolution of a nearly extremal Gorenstein algebra is obtained.

  8. Iron deficiency anemia

    Science.gov (United States)

    Anemia - iron deficiency ... iron from old red blood cells. Iron deficiency anemia develops when your body's iron stores run low. ... You may have no symptoms if the anemia is mild. Most of the time, ... slowly. Symptoms may include: Feeling weak or tired more often ...

  9. Muscle phosphorylase kinase deficiency

    DEFF Research Database (Denmark)

    Preisler, N; Orngreen, M C; Echaniz-Laguna, A;

    2012-01-01

    To examine metabolism during exercise in 2 patients with muscle phosphorylase kinase (PHK) deficiency and to further define the phenotype of this rare glycogen storage disease (GSD).......To examine metabolism during exercise in 2 patients with muscle phosphorylase kinase (PHK) deficiency and to further define the phenotype of this rare glycogen storage disease (GSD)....

  10. Growth Hormone Deficiency

    Directory of Open Access Journals (Sweden)

    Ömer Tarım

    2010-05-01

    Full Text Available Growth hormone deficiency is the most promising entity in terms of response to therapy among the treatable causes of growth retardation. It may be due to genetic or acquired causes. It may be isolated or a part of multiple hormone deficiencies. Diagnostic criteria and therefore treatment indications are still disputed. (Journal of Current Pediatrics 2010; 8: 36-8

  11. Iron induced nickel deficiency

    Science.gov (United States)

    It is increasingly apparent that economic loss due to nickel (Ni) deficiency likely occurs in horticultural and agronomic crops. While most soils contain sufficient Ni to meet crop requirements, situations of Ni deficiency can arise due to antagonistic interactions with other metals. This study asse...

  12. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Blood Tests Blood Transfusion Restless Legs Syndrome Send a link to NHLBI to someone by E-MAIL | ... Iron-Deficiency Anemia? Español Iron-deficiency anemia is a common, easily treated condition that occurs if you ...

  13. Nutritional iron deficiency

    NARCIS (Netherlands)

    Zimmermann, M.B.; Hurrell, R.F.

    2007-01-01

    Iron deficiency is one of the leading risk factors for disability and death worldwide, affecting an estimated 2 billion people. Nutritional iron deficiency arises when physiological requirements cannot be met by iron absorption from diet. Dietary iron bioavailability is low in populations consuming

  14. Iron deficiency in childhood

    NARCIS (Netherlands)

    Uijterschout, L.

    2015-01-01

    Iron deficiency (ID) is the most common micronutrient deficiency in the world. Iron is involved in oxygen transport, energy metabolism, immune response, and plays an important role in brain development. In infancy, ID is associated with adverse effects on cognitive, motor, and behavioral development

  15. 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...

  16. 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.

  17. Interpreting EEG alpha activity.

    Science.gov (United States)

    Bazanova, O M; Vernon, D

    2014-07-01

    Exploring EEG alpha oscillations has generated considerable interest, in particular with regards to the role they play in cognitive, psychomotor, psycho-emotional and physiological aspects of human life. However, there is no clearly agreed upon definition of what constitutes 'alpha activity' or which of the many indices should be used to characterize it. To address these issues this review attempts to delineate EEG alpha-activity, its physical, molecular and morphological nature, and examine the following indices: (1) the individual alpha peak frequency; (2) activation magnitude, as measured by alpha amplitude suppression across the individual alpha bandwidth in response to eyes opening, and (3) alpha "auto-rhythmicity" indices: which include intra-spindle amplitude variability, spindle length and steepness. Throughout, the article offers a number of suggestions regarding the mechanism(s) of alpha activity related to inter and intra-individual variability. In addition, it provides some insights into the various psychophysiological indices of alpha activity and highlights their role in optimal functioning and behavior.

  18. 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....

  19. 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...

  20. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... chest pain, and other symptoms. Severe iron-deficiency anemia can lead to heart problems, infections, problems with growth and development in children, and other complications. Infants and young children and ...

  1. Vitamin D Deficiency

    Science.gov (United States)

    ... fractures), muscle weakness, and the bone-thinning disease osteoporosis. Severe vitamin D deficiency can cause rickets in children and osteomalacia in adults. Both problems cause soft, weak bones, as well ...

  2. Factor II deficiency

    Science.gov (United States)

    ... if one or more of these factors are missing or are not functioning like they should. Factor II is one such coagulation factor. Factor II deficiency runs in families (inherited) and is very rare. Both parents must ...

  3. Factor VII deficiency

    Science.gov (United States)

    ... if one or more of these factors are missing or are not functioning like they should. Factor VII is one such coagulation factor. Factor VII deficiency runs in families (inherited) and is very rare. Both parents must ...

  4. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Events Spokespeople Email Alerts E-Newsletters About NHLBI Organization NHLBI Director Budget, Planning, & Legislative Advisory Committees Jobs ... food. Overview Iron-deficiency anemia is a common type of anemia . The term "anemia" usually refers to ...

  5. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... CAUSES WHO IS AT RISK SIGNS & SYMPTOMS DIAGNOSIS TREATMENTS PREVENTION LIVING WITH CLINICAL TRIALS LINKS Related Topics ... Doctors usually can successfully treat iron-deficiency anemia. Treatment will depend on the cause and severity of ...

  6. Manganese deficiency in plants

    DEFF Research Database (Denmark)

    Schmidt, Sidsel Birkelund; Jensen, Poul Erik; Husted, Søren

    2016-01-01

    Manganese (Mn) is an essential plant micronutrient with an indispensable function as a catalyst in the oxygen-evolving complex (OEC) of photosystem II (PSII). Even so, Mn deficiency frequently occurs without visual leaf symptoms, thereby masking the distribution and dimension of the problem...... restricting crop productivity in many places of the world. Hence, timely alleviation of latent Mn deficiency is a challenge in promoting plant growth and quality. We describe here the key mechanisms of Mn deficiency in plants by focusing on the impact of Mn on PSII stability and functionality. We also address...... the mechanisms underlying the differential tolerance towards Mn deficiency observed among plant genotypes, which enable Mn-efficient plants to grow on marginal land with poor Mn availability....

  7. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Digg. Share this page from the NHLBI on Facebook. Add this link to the NHLBI to my ... Deficiency Anemia article. Updated: March 26, 2014 Twitter Facebook YouTube Google+ SITE INDEX ACCESSIBILITY PRIVACY STATEMENT FOIA ...

  8. Proximal Focal Femoral Deficiency

    OpenAIRE

    Vishal Kalia, Vibhuti

    2008-01-01

    Proximal focal femoral deficiency (PFFD) is a developmental disorder of the proximal segment of thefemur and of acetabulum resulting in shortening of the affected limb and impairment of the function. It isa spectrum of congenital osseous anomalies characterized by a deficiency in the structure of the proximalfemur. The diagnosis is often made by radiological evaluation which includes identification and descriptionof PFFD and evaluation of associated limb anomalies by plain radiographs. Contra...

  9. Iron deficiency anemia

    OpenAIRE

    Naigamwalla, Dinaz Z.; Webb, Jinelle A.; Giger, Urs

    2012-01-01

    Iron is essential to virtually all living organisms and is integral to multiple metabolic functions. The most important function is oxygen transport in hemoglobin. Iron deficiency anemia in dogs and cats is usually caused by chronic blood loss and can be discovered incidentally as animals may have adapted to the anemia. Severe iron deficiency is characterized by a microcytic, hypochromic, potentially severe anemia with a variable regenerative response. Iron metabolism and homeostasis will be ...

  10. Glucose-6-phosphatase deficiency.

    OpenAIRE

    Labrune Philippe; Gajdos Vincent; Eberschweiler Pascale; Hubert-Buron Aurélie; Petit François; Vianey-Saban Christine; Boudjemline Alix; Piraud Monique; Froissart Roseline

    2011-01-01

    Abstract Glucose-6-phosphatase deficiency (G6P deficiency), or glycogen storage disease type I (GSDI), is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, betw...

  11. Laser assisted {alpha} decay

    Energy Technology Data Exchange (ETDEWEB)

    Castaneda Cortes, Hector Mauricio

    2012-02-01

    Excited or short-lived nuclei often decay by emitting alpha particles that are assumed to be preformed inside the nucleus and confined in the nuclear potential well. In this picture, {alpha} decay refers to the tunneling of the alpha particle through the potential barrier. In this thesis we investigate for the first time how strong laser fields can assist the tunneling of the alpha particle and thus influence the nuclear decay. Generally speaking, laser-assisted {alpha} decay can be described as laser-assisted tunneling of a quasistationary state, i.e, a slowly decaying state. Our theoretical treatment is developed starting from the complex trajectory formulation of the well-known strong-field approximation used to describe laser-induced ionization. We extend this formulation and develop a method to treat the decay of quasistationary states. The effect of both static and optical and X-ray monochromatic fields on the lifetimes and {alpha}-particle emission spectra are investigated for a number of {alpha}-emitting nuclei. We find that even at strong intensities, the laser-induced acceleration of the {alpha} decay is negligible, ranging from a relative modification in the decay rate of 10{sup -3} for static fields of electric field strengths of 10{sup 15} V/m, to 10{sup -8} for strong optical fields with intensities of 10{sup 22} W/cm{sup 2}, and to 10{sup -6} for strong X-ray fields with laser intensities around 10{sup 24} W/cm{sup 2}. However, the effect of the external field is visible in the spectrum of emitted alpha particles, leading in the case of optical fields even to rescattering phenomena for intensities approaching 6 x 10{sup 22} W/cm{sup 2}. The dynamics of the alpha particle in laser fields of intensities below the rescattering limit is investigated.

  12. Genetics Home Reference: alpha thalassemia

    Science.gov (United States)

    ... Understand Genetics Home Health Conditions alpha thalassemia alpha thalassemia Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Alpha thalassemia is a blood disorder that reduces the production ...

  13. Iron deficiency anaemia.

    Science.gov (United States)

    Lopez, Anthony; Cacoub, Patrice; Macdougall, Iain C; Peyrin-Biroulet, Laurent

    2016-02-27

    Anaemia affects roughly a third of the world's population; half the cases are due to iron deficiency. It is a major and global public health problem that affects maternal and child mortality, physical performance, and referral to health-care professionals. Children aged 0-5 years, women of childbearing age, and pregnant women are particularly at risk. Several chronic diseases are frequently associated with iron deficiency anaemia--notably chronic kidney disease, chronic heart failure, cancer, and inflammatory bowel disease. Measurement of serum ferritin, transferrin saturation, serum soluble transferrin receptors, and the serum soluble transferrin receptors-ferritin index are more accurate than classic red cell indices in the diagnosis of iron deficiency anaemia. In addition to the search for and treatment of the cause of iron deficiency, treatment strategies encompass prevention, including food fortification and iron supplementation. Oral iron is usually recommended as first-line therapy, but the most recent intravenous iron formulations, which have been available for nearly a decade, seem to replenish iron stores safely and effectively. Hepcidin has a key role in iron homoeostasis and could be a future diagnostic and therapeutic target. In this Seminar, we discuss the clinical presentation, epidemiology, pathophysiology, diagnosis, and acute management of iron deficiency anaemia, and outstanding research questions for treatment.

  14. alpha_s from tau decays revisited

    CERN Document Server

    Boito, D; Golterman, M; Jamin, M; Maltman, K; Osborne, J; Peris, S

    2011-01-01

    Being a determination at low energies, the analysis of hadronic tau decay data provides a rather precise determination of the strong coupling alpha_s after evolving the result to M_Z. At such a level of precision, even small non-perturbative effects become relevant for the central value and error. While those effects had been taken into account in the framework of the operator product expansion, contributions going beyond it, so-called duality violations, have previously been neglected. The following investigation fills this gap through a finite-energy sum rule analysis of tau decay spectra from the OPAL experiment, including duality violations and performing a consistent fit of all appearing QCD parameters. The resulting values for alpha_s(M_tau) are 0.307(19) in fixed-order perturbation theory and 0.322(26) in contour-improved perturbation theory, which translates to the n_f=5 values 0.1169(25) and 0.1187(32) at M_Z, respectively.

  15. AlphaACT

    Science.gov (United States)

    2014-07-20

    CBR can be found in the world around us (e.g., a doctor’s diagnosis based on a prior patient case, a lawyer preparing arguments based on legal ... metaphors in decision research. Judgment & Decision Making, 3(3), 195-204. Payne, J., Bettman, J., & Johnson, E. (1993). The Adaptive Decision Maker...alphaact. com 64 AlphaACT HAZMAT User Guide 8.3 Changing Measurement Units AlphaACT HAZMAT lets you show distances in either metric or English

  16. Antepartum Ornithine Transcarbamylase Deficiency

    Directory of Open Access Journals (Sweden)

    Hitoshi Nakajima

    2014-11-01

    Full Text Available Ornithine transcarbamylase deficiency (OTCD is the most common type urea cycle enzyme deficiencies. This syndrome results from a deficiency of the mitochondrial enzyme ornithine transcarbamylase, which catalyzes the conversion of ornithine and carbamoyl phosphate to citrullin. Our case was a 28-year-old female diagnosed with OTCD following neurocognitive deficit during her first pregnancy. Although hyperammonemia was suspected as the cause of the patient's mental changes, there was no evidence of chronic liver disease. Plasma amino acid and urine organic acid analysis revealed OTCD. After combined modality treatment with arginine, sodium benzoate and hemodialysis, the patient's plasma ammonia level stabilized and her mental status returned to normal. At last she recovered without any damage left.

  17. 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.&...

  18. Iatrogenic “buffalo chest” bilateral pneumothoraces following unilateral transbronchial lung biopsies in a bilateral lung transplant recipient

    Directory of Open Access Journals (Sweden)

    Leith Sawalha

    2015-01-01

    Full Text Available We present a 54 year old male patient who had a bilateral lung transplant sixteen years ago for Alpha-1 Antitrypsin Deficiency-related emphysema. He was referred for flexible bronchoscopy with transbronchial biopsies to evaluate new mild exertional dyspnea and worsening of his FEV1. Eight transbronchial biopsies were done from the right middle lobe and the right lower lobe. Post procedure he developed bilateral pneumothoces that required emergent bilateral pleural ‘pigtail’ catheters. To our knowledge, this is the first reported case of bilateral pneumothoraces that developed after a unilateral procedure in a bilateral lung transplant recipient relatively late after the transplant.

  19. Mortality and GH deficiency

    DEFF Research Database (Denmark)

    Stochholm, Kirstine; Gravholt, Claus Højbjerg; Laursen, Torben;

    2007-01-01

    OBJECTIVE: To estimate the mortality in Denmark in patients suffering from GH deficiency (GHD). DESIGN: Mortality was analyzed in 1794 GHD patients and 8014 controls matched on age and gender. All records in GHD patients were studied and additional morbidity noted. Patients were divided into chil......OBJECTIVE: To estimate the mortality in Denmark in patients suffering from GH deficiency (GHD). DESIGN: Mortality was analyzed in 1794 GHD patients and 8014 controls matched on age and gender. All records in GHD patients were studied and additional morbidity noted. Patients were divided...

  20. Non-redundant properties of IL-1alpha and IL-1beta during acute colon inflammation in mice

    NARCIS (Netherlands)

    Bersudsky, M.; Luski, L.; Fishman, D.; White, R.M.; Ziv-Sokolovskaya, N.; Dotan, S.; Rider, P.; Kaplanov, I.; Aychek, T.; Dinarello, C.A.; Apte, R.N.; Voronov, E.

    2014-01-01

    OBJECTIVE: The differential role of the IL-1 agonists, IL-1alpha, which is mainly cell-associated versus IL-1beta, which is mostly secreted, was studied in colon inflammation. DESIGN: Dextran sodium sulfate (DSS) colitis was induced in mice globally deficient in either IL-1alpha or IL-1beta, and in

  1. Collectivity of the neutron-deficient odd yttrium isotopes

    Energy Technology Data Exchange (ETDEWEB)

    Bucurescu, D.; Cata, G.; Ivascu, M.; Zamfir, N.V.; Liang, C.F.; Paris, P.

    1988-08-01

    Multishell IBFM-1 calculations are reported for the neutron-deficient odd yttrium isotopes (79-85), which give a good description of both the positive and negative parity levels known experimentally. An exchange force whose intensity varies with the mass number is required. This phenomenological variation reflects qualitatively the microscopic origin of the exchange term, and also points to possible systematics of the model parameters in the ALPHA approx. = 80 region of the Nsub(p)Nsub(n) type.

  2. Diagnosing oceanic nutrient deficiency

    Science.gov (United States)

    Moore, C. Mark

    2016-11-01

    The supply of a range of nutrient elements to surface waters is an important driver of oceanic production and the subsequent linked cycling of the nutrients and carbon. Relative deficiencies of different nutrients with respect to biological requirements, within both surface and internal water masses, can be both a key indicator and driver of the potential for these nutrients to become limiting for the production of new organic material in the upper ocean. The availability of high-quality, full-depth and global-scale datasets on the concentrations of a wide range of both macro- and micro-nutrients produced through the international GEOTRACES programme provides the potential for estimation of multi-element deficiencies at unprecedented scales. Resultant coherent large-scale patterns in diagnosed deficiency can be linked to the interacting physical-chemical-biological processes which drive upper ocean nutrient biogeochemistry. Calculations of ranked deficiencies across multiple elements further highlight important remaining uncertainties in the stoichiometric plasticity of nutrient ratios within oceanic microbial systems and caveats with regards to linkages to upper ocean nutrient limitation. This article is part of the themed issue 'Biological and climatic impacts of ocean trace element chemistry'.

  3. Factor V deficiency

    Science.gov (United States)

    ... When certain blood clotting factors are low or missing, your blood does not clot properly. Factor V deficiency is rare. It may be caused by: A defective Factor V gene passed down through families (inherited) An antibody that interferes with normal Factor ...

  4. Iodine-deficiency disorders

    NARCIS (Netherlands)

    Zimmermann, M.B.; Jooste, P.L.; Pandav, C.S.

    2008-01-01

    billion individuals worldwide have insufficient iodine intake, with those in south Asia and sub-Saharan Africa particularly affected. Iodine deficiency has many adverse effects on growth and development. These effects are due to inadequate production of thyroid hormone and are termed iodine-deficien

  5. Sleep Deprivation and Deficiency

    Science.gov (United States)

    ... page from the NHLBI on Twitter. What Are Sleep Deprivation and Deficiency? Sleep deprivation (DEP-rih-VA-shun) is a condition that ... the following: You don't get enough sleep (sleep deprivation) You sleep at the wrong time of day ( ...

  6. Morbidity and GH deficiency

    DEFF Research Database (Denmark)

    Stochholm, Kirstine; Laursen, Torben; Green, Anders;

    2008-01-01

    OBJECTIVE: To estimate morbidity in Denmark in all patients with GH deficiency (GHD). DESIGN: Morbidity was analyzed in 1794 GHD patients and 8014 controls matched on age and gender. All records in the GHD patients were studied and additional morbidity noted. Diagnoses and dates of admissions were...

  7. Deficient SOCS3 and SHP-1 Expression in Psoriatic T Cells

    DEFF Research Database (Denmark)

    Eriksen, Karsten W; Woetmann, Anders; Skov, Lone

    2010-01-01

    , we show that psoriatic T cells display deficient expression of the suppressor of cytokine signaling (SOCS)3 in response to IFN-alpha and a low baseline expression of the SH2-domain-containing protein-tyrosine phosphatase (SHP)-1 when compared with skin T cells from nonpsoriatic donors. Moreover, IFN......IFN-alpha and skin-infiltrating activated T lymphocytes have important roles in the pathogenesis of psoriasis. T cells from psoriatic patients display an increased sensitivity to IFN-alpha, but the pathological mechanisms behind the hyperresponsiveness to IFN-alpha remained unknown. In this study......-alpha-stimulated psoriatic T cells show enhanced activation of JAKs (JAK1 and TYK2) and signal transducers and activators of transcription. Increased expression of SOCS3 proteins resulting from proteasomal blockade partially inhibits IFN-alpha response. Similarly, forced expression of SOCS3 and SHP-1 inhibits IFN...

  8. Glucose-6-phosphate dehydrogenase deficiency

    Science.gov (United States)

    ... medlineplus.gov/ency/article/000528.htm Glucose-6-phosphate dehydrogenase deficiency To use the sharing features on this page, please enable JavaScript. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a condition in which ...

  9. Growth Hormone Deficiency in Children

    Science.gov (United States)

    ... c m y one in Children What is growth hormone deficiency? Growth hormone deficiency (GHD) is a rare condition in which the body does not make enough growth hormone (GH). GH is made by the pituitary gland, ...

  10. ALPHA MIS: Reference manual

    Energy Technology Data Exchange (ETDEWEB)

    Lovin, J.K.; Haese, R.L.; Heatherly, R.D.; Hughes, S.E.; Ishee, J.S.; Pratt, S.M.; Smith, D.W.

    1992-02-01

    ALPHA is a powerful and versatile management information system (MIS) initiated and sponsored and by the Finance and Business Management Division of Oak Ridge National Laboratory, who maintain and develop it in concert with the Business Systems Division for its Information Center. A general-purpose MIS, ALPHA allows users to access System 1022 and System 1032 databases to obtain and manage information. From a personal computer or a data terminal, Energy Systems employees can use ALPHA to control their own report reprocessing. Using four general commands (Database, Select, Sort, and Report) they can (1) choose a mainframe database, (2) define subsets within it, (3) sequentially order a subset by one or more variables, and (4) generate a report with their own or a canned format.

  11. AlphaSphere

    OpenAIRE

    Place, A.; Lacey, L.; Mitchell, T.

    2013-01-01

    The AlphaSphere is an electronic musical instrument featuring a series of tactile, pressure sensitive touch pads arranged in a spherical form. It is designed to offer a new playing style, while allowing for the expressive real-time modulation of sound available in electronic-based music. It is also designed to be programmable, enabling the flexibility to map a series of different notational arrangements to the pad-based interface.\\ud \\ud The AlphaSphere functions as an HID, MIDI and OSC devic...

  12. Monoclonal antibody based immunoassays to screen for alpha-thalassemia in adults

    Energy Technology Data Exchange (ETDEWEB)

    Epstein, N.; Than, K.A. Culp, K.M. [Isolab, Inc., Akron, OH (United States)] [and others

    1994-09-01

    Alpha-thalassemia (alpha-thal) is characterized by the absence or reduction in synthesis of the alpha-globin chain due to either deletions or other abnormalities involving the alpha-globin genes located on the short arm of chromosome 16. The diploid cells have four alpha chain genes. The deletion of one, two, three or all four of these genes could result in mild to a complete alpha chain deficiency known as the Hydrops fetalis syndrome or alpha-thal-1, which causes fetal death. It is important to develop a sensitive test to detect carriers of alpha-thal-1 trait for genetic counseling. It has recently been observed that the presence of minute amounts of zeta-globin chains (0.01-1%) could serve as a biological marker of alpha-thal carriers. Because high sensitivity is required, we constructed a monoclonal antibody-based immunoassay which can be analyzed either by colorimetric or fluorimetric methods. By testing blood samples from individuals of Southeast Asian ancestry, we were able to show that various forms and combinations of deletions or inactivations of two or three alpha-globin genes results in alpha-thalassemia conditions that have elevated levels of the zeta-chain. Sensitivity achieved in these tests was < 0.1% zeta chain, or as low as 5 ng zeta-chain. Data correlate with results from reversed phase HPLC.

  13. Iron deficiency and cognitive functions

    Directory of Open Access Journals (Sweden)

    Jáuregui-Lobera I

    2014-11-01

    Full Text Available Ignacio Jáuregui-Lobera Department of Nutrition and Bromatology, Pablo de Olavide University, Seville, Spain Abstract: Micronutrient deficiencies, especially those related to iodine and iron, are linked to different cognitive impairments, as well as to potential long-term behavioral changes. Among the cognitive impairments caused by iron deficiency, those referring to attention span, intelligence, and sensory perception functions are mainly cited, as well as those associated with emotions and behavior, often directly related to the presence of iron deficiency anemia. In addition, iron deficiency without anemia may cause cognitive disturbances. At present, the prevalence of iron deficiency and iron deficiency anemia is 2%–6% among European children. Given the importance of iron deficiency relative to proper cognitive development and the alterations that can persist through adulthood as a result of this deficiency, the objective of this study was to review the current state of knowledge about this health problem. The relevance of iron deficiency and iron deficiency anemia, the distinction between the cognitive consequences of iron deficiency and those affecting specifically cognitive development, and the debate about the utility of iron supplements are the most relevant and controversial topics. Despite there being methodological differences among studies, there is some evidence that iron supplementation improves cognitive functions. Nevertheless, this must be confirmed by means of adequate follow-up studies among different groups. Keywords: iron deficiency, anemia, cognitive functions, supplementation

  14. Proximal Focal Femoral Deficiency

    Directory of Open Access Journals (Sweden)

    Vishal Kalia, Vibhuti

    2008-01-01

    Full Text Available Proximal focal femoral deficiency (PFFD is a developmental disorder of the proximal segment of thefemur and of acetabulum resulting in shortening of the affected limb and impairment of the function. It isa spectrum of congenital osseous anomalies characterized by a deficiency in the structure of the proximalfemur. The diagnosis is often made by radiological evaluation which includes identification and descriptionof PFFD and evaluation of associated limb anomalies by plain radiographs. Contrast arthrography orMagnetic Resonance Imaging is indicated when radiological features are questionable and to disclose thepresence and location of the femoral head and any cartilagenous anlage. The disorder is more commonlyunilateral and is apparent at birth. However, bilateral involvement is rarely seen. Therapy of the disorder isdirected towards satisfactory ambulation and specific treatment depending on the severity of dysplasia.

  15. Micronutrient deficiency in children.

    Science.gov (United States)

    Bhan, M K; Sommerfelt, H; Strand, T

    2001-05-01

    Malnutrition increases morbidity and mortality and affects physical growth and development, some of these effects resulting from specific micronutrient deficiencies. While public health efforts must be targeted to improve dietary intakes in children through breast feeding and appropriate complementary feeding, there is a need for additional measures to increase the intake of certain micronutrients. Food-based approaches are regarded as the long-term strategy for improving nutrition, but for certain micronutrients, supplementation, be it to the general population or to high risk groups or as an adjunct to treatment must also be considered. Our understanding of the prevalence and consequences of iron, vitamin A and iodine deficiency in children and pregnant women has advanced considerably while there is still a need to generate more knowledge pertaining to many other micronutrients, including zinc, selenium and many of the B-vitamins. For iron and vitamin A, the challenge is to improve the delivery to target populations. For disease prevention and growth promotion, the need to deliver safe but effective amounts of micronutrients such as zinc to children and women of fertile age can be determined only after data on deficiency prevalence becomes available and the studies on mortality reduction following supplementation are completed. Individual or multiple micronutrients must be used as an adjunct to treatment of common infectious diseases and malnutrition only if the gains are substantial and the safety window sufficiently wide. The available data for zinc are promising with regard to the prevention of diarrhea and pneumonia. It should be emphasized that there must be no displacement of important treatment such as ORS in acute diarrhea by adjunct therapy such as zinc. Credible policy making requires description of not only the clinical effects but also the underlying biological mechanisms. As findings of experimental studies are not always feasible to extrapolate to

  16. Orexin deficiency and narcolepsy

    OpenAIRE

    Sakurai, Takeshi

    2013-01-01

    Orexin deficiency results in the sleep disorder narcolepsy in many mammalian species, including mice, dogs, and humans, suggesting that the orexin system is particularly important for normal regulation of sleep/wakefulness states, and especially for maintenance of wakefulness. This review discusses animal models of narcolepsy; the contribution of each orexin receptor subtype to the narcoleptic phenotypes; and the etiology of orexin neuronal death. It also raises the possibility of novel thera...

  17. Alpha Antihydrogen Experiment

    CERN Document Server

    Fujiwara, M C; Ashkezari, M D; Baquero-Ruiz, M; Bertsche, W; Bray, C C; Butler, E; Cesar, C L; Chapman, S; Charlton, M; Cesar, C L; Fajans, J; Friesen, T; Gill, D R; Hangst, J S; Hardy, W N; Hayano, R S; Hayden, M E; Humphries, A J; Hydomako, R; Jonsell, S; Kurchaninov, L; Lambo, R; Madsen, N; Menary, S; Nolan, P; Olchanski, K; Olin, A; Povilus, A; Pusa, P; Robicheaux, F; Sarid, E; Silveira, D M; So, C; Storey, J W; Thompson, R I; van der Werf, D P; Wilding, D; Wurtele, J S; Yamazaki, Y

    2011-01-01

    ALPHA is an experiment at CERN, whose ultimate goal is to perform a precise test of CPT symmetry with trapped antihydrogen atoms. After reviewing the motivations, we discuss our recent progress toward the initial goal of stable trapping of antihydrogen, with some emphasis on particle detection techniques.

  18. 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.’

  19. 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...

  20. Iron-Deficiency Anemia (For Parents)

    Science.gov (United States)

    ... Your 1- to 2-Year-Old Iron-Deficiency Anemia KidsHealth > For Parents > Iron-Deficiency Anemia Print A ... common nutritional deficiency in children. About Iron-Deficiency Anemia Every red blood cell in the body contains ...

  1. Iron-Deficiency Anemia (For Parents)

    Science.gov (United States)

    ... Your 1- to 2-Year-Old Iron-Deficiency Anemia KidsHealth > For Parents > Iron-Deficiency Anemia A A ... common nutritional deficiency in children. About Iron-Deficiency Anemia Every red blood cell in the body contains ...

  2. Alpha-synuclein gene deletion decreases brain palmitate uptake and alters the palmitate metabolism in the absence of alpha-synuclein palmitate binding

    DEFF Research Database (Denmark)

    Golovko, Mikhail Y; Færgeman, Nils J.; Cole, Nelson B;

    2005-01-01

    . To better define a role for alpha-synuclein in brain fatty acid uptake and metabolism, we infused awake, wild-type, or alpha-synuclein gene-ablated mice with [1-(14)C]palmitic acid (16:0) and assessed fatty acid uptake and turnover kinetics in brain phospholipids. Alpha-synuclein deficiency decreased brain......Alpha-synuclein is an abundant protein in the central nervous system that is associated with a number of neurodegenerative disorders, including Parkinson's disease. Its physiological function is poorly understood, although recently it was proposed to function as a fatty acid binding protein...... 16:0 uptake 35% and reduced its targeting to the organic fraction. The incorporation coefficient for 16:0 entering the brain acyl-CoA pool was significantly decreased 36% in alpha-synuclein gene-ablated mice. Because incorporation coefficients alone are not predictive of fatty acid turnover...

  3. Phenylalanine hydroxylase deficiency.

    Science.gov (United States)

    Mitchell, John J; Trakadis, Yannis J; Scriver, Charles R

    2011-08-01

    Phenylalanine hydroxylase deficiency is an autosomal recessive disorder that results in intolerance to the dietary intake of the essential amino acid phenylalanine. It occurs in approximately 1:15,000 individuals. Deficiency of this enzyme produces a spectrum of disorders including classic phenylketonuria, mild phenylketonuria, and mild hyperphenylalaninemia. Classic phenylketonuria is caused by a complete or near-complete deficiency of phenylalanine hydroxylase activity and without dietary restriction of phenylalanine most children will develop profound and irreversible intellectual disability. Mild phenylketonuria and mild hyperphenylalaninemia are associated with lower risk of impaired cognitive development in the absence of treatment. Phenylalanine hydroxylase deficiency can be diagnosed by newborn screening based on detection of the presence of hyperphenylalaninemia using the Guthrie microbial inhibition assay or other assays on a blood spot obtained from a heel prick. Since the introduction of newborn screening, the major neurologic consequences of hyperphenylalaninemia have been largely eradicated. Affected individuals can lead normal lives. However, recent data suggest that homeostasis is not fully restored with current therapy. Treated individuals have a higher incidence of neuropsychological problems. The mainstay of treatment for hyperphenylalaninemia involves a low-protein diet and use of a phenylalanine-free medical formula. This treatment must commence as soon as possible after birth and should continue for life. Regular monitoring of plasma phenylalanine and tyrosine concentrations is necessary. Targets of plasma phenylalanine of 120-360 μmol/L (2-6 mg/dL) in the first decade of life are essential for optimal outcome. Phenylalanine targets in adolescence and adulthood are less clear. A significant proportion of patients with phenylketonuria may benefit from adjuvant therapy with 6R-tetrahydrobiopterin stereoisomer. Special consideration must be

  4. HB Hillingdon [alpha46(CE4)Phe-->Val (alpha1 Or alpha2)]: a new alpha chain hemoglobin variant.

    Science.gov (United States)

    Babb, Anna; Solaiman, Susannah; Green, Brian N; Mantio, Debbie; Patel, Ketan

    2009-01-01

    Routine antenatal hemoglobinopathy screening detected a new alpha chain variant that eluted with Hb A(2) on cation exchange high performance liquid chromatography (HPLC) in a lady of Sri Lankan origin who had normal hematological indices. The mutation was identified by electrospray ionization mass spectrometry (ESI-MS) as alpha46(CE4)Phe-->Val, inferring that the variant was due to a single base change at codon 46 (TTC>GTC) of the alpha1- or alpha2-globin genes.

  5. $\\alpha$-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.

  6. Alpha-mannosidase activity in goats fed with Sida carpinifolia.

    Science.gov (United States)

    Bedin, Marisete; Moleta Colodel, Edson; Viapiana, Marli; Matte, Ursula; Driemeier, David; Giugliani, Roberto

    2010-03-01

    Human alpha-mannosidosis results from alpha-mannosidase deficiency and progressive accumulation of mannose-rich oligosaccharides in lysosomes. Two days before Saanen goats were fed with Sida carpinifolia, alpha-mannosidase activity in leukocytes was 128+/-28 nmoles4-MU/h/mgprotein (first trial) and 104+/-6 nmoles4-MU/h/mgprotein (second trial). At day 5, after the introduction of S. carpinifolia diet, the alpha-mannosidase activity in leukocytes was significantly increased, both in the first (288+/-13 nmoles4-MU/h/mgprotein) and in the second trial (303+/-45 nmoles4-MU/h/mgprotein), and it returned to normal levels 2 days after the withdrawal of the plant from the diet (114+/-7 nmoles4-MU/h/mgprotein in first trial, and 108+/-25 nmoles4-MU/h/mgprotein in the second one). Plasma alpha-mannosidase activity decreased significantly 4 days after animal exposure to the S. carpinifolia diet (769+/-167 nmoles4-MU/h/ml) and returned to normal values 10 days after the withdrawal of the plant from the diet (1289+/-163 nmoles4-MU/h/ml). Thin-layer chromatography showed an abnormal excretion of oligosaccharides in urine as of day 2 after diet exposure, which persisted until one day after the withdrawal of the plant. Animals presented neurological clinical signs beginning at day 37 (in the first trial) and at day 25 (in the second trial) after being fed with the plant. The results obtained herein suggest that oligosaccharides observed in urine are a result of a decrease in alpha-mannosidase activity in plasma. S. carpinifolia seems to have other compounds that act on alpha-mannosidase enzyme in leukocytes in a competitive manner with swainsonine. The increase in alpha-mannosidase enzyme in leukocytes could be attributed to one of these compounds present in S. carpinifolia.

  7. Iatrogenic nutritional deficiencies.

    Science.gov (United States)

    Young, R C; Blass, J P

    1982-01-01

    This article catalogs the nutritional deficiencies inadvertently introduced by certain treatment regimens. Specifically, the iatrogenic effects on nutrition of surgery, hemodialysis, irradiation, and drugs are reviewed. Nutritional problems are particularly frequent consequences of surgery on the gastrointestinal tract. Gastric surgery can lead to deficiencies of vitamin B12, folate, iron, and thiamine, as well as to metabolic bone disease. The benefits of small bowel bypass are limited by the potentially severe nutritional consequences of this procedure. Following bypass surgery, patients should be monitored for signs of possible nutritional probems such as weight loss, neuropathy, cardiac arrhythmias, loss of stamina, or changes in mental status. Minimal laboratory tests should include hematologic evaluation, B12, folate, iron, albumin, calcium, phosphorus, alkaline phosphatase, transaminases, sodium, potassium, chloride, and carbon dioxide levels. Roentgenologic examination of the bone should also be obtained. Loss of bone substance is a major consequence of many forms of treatment, and dietary supplementation with calcium is warranted. Patients undergoing hemodialysis have shown carnitine and choline deficiencies, potassium depletion, and hypovitaminosis, as well as osteomalacia. Chronic drug use may alter intake, synthesis, absorption, transport, storage, metabolism, or excretion of nutrients. Patients vary markedly in the metabolic effects of drugs, and recommendations for nutrition must be related to age, sex, reproductive status, and genetic endowment. Moreover, the illness being treated can itself alter nutritional requirements and the effect of the treatment on nutrient status. The changes in nutritional levels induced by use of estrogen-containing oral contraceptives (OCs) are obscure; however, the effects on folate matabolism appear to be of less clinical import than previously suggested. Reduction in pyridoxine and serum vitamin B12 levels has been

  8. Treatment of carnitine deficiency.

    Science.gov (United States)

    Winter, S C

    2003-01-01

    Carnitine deficiency is a secondary complication of many inborn errors of metabolism. Pharmacological treatment with carnitine not only corrects the deficiency, it facilitates removal of accumulating toxic acyl intermediates and the generation of mitochondrial free coenzyme A (CoA). The United States Food and Drug Administration (US FDA) approved the use of carnitine for the treatment of inborn errors of metabolism in 1992. This approval was based on retrospective chart analysis of 90 patients, with 18 in the untreated cohort and 72 in the treated cohort. Efficacy was evaluated on the basis of clinical and biochemical findings. Compelling data included increased excretion of disease-specific acylcarnitine derivatives in a dose-response relationship, decreased levels of metabolites in the blood, and improved clinical status with decreased hospitalization frequency, improved growth and significantly lower mortality rates as compared to historical controls. Complications of carnitine treatment were few, with gastrointestinal disturbances and odour being the most frequent. No laboratory or clinical safety issues were identified. Intravenous carnitine preparations were also approved for treatment of secondary carnitine deficiency. Since only 25% of enteral carnitine is absorbed and gastrointestinal tolerance of high doses is poor, parenteral carnitine treatment is an appealing alternative therapeutic approach. In 7 patients treated long term with high-dose weekly to daily venous boluses of parenteral carnitine through a subcutaneous venous port, benefits included decreased frequency of decompensations, improved growth, improved muscle strength and decreased reliance on medical foods with liberalization of protein intake. Port infections were the most troubling complication. Theoretical concerns continue to be voiced that carnitine might result in fatal arrhythmias in patients with long-chain fat metabolism defects. No published clinical studies substantiate these

  9. α1-ANTITRYPSIN ATTENUATES ENDOTOXIN-INDUCED ACUTE LUNG INJURY IN RABBITS

    Institute of Scientific and Technical Information of China (English)

    揭志军; 蔡映云; 杨文兰; 金美玲; 朱威; 祝慈芳

    2003-01-01

    Objective To investigate whether pretreatment with α1-AT can attenuate acute lung injury (ALI) in rabbits induced with endotoxin. Methods Thirty-two New Zealand rabbits were randomly assigned to four groups(n=8):1.Infusion of endotoxin(Lipopolysaccharide,LPS 500μg/kg)without α1-AT (group LPS).2.Infusion α1-AT 120mg/kg at 15min before challenge with LPS(group LAV).3.Infusion of α1-AT 120mg/kg(group AAT).4 Infusion of saline 4ml/kg as control (group NS).Arterial blood gases,peripheral leukocyte counts and airway pressure were recorded every 1h.Physiologic intrapulmonary shunting (Qs/Qt) was measured every 4h.After 8h the bloods were collected for measurement of plasma concentration and activity of α1-AT.Then bronchoalveolar lavage fluid (BALF)was collected for measurement of concentrations of total protein (TP),interleukin-8(IL-8),tumor necrosis factor(TNF-α),the activities of elastase-like and α1-AT,total phospholipids(TPL) and disaturated phosphatidylcholine (DSPC).In addition,the wet-to-dry lung weight ratio(W/D) was measured. Results After infusion of endotoxin,it was observed that PaO2,peripheral luekocyte counts,total respiratory compliance progressively decreased and Ppeak and Qs/Qt increased comparing with the baseline values.In contrast to group NS,the increased plasma concentration but reduced activity of α1-AT was found in group LPS.In the BALF,the activity of α1-AT,TPL,DSPC/TPL were lower,but the concentrations of albumin,IL-8,TNF-α,and the activity of NE were higher.The ratio of W/D also increased.The pretreatment of α1-AT attenuated the deterioration of oxygenation,the reduction of compliance and the deterioration of other physiological,biochemical parameters mentioned above. Conclusion Pretreatment with α1-AT could attenuate endotoxin-induced lung injury in rabbits.Those beneficial effects of α1-AT might be due in part to the inhibitory effect on neutrophil elastase.

  10. Alpha and Beta Determinations

    CERN Document Server

    Dunietz, Isard

    1999-01-01

    Because the Bd -> J/psi Ks asymmetry determines only sin(2 beta), a discrete ambiguity in the true value of beta remains. This note reviews how the ambiguity can be removed. Extractions of the CKM angle alpha are discussed next. Some of the methods require very large data samples and will not be feasible in the near future. In the near future, semi-inclusive CP-violating searches could be undertaken, which are reviewed last.

  11. 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.

  12. Orthopositronium lifetime. Analytic results in O ({alpha}) and O ({alpha}{sup 3} ln {alpha})

    Energy Technology Data Exchange (ETDEWEB)

    Kniehl, B.A.; Kotikov, A.V.; Veretin, O.L. [Hamburg Univ. (Germany). 2. Inst. fuer Theoretische Physik

    2008-06-15

    We present the O({alpha}) and O({alpha}{sup 3}ln {alpha}) corrections to the total decay width of orthopositronium in closed analytic form, in terms of basic transcendental numbers, which can be evaluated numerically to arbitrary precision. (orig.)

  13. Phosphorus Deficiency in Ducklins

    Institute of Scientific and Technical Information of China (English)

    CuiHengmin; LuoLingping

    1995-01-01

    20 one-day-old Tianfu ducklings were fed on a natural diet deficient in phosphorus(Ca 0.80%,P 0.366%)for three weeks and examined for signs and lesions.Signs began to appear at the age of one week,and became serous at two weeks.13 ducklings died during the experiment.Morbidity was 100% and mortality was 65%.The affected ducklings mainly showed leg weakness,severe lamencess,deprssion,lack of appetite and stunted growth,The serum alkaline phosphatase activities increased markedly.The serum phosphorus concentration,tibial ash,ash calcium and phosphorus content decreased obviously.At necropsy,maxillae and ribe were soft,and the latter was crooked.Long ones were soft and broke easily.The hypertrophic zone of the growth-plate in the epiphysis of long ones was lengthened and osteoid tissue increased in the metaphyseal spongiosa histopathologically.The above mentioned symptoms and lesions could be prevented by adding phosphorus to the natural deficient diet(up to 0.65%),The relationship between lesions and signs,pathomorphological characterisation and pathogensis were also discussed in this paper.

  14. [Iron deficiency and digestive disorders].

    Science.gov (United States)

    Cozon, G J N

    2014-11-01

    Iron deficiency anemia still remains problematic worldwide. Iron deficiency without anemia is often undiagnosed. We reviewed, in this study, symptoms and syndromes associated with iron deficiency with or without anemia: fatigue, cognitive functions, restless legs syndrome, hair loss, and chronic heart failure. Iron is absorbed through the digestive tract. Hepcidin and ferroportin are the main proteins of iron regulation. Pathogenic micro-organisms or intestinal dysbiosis are suspected to influence iron absorption.

  15. Management of Iron Deficiency Anemia

    OpenAIRE

    Jimenez, Kristine; Kulnigg-Dabsch, Stefanie; Gasche, Christoph

    2015-01-01

    Anemia affects one-fourth of the world’s population, and iron deficiency is the predominant cause. Anemia is associated with chronic fatigue, impaired cognitive function, and diminished well-being. Patients with iron deficiency anemia of unknown etiology are frequently referred to a gastroenterologist because in the majority of cases the condition has a gastrointestinal origin. Proper management improves quality of life, alleviates the symptoms of iron deficiency, and reduces the need for blo...

  16. Nutritional deficiencies after bariatric surgery.

    Science.gov (United States)

    Bal, Bikram S; Finelli, Frederick C; Shope, Timothy R; Koch, Timothy R

    2012-09-01

    Lifestyle intervention programmes often produce insufficient weight loss and poor weight loss maintenance. As a result, an increasing number of patients with obesity and related comorbidities undergo bariatric surgery, which includes approaches such as the adjustable gastric band or the 'divided' Roux-en-Y gastric bypass (RYGB). This Review summarizes the current knowledge on nutrient deficiencies that can develop after bariatric surgery and highlights follow-up and treatment options for bariatric surgery patients who develop a micronutrient deficiency. The major macronutrient deficiency after bariatric surgery is protein malnutrition. Deficiencies in micronutrients, which include trace elements, essential minerals, and water-soluble and fat-soluble vitamins, are common before bariatric surgery and often persist postoperatively, despite universal recommendations on multivitamin and mineral supplements. Other disorders, including small intestinal bacterial overgrowth, can promote micronutrient deficiencies, especially in patients with diabetes mellitus. Recognition of the clinical presentations of micronutrient deficiencies is important, both to enable early intervention and to minimize long-term adverse effects. A major clinical concern is the relationship between vitamin D deficiency and the development of metabolic bone diseases, such as osteoporosis or osteomalacia; metabolic bone diseases may explain the increased risk of hip fracture in patients after RYGB. Further studies are required to determine the optimal levels of nutrient supplementation and whether postoperative laboratory monitoring effectively detects nutrient deficiencies. In the absence of such data, clinicians should inquire about and treat symptoms that suggest nutrient deficiencies.

  17. [Comparative studies on the value of acute phase proteins and CA-125 for monitoring patients with ovarian cancer].

    Science.gov (United States)

    Kölbl, H; Tatra, G; Schieder, K; Bieglmayer, C

    1988-12-01

    In a study of 71 patients with malignant ovarian tumors serum levels of CA-125, C-reactive protein (CRP), alpha-1-antitrypsin and coeruloplasmin were analysed. In contrast to the tumor-free group significantly higher values of CA-125, CRP and alpha-1-antitrypsin were found in the group with recurrent disease. However, the serum-concentrations of coeruloplasmin remained unchanged in both groups. In the group with progressive disease the median values of CA-125 were greater than 65 U/ml and of CRP greater than 12 micron/ml, respectively. The median serum concentrations of alpha-1-antitrypsin (2 to 4 mg/ml) and coeruloplasmin (150 to 600 ng/ml) did not reach their cut-off levels. Beside CA-125 the analysis of CRP and alpha-1-antitrypsin is an additional helpful procedure for the monitoring of patients with malignant ovarian tumors.

  18. Panlobular emphysema in young intravenous Ritalin abusers

    Energy Technology Data Exchange (ETDEWEB)

    Schmidt, R.A.; Glenny, R.W.; Godwin, J.D.; Hampson, N.B.; Cantino, M.E.; Reichenbach, D.D. (Univ. of Washington, Seattle (USA))

    1991-03-01

    We studied a distinctive group of young intravenous Ritalin abusers with profound obstructive lung disease. Clinically, they seemed to have severe emphysema, but the pathologic basis of their symptoms had not been investigated previously. Seven patients have died and been autopsied: in four, the lungs were fixed, inflated, dried, and examined in detail radiologically, grossly, microscopically, and by electron probe X-ray microanalysis. All seven patients had severe panlobular (panacinar) emphysema that tended to be more severe in the lower lung zones and that was associated with microscopic talc granulomas. Vascular involvement by talc granulomas was variable, but significant interstitial fibrosis was not present. Five patients were tested for alpha-1-antitrypsin deficiency and found to be normal, as were six similar living patients. These findings indicate that some intravenous drug abusers develop emphysema that clinically, radiologically, and pathologically resembles that caused by alpha-1-antitrypsin deficiency but which must have a different pathogenesis. Talc from the Ritalin tablets may be important, but the mechanism remains to be elucidated.

  19. Iodine deficiency in Europe.

    Science.gov (United States)

    Delange, F

    1995-01-18

    Iodine is a trace element present in the human body in minute amounts (15-20 mg in adults, i.e. 0.0285 x 10(-3)% of body weight). The only confirmed function of iodine is to constitute an essential substrate for the synthesis of thyroid hormones, tetraiodothyronine, thyroxine or T4 and triiodothyronine, T3 (1). In thyroxine, iodine is 60% by weight. Thyroid hormones, in turn, play a decisive role in the metabolism of all cells of the organism (2) and in the process of early growth and development of most organs, especially of the brain (3). Brain development in humans occurs from fetal life up to the third postnatal year (4). Consequently, a deficit in iodine and/or in thyroid hormones occurring during this critical period of life will result not only in the slowing down of the metabolic activities of all the cells of the organism but also in irreversible alterations in the development of the brain. The clinical consequence will be mental retardation (5). When the physiological requirements of iodine are not met in a given population, a series of functional and developmental abnormalities occur (Table 1), including thyroid function abnormalities and, when iodine deficiency is severe, endemic goiter and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death, and infant mortality. These complications, which constitute an hindrance to the development of the affected population, are grouped under the general heading of Iodine Deficiency Disorders, IDD (6). Broad geographic areas exist in which the population is affected by IDD.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. Regulation of gene expression by dietary Ca2+ in kidneys of 25-hydroxyvitamin D3-1 alpha-hydroxylase knockout mice.

    NARCIS (Netherlands)

    Hoenderop, J.G.J.; Chon, H.; Gkika, D.; Bluyssen, H.A.; Holstege, F.C.; St. Arnaud, R.; Braam, B.; Bindels, R.J.M.

    2004-01-01

    BACKGROUND: Pseudovitamin D deficiency rickets (PDDR) is an autosomal disease, characterized by undetectable levels of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), rickets and secondary hyperparathyroidism. Mice in which the 25-hydroxyvitamin D3-1 alpha-hydroxylase (1 alpha-OHase) gene was inactivated, p

  1. Iron deficiency and iron deficiency anemia in women.

    Science.gov (United States)

    Coad, Jane; Pedley, Kevin

    2014-01-01

    Iron deficiency is one of the most common nutritional problems in the world and disproportionately affects women and children. Stages of iron deficiency can be characterized as mild deficiency where iron stores become depleted, marginal deficiency where the production of many iron-dependent proteins is compromised but hemoglobin levels are normal and iron deficiency anemia where synthesis of hemoglobin is decreased and oxygen transport to the tissues is reduced. Iron deficiency anemia is usually assessed by measuring hemoglobin levels but this approach lacks both specificity and sensitivity. Failure to identify and treat earlier stages of iron deficiency is concerning given the neurocognitive implications of iron deficiency without anemia. Most of the daily iron requirement is derived from recycling of senescent erythrocytes by macrophages; only 5-10 % comes from the diet. Iron absorption is affected by inhibitors and enhancers of iron absorption and by the physiological state. Inflammatory conditions, including obesity, can result in iron being retained in the enterocytes and macrophages causing hypoferremia as a strategic defense mechanism to restrict iron availability to pathogens. Premenopausal women usually have low iron status because of iron loss in menstrual blood. Conditions which further increase iron loss, compromise absorption or increase demand, such as frequent blood donation, gastrointestinal lesions, athletic activity and pregnancy, can exceed the capacity of the gastrointestinal tract to upregulate iron absorption. Women of reproductive age are at particularly high risk of iron deficiency and its consequences however there is a controversial argument that evolutionary pressures have resulted in an iron deficient phenotype which protects against infection.

  2. Alpha phoenix公司

    Institute of Scientific and Technical Information of China (English)

    2012-01-01

    德国Alpha phoenix公司成立于2009年.专注于制药领域清洗机器的研发和生产,产品符合cGMP的要求。公司的人员是制药领域清洗机器研发和生产的专家,他们具有20多年的全自动清洗机器的设计和生产经验。

  3. The double-lined spectroscopic binary $\\alpha$ Andromedae orbital elements and elemental abundances

    CERN Document Server

    Ryabchikova, T A; Adelman, S J

    1998-01-01

    We performed a spectroscopic study of the SB2 Mercury-Manganese star alpha And. Our measurements of the secondary's radial velocities result in improved orbital elements. The secondary shows abundances typical of the metallic-line stars: a Ca deficiency, small overabundances of the iron-peak elements, and 1.0 dex overabundances of Sr and Ba.

  4. Shared receptor components but distinct complexes for alpha and beta interferons.

    Science.gov (United States)

    Lewerenz, M; Mogensen, K E; Uzé, G

    1998-09-25

    The type I interferon family includes 13 alpha, one omega and one beta subtypes recognized by a complex containing the receptor subunits ifnar1 and ifnar2 and their associated Janus tyrosine kinases, Tyk2 and Jak1. To investigate the reported differences in the way that alpha and beta interferons signal through the receptor, we introduced alanine-substitutions in the ifnar2 extracellular domain, and expressed the mutants in U5A cells, lacking endogenous ifnar2. A selection, designed to recover mutants that responded preferentially to alpha or beta interferon yielded three groups: I, neutral; II, sensitive to alpha interferon, partially resistant to beta interferon; III, resistant to alpha interferon, partially sensitive to beta interferon. A mutant clone, TMK, fully resistant to alpha interferon with good sensitivity to beta interferon, was characterized in detail and compared with U5A cells complemented with wild-type ifnar2 and also with Tyk2-deficient 11.1 cells, which exhibit a similar alpha-unresponsive phenotype with a partial beta interferon response. Using anti-receptor antibodies and mutant forms of beta interferon, three distinct modes of ligand interaction could be discerned: (i) alpha interferon with ifnar1 and ifnar2; (ii) beta interferon with ifnar1 and ifnar2; (iii) beta interferon with ifnar2 alone. We conclude that alpha and beta interferons signal differently through their receptors because the two ligand subtypes interact with the receptor subunits ifnar 1 and ifnar2 in entirely different ways.

  5. Iron deficiency and cardiovascular disease

    NARCIS (Netherlands)

    von Haehling, Stephan; Jankowska, Ewa A.; van Veldhuisen, Dirk J.; Ponikowski, Piotr; Anker, Stefan D.

    2015-01-01

    Iron deficiency affects up to one-third of the world's population, and is particularly common in elderly individuals and those with certain chronic diseases. Iron excess can be detrimental in cardiovascular illness, and research has now also brought anaemia and iron deficiency into the focus of card

  6. Iron deficiency anemia in children

    OpenAIRE

    Pochinok, T. V.

    2016-01-01

    In the article the role of iron in the human body is highlighted. The mechanism of development of iron deficiency states, their consequences and the basic principles of diagnosis and correction of children of different ages are shown.Key words: children, iron deficiency anemia, treatment.

  7. Iron deficiency anemia in children.

    Science.gov (United States)

    Subramaniam, Girish; Girish, Meenakshi

    2015-06-01

    Iron deficiency is not just anemia; it can be responsible for a long list of other manifestations. This topic is of great importance, especially in infancy and early childhood, for a variety of reasons. Firstly, iron need is maximum in this period. Secondly, diet in infancy is usually deficient in iron. Thirdly and most importantly, iron deficiency at this age can result in neurodevelopmental and cognitive deficits, which may not be reversible. Hypochromia and microcytosis in a complete blood count (CBC) makes iron deficiency anemia (IDA) most likely diagnosis. Absence of response to iron should make us look for other differential diagnosis like β thalassemia trait and anemia of chronic disease. Celiac disease is the most important cause of true IDA not responding to oral iron therapy. While oral ferrous sulphate is the cheapest and most effective therapy for IDA, simple nonpharmacological and pharmacological measures can go a long way in prevention of iron deficiency.

  8. Distinct roles of HNF1beta, HNF1alpha, and HNF4alpha in regulating pancreas development, beta-cell function and growth.

    Science.gov (United States)

    Maestro, Miguel Angel; Cardalda, Carina; Boj, Sylvia F; Luco, Reini F; Servitja, Joan Marc; Ferrer, Jorge

    2007-01-01

    Mutations in the genes encoding transcriptional regulators HNF1beta (TCF2), HNF1alpha (TCF1), and HNF4alpha cause autosomal dominant diabetes (also known as maturity-onset diabetes of the young). Herein, we review what we have learnt during recent years concerning the functions of these regulators in the developing and adult pancreas. Mouse studies have revealed that HNF1beta is a critical regulator of a transcriptional network that controls the specification, growth, and differentiation of the embryonic pancreas. HNF1beta mutations in humans accordingly often cause pancreas hypoplasia. By contrast, HNF1alpha and HNF4alpha have been shown to regulate the function of differentiated beta-cells. HNF1alpha and HNF4alpha mutations in patients thus cause decreased glucose-induced insulin secretion that leads to a progressive form of diabetes. HNF4alpha mutations paradoxically also cause in utero and neonatal hyperinsulinism, which later evolves to decreased glucose-induced secretion. Recent studies show that Hnf4alpha deficiency in mice causes not only abnormal insulin secretion, but also an impairment of the expansion of beta-cell mass that normally occurs during pregnancy. In line with this finding, we present data that Hnf1alpha-/- beta-cells expressing SV40 large T antigen show a severe impairment of proliferation and failure to form tumours. Collectively, these findings implicate HNF1beta as a regulator of pancreas organogenesis and differentiation, whereas HNF1alpha and HNF4alpha primarily regulate both growth and function of islet beta-cells.

  9. Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha.

    Science.gov (United States)

    Qian, David Z; Kachhap, Sushant K; Collis, Spencer J; Verheul, Henk M W; Carducci, Michael A; Atadja, Peter; Pili, Roberto

    2006-09-01

    Hypoxia-inducible factor 1 alpha (HIF-1 alpha) plays a critical role in transcriptional gene activation involved in tumor angiogenesis. A novel class of agents, the histone deacetylase (HDAC) inhibitors, has been shown to inhibit tumor angiogenesis and HIF-1 alpha protein expression. However, the molecular mechanism responsible for this inhibition remains to be elucidated. In the current study, we investigated the molecular link between HIF-1 alpha inhibition and HDAC inhibition. Treatment of the VHL-deficient human renal cell carcinoma cell line UMRC2 with the hydroxamic HDAC inhibitor LAQ824 resulted in a dose-dependent inhibition of HIF-1 alpha protein via a VHL-independent mechanism and reduction of HIF-1 alpha transcriptional activity. HIF-1 alpha inhibition by LAQ824 was associated with HIF-1 alpha acetylation and polyubiquitination. HIF-1 alpha immunoprecipitates contained HDAC activity. Then, we tested different classes of HDAC inhibitors with diverse inhibitory activity of class I versus class II HDACs and assessed their capability of targeting HIF-1 alpha. Hydroxamic acid derivatives with known activity against both class I and class II HDACs were effective in inhibiting HIF-1 alpha at low nanomolar concentrations. In contrast, valproic acid and trapoxin were able to inhibit HIF-1 alpha only at concentrations that are effective against class II HDACs. Coimmunoprecipitation studies showed that class II HDAC4 and HDAC6 were associated with HIF-1 alpha protein. Inhibition by small interfering RNA of HDAC4 and HDAC6 reduced HIF-1 alpha protein expression and transcriptional activity. Taken together, these results suggest that class II HDACs are associated with HIF-1 alpha stability and provide a rationale for targeting HIF-1 alpha with HDAC inhibitors against class II isozymes.

  10. Are alpha-gliadins glycosylated?

    Science.gov (United States)

    Turner, J B; Garner, G V; Gordon, D B; Brookes, S J; Smith, C A

    2002-02-01

    Alpha-gliadins isolated by carboxymethylcellulose chromatography contain noncovalently bound glucose probably due to contaminating proteoglycans and to material shed from the column. Traces of carbohydrate remain strongly bound to alpha-gliadins even after harsh denaturation, but our results indicate alpha-gliadins are not glycoproteins. Suggestions that gliadins are glycoproteins are probably due to contamination with this glucose and the presence of these proteoglycans.

  11. Robust estimation of Cronbach's alpha

    OpenAIRE

    2002-01-01

    Cronbach’s alpha is a popular method to measure reliability, e.g. in quantifying the reliability of a score to summarize the information of several items in questionnaires. The alpha coefficient is known to be non-robust. We study the behavior of this coefficient in different settings to identify situations, which can easily occur in practice, but under which the Cronbach’s alpha coefficient is extremely sensitive to violations of the classical model assumptions. Furthermore, we construct a r...

  12. Decay-Assisted Laser Spectroscopy of Neutron-Deficient Francium

    CERN Document Server

    Lynch, K M; Bissell, M L; Budincevic, I; Cocolios, T E; De Groote, R P; De Schepper, S; Fedosseev, V N; Flanagan, K T; Franchoo, S; Garcia Ruiz, R F; Heylen, H; Marsh, B A; Neyens, G; Procter, T J; Rossel, R E; Rothe, S; Strashnov, I; Stroke, H H; Wendt, K D A

    2014-01-01

    This paper reports on the hyperfine-structure and radioactive-decay studies of the neutron-deficient francium isotopes $^{202-206}$Fr performed with the Collinear Resonance Ionization Spectroscopy (CRIS) experiment at the ISOLDE facility, CERN. The high resolution innate to collinear laser spectroscopy is combined with the high efficiency of ion detection to provide a highly-sensitive technique to probe the hyperfine structure of exotic isotopes. The technique of decay-assisted laser spectroscopy is presented, whereby the isomeric ion beam is deflected to a decay spectroscopy station for alpha-decay tagging of the hyperfine components. Here, we present the first hyperfine-structure measurements of the neutron-deficient francium isotopes $^{202-206}$Fr, in addition to the identification of the low-lying states of $^{202,204}$Fr performed at the CRIS experiment.

  13. Newborn screening for dihydrolipoamide dehydrogenase deficiency: Citrulline as a useful analyte

    Directory of Open Access Journals (Sweden)

    Shane C. Quinonez

    2014-01-01

    Full Text Available Dihydrolipoamide dehydrogenase deficiency, also known as maple syrup urine disease (MSUD type III, is caused by the deficiency of the E3 subunit of branched chain alpha-ketoacid dehydrogenase (BCKDH, α-ketoglutarate dehydrogenase (αKGDH, and pyruvate dehydrogenase (PDH. DLD deficiency variably presents with either a severe neonatal encephalopathic phenotype or a primarily hepatic phenotype. As a variant form of MSUD, it is considered a core condition recommended for newborn screening. The detection of variant MSUD forms has proven difficult in the past with no asymptomatic DLD deficiency patients identified by current newborn screening strategies. Citrulline has recently been identified as an elevated dried blood spot (DBS metabolite in symptomatic patients affected with DLD deficiency. Here we report the retrospective DBS analysis and second-tier allo-isoleucine testing of 2 DLD deficiency patients. We show that an elevated citrulline and an elevated allo-isoleucine on second-tier testing can be used to successfully detect DLD deficiency. We additionally recommend that DLD deficiency be included in the “citrullinemia/elevated citrulline” ACMG Act Sheet and Algorithm.

  14. Genetics Home Reference: isolated growth hormone deficiency

    Science.gov (United States)

    ... Home Health Conditions isolated growth hormone deficiency isolated growth hormone deficiency Enable Javascript to view the expand/collapse ... Download PDF Open All Close All Description Isolated growth hormone deficiency is a condition caused by a severe ...

  15. Genetics Home Reference: familial HDL deficiency

    Science.gov (United States)

    ... Genetics Home Health Conditions familial HDL deficiency familial HDL deficiency Enable Javascript to view the expand/collapse ... Download PDF Open All Close All Description Familial HDL deficiency is a condition characterized by low levels ...

  16. Genetics Home Reference: eosinophil peroxidase deficiency

    Science.gov (United States)

    ... Genetics Home Health Conditions eosinophil peroxidase deficiency eosinophil peroxidase deficiency Enable Javascript to view the expand/collapse ... Download PDF Open All Close All Description Eosinophil peroxidase deficiency is a condition that affects certain white ...

  17. Genetics Home Reference: protein C deficiency

    Science.gov (United States)

    ... Management Genetic Testing (1 link) Genetic Testing Registry: Thrombophilia, hereditary, due to protein C deficiency, autosomal dominant ... my area? Other Names for This Condition hereditary thrombophilia due to protein C deficiency PROC deficiency Related ...

  18. PDFs, $\\alpha_s$, and quark masses from global fits

    CERN Document Server

    Alekhin, S; Moch, S; Placakyte, R

    2016-01-01

    The strong coupling constant $\\alpha_s$ and the heavy-quark masses, $m_c$, $m_b$, $m_t$ are extracted simultaneosly with the parton distribution functions (PDFs) in the updated ABM12 fit including recent data from CERN-SPS, HERA, Tevatron, and the LHC. The values of \\begin{eqnarray} \

  19. 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.

  20. Red cell pyruvate kinase deficiency in Southern Sardinia.

    Science.gov (United States)

    Perseu, L; Giagu, N; Satta, S; Sollaino, M C; Congiu, R; Galanello, R

    2010-12-15

    Pyruvate kinase (PK) deficiency is the most frequent red cell enzymatic defect responsible for hereditary non-spherocytic hemolytic anemia. The clinical picture is quite variable and the reasons of this variability have been only partially clarified. We report the clinical description and the extended molecular analysis in 3 PK deficient patients with clinical phenotype of variable severity. We studied the clinical and hematological aspects of 3 patients and analyzed the following genes: pyruvate kinase-R, glucose-6-phosphate-dehydrogenase, α-globin, uridindiphosphoglucuronil transferase and HFE. One patient (A) with a severe clinical picture resulted homozygote for exon 8 nt994A substitution, the other 2 (brothers) were compound heterozygotes for exon 8 nt994A and exon 11 nt1456T mutation. One of the two brothers with a more severe phenotype coinherited also had G6PD deficiency, while both had microcytosis due to the homozygosity for the non-deletional form of α-thalassemia ATG→ACG substitution at the initiation codon of the alpha2 globin gene. Our results suggest that extended molecular analysis is useful for studying how several interacting gene mutations contribute to the clinical variability of pyruvate kinase deficiency.

  1. An immunologic approach to induction of epidermal growth factor deficiency

    DEFF Research Database (Denmark)

    Raaberg, Lasse; Nexø, Ebba; Poulsen, Steen Seier;

    1995-01-01

    Epidermal growth factor (EGF) in pharmacologic doses is able to induce growth and development in the fetus and the newborn. To investigate the opposite situation, the effects of insufficient amounts of EGF during development, we wanted to establish an in vivo model with a state of EGF deficiency......(-9) mol/L. The antibodies recognized purified EGF from the submandibular glands (6 kD) and from urine (45 kD) and further native EGF in saliva and urine. The cross-reactivity toward transforming growth factor-alpha was below 3%. Binding of EGF by antibodies inhibited its binding to the EGF...

  2. Iron Deficiency Anemia in Pregnancy.

    Science.gov (United States)

    Breymann, Christian

    2015-10-01

    Anemia is a common problem in obstetrics and perinatal care. Any hemoglobin below 10.5 g/dL can be regarded as true anemia regardless of gestational age. Reasons for anemia in pregnancy are mainly nutritional deficiencies, parasitic and bacterial diseases, and inborn red blood cell disorders such as thalassemias. The main cause of anemia in obstetrics is iron deficiency, which has a worldwide prevalence between estimated 20%-80% and consists of a primarily female population. Stages of iron deficiency are depletion of iron stores, iron-deficient erythropoiesis without anemia, and iron deficiency anemia, the most pronounced form of iron deficiency. Pregnancy anemia can be aggravated by various conditions such as uterine or placental bleedings, gastrointestinal bleedings, and peripartum blood loss. In addition to the general consequences of anemia, there are specific risks during pregnancy for the mother and the fetus such as intrauterine growth retardation, prematurity, feto-placental miss ratio, and higher risk for peripartum blood transfusion. Besides the importance of prophylaxis of iron deficiency, the main therapy options for the treatment of pregnancy anemia are oral iron and intravenous iron preparations.

  3. Alpha-mannosidosis

    DEFF Research Database (Denmark)

    Borgwardt, Line Gutte; Danielsen, E R; Thomsen, Carsten;

    2016-01-01

    Alpha-mannosidosis (AM) (OMIM 248500) is a rare lysosomal storage disease. The understanding of the central nervous system (CNS) pathology is limited. This study is the first describing the CNS pathology and the correlation between the CNS pathology and intellectual disabilities in human AM. Thirty......-protein, glial fibrillary acidic protein and neurofilament light protein in 97 patients, 74% and 41% of CSF samples, respectively. A negative correlation between CSF-biomarkers and cognitive function and CSF-oligosaccharides and cognitive function was found. The combination of MRS/MRI changes, elevated...... concentrations of CSF-biomarkers and CSF-oligosaccharides suggests gliosis and reduced myelination, as part of the CNS pathology in AM. Our data demonstrate early neuropathological changes, which may be taken into consideration when planning initiation of treatment....

  4. Genetics Home Reference: hereditary antithrombin deficiency

    Science.gov (United States)

    ... Merck Manual Home Edition for Patients and Caregivers: Thrombophilia National Blood Clot Alliance: Antithrombin Deficiency Orphanet: Hereditary thrombophilia due to congenital antithrombin deficiency Patient Support and ...

  5. DFT CONFORMATIONAL STUDIES OF ALPHA-MALTOTRIOSE

    Science.gov (United States)

    Recent DFT optimization studies on alpha-maltose improved our understanding of the preferred conformations of alpha-maltose and the present study extends these studies to alpha-maltotriose with three alpha-D-glucopyranose residues linked by two alpha-[1-4] bridges, denoted herein as DP-3's. Combina...

  6. The ALPHA antihydrogen trapping apparatus

    Energy Technology Data Exchange (ETDEWEB)

    Amole, C. [Department of Physics and Astronomy, York University, Toronto ON Canada, M3J 1P3 (Canada); Andresen, G.B. [Department of Physics and Astronomy, Aarhus University, DK-8000 Aarhus C (Denmark); Ashkezari, M.D. [Department of Physics, Simon Fraser University, Burnaby, BC Canada, V5A 1S6 (Canada); Baquero-Ruiz, M. [Department of Physics, University of California at Berkeley, Berkeley, CA 94720-7300 (United States); Bertsche, W. [Department of Physics, College of Science, Swansea University, Swansea SA2 8PP (United Kingdom); School of Physics and Astronomy, University of Manchester, Manchester M13 9PL (United Kingdom); The Cockcroft Institute, Warrington WA4 4AD (United Kingdom); Bowe, P.D. [Department of Physics and Astronomy, Aarhus University, DK-8000 Aarhus C (Denmark); Butler, E. [Physics Department, CERN, CH-1211 Geneva 23 (Switzerland); Capra, A. [Department of Physics and Astronomy, York University, Toronto ON Canada, M3J 1P3 (Canada); Carpenter, P.T. [Department of Physics, Auburn University, Auburn, AL 36849-5311 (United States); Cesar, C.L. [Instituto de Física, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-972 (Brazil); Chapman, S. [Department of Physics, University of California at Berkeley, Berkeley, CA 94720-7300 (United States); Charlton, M.; Deller, A.; Eriksson, S. [Department of Physics, College of Science, Swansea University, Swansea SA2 8PP (United Kingdom); Escallier, J. [Brookhaven National Laboratory, Upton, NY 11973 (United States); Fajans, J. [Department of Physics, University of California at Berkeley, Berkeley, CA 94720-7300 (United States); Friesen, T. [Department of Physics and Astronomy, University of Calgary, Calgary AB, Canada, T2N 1N4 (Canada); Fujiwara, M.C.; Gill, D.R. [TRIUMF, 4004 Wesbrook Mall, Vancouver BC, Canada V6T 2A3 (Canada); Gutierrez, A. [Department of Physics and Astronomy, University of British Columbia, Vancouver BC, Canada V6T 1Z4 (Canada); and others

    2014-01-21

    The ALPHA collaboration, based at CERN, has recently succeeded in confining cold antihydrogen atoms in a magnetic minimum neutral atom trap and has performed the first study of a resonant transition of the anti-atoms. The ALPHA apparatus will be described herein, with emphasis on the structural aspects, diagnostic methods and techniques that have enabled antihydrogen trapping and experimentation to be achieved.

  7. Alpha particle emitters in medicine

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, D.R.

    1989-09-01

    Radiation-induced cancer of bone, liver and lung has been a prominent harmful side-effect of medical applications of alpha emitters. In recent years, however, the potential use of antibodies labeled with alpha emitting radionuclides against cancer has seemed promising because alpha particles are highly effective in cell killing. High dose rates at high LET, effectiveness under hypoxic conditions, and minimal expectancy of repair are additional advantages of alpha emitters over antibodies labeled with beta emitting radionuclides for cancer therapy. Cyclotron-produced astatine-211 ({sup 211}At) and natural bismuth-212 ({sup 212}Bi) have been proposed and are under extensive study in the United States and Europe. Radium-223 ({sup 223}Ra) also has favorable properties as a potential alpha emitting label, including a short-lived daughter chain with four alpha emissions. The radiation dosimetry of internal alpha emitters is complex due to nonuniformly distributed sources, short particle tracks, and high relative specific ionization. The variations in dose at the cellular level may be extreme. Alpha-particle radiation dosimetry, therefore, must involve analysis of statistical energy deposition probabilities for cellular level targets. It must also account fully for nonuniform distributions of sources in tissues, source-target geometries, and particle-track physics. 18 refs., 4 figs.

  8. 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...

  9. Alpha radioactivity for proton-rich even Pb isotopes

    Indian Academy of Sciences (India)

    Arati Devi; S Prakash; I Mehrotra

    2009-04-01

    Half-lives for alpha radioactivity from proton-rich even Pb isotopes in the range = 182–202 have been calculated using the unified fission-like approach. The geometrical shape of the potential barrier is parametrized in terms of a highly versatile, asymmetric and analytically solvable form of potential based on Ginnochio’s potential. Good agreement with the experimental data has been obtained with the variation of just one parameter. Half-lives of three unknown alpha emitters in the neutron-deficient Pb chain (198Pb, 200Pb and 204Pb) have been predicted. The exact expression for the transmission coefficient has been compared with those obtained from WKB approximation method for symmetric Eckart potential.

  10. The alpha -Process and the r-Process

    Science.gov (United States)

    Woosley, S. E.; Hoffman, R. D.

    1992-12-01

    If material initially in nuclear statistical equilibrium (NSE) at high temperature and containing a large fraction of alpha -particles (or nucleons) is expanded and cooled so rapidly that not all the alpha -particles have time to reassemble, its final composition will differ substantially from what is traditionally calculated for particle-deficient freeze-outs. It has long been known that this phenomenon, the ``alpha -rich freeze-out," can lead to the production of elements heavier than the iron group, but only up to about zinc (A ~ 66). Here we explore the alpha -rich freeze-out for values of neutron excess larger than previously treated and discover nuclear systematics that, for neutron excesses greater than about 0.05, allow the creation of heavier elements all the way up to A ~ 100, even when most of the ejecta is in the form of heavy elements. In the limit of a very large fraction of unassembled alpha -particles and a large neutron excess, the alpha -rich freeze-out merges smoothly into the classical r-process. In contrast to previous studies, we find that a large part of the nuclear flow in the r-process may be carried by charged particle reactions up to about A = 100. We speculate that the site of these processes is the high entropy ``wind'' of a young (age 1-10 s) neutron star in which neutrino energy deposition is driving mass loss. The appropriate conditions exist in the delayed supernova explosion mechanism of Mayle & Wilson, but they may occur in other models as well. The mass of r-process ejected per supernova is expected to be ~ 10(-4) M\\sun \\ per Type II or Type Ib supernova, but this will be sensitive to details of the presupernova structure, the explosion mechanism, and the amount of material that falls back onto the neutron star when the reverse shock arrives there.

  11. Development of rabbit monoclonal antibodies for detection of alpha-dystroglycan in normal and dystrophic tissue.

    Directory of Open Access Journals (Sweden)

    Marisa J Fortunato

    Full Text Available Alpha-dystroglycan requires a rare O-mannose glycan modification to form its binding epitope for extracellular matrix proteins such as laminin. This functional glycan is disrupted in a cohort of muscular dystrophies, the secondary dystroglycanopathies, and is abnormal in some metastatic cancers. The most commonly used reagent for detection of alpha-dystroglycan is mouse monoclonal antibody IIH6, but it requires the functional O-mannose structure for recognition. Therefore, the ability to detect alpha-dystroglycan protein in disease states where it lacks the full O-mannose glycan has been limited. To overcome this hurdle, rabbit monoclonal antibodies against the alpha-dystroglycan C-terminus were generated. The new antibodies, named 5-2, 29-5, and 45-3, detect alpha-dystroglycan from mouse, rat and pig skeletal muscle by Western blot and immunofluorescence. In a mouse model of fukutin-deficient dystroglycanopathy, all antibodies detected low molecular weight alpha-dystroglycan in disease samples demonstrating a loss of functional glycosylation. Alternately, in a porcine model of Becker muscular dystrophy, relative abundance of alpha-dystroglycan was decreased, consistent with a reduction in expression of the dystrophin-glycoprotein complex in affected muscle. Therefore, these new rabbit monoclonal antibodies are suitable reagents for alpha-dystroglycan core protein detection and will enhance dystroglycan-related studies.

  12. Helicobacterpy loriinfection and micronutrient deficiencies

    Institute of Scientific and Technical Information of China (English)

    Javed Yakoob; Wasim Jafri; Shahab Abid

    2003-01-01

    It is known that deficiencies of micronutrients due to infections increase morbidity and mortality. This phenomenon depicts itself conspicuously in developing countries.Deficiencies of iron, vitamins A, E, C, B12, etc are widely prevalent among populations living in the third world countries. Helicobacterpylori (Hpylori) infection has a high prevalence throughout the world. Deficiencies of several micronutrients due to Hpylori infection may be concomitantly present and vary from subtle sub-clinical states to severe clinical disorders. These essential trace elementsl micronutrients are involved in host defense mechanisms,maintaining epithelial cell integrity, glycoprotein synthesis,transport mechanisms, myocardial contractility, brain development, cholesterol and glucose metabolism. In this paper Hpyloriinfection in associaed with various micronutrients deficiencies is briefly reviewed.

  13. Retinol and Alpha-Tocopherol Levels Among Hemodialysis Patients.

    Directory of Open Access Journals (Sweden)

    Awatif M. Abd El Maksoud*, Asmaa M. Abd Allah*, Waleed Massoud

    2004-06-01

    Full Text Available Plasma retinol, alpha tocopherol, total cholesterol and triglycerides were measured in 40 patients aged 27-65 years, under regular hemodialysis (HD for 1.8-13 years at Ahmed Maher teaching Hospital and in 28 healthy age and sex matched control. Predialysis and postdialysis measurements were also, done for a subset of 13 hemodialytic patients. Among hemodialytic patients ,all values ( Plasma retinol ,alpha- tocopherol, total cholesterol and triglycerides were significantly higher ( p 100 ug /dl except for one patient . On the other hand ,alpha-tocopherol level in hemodialytic patients was ranged between deficiency ( 1080 ug/dl. Comparing predialysis and postdialysis measurements , the hemodialytic patients showed non significant difference concerning retinol level , while alpha tocopherol was significantly decreased in postdialytic state .In conclusion ; further studies are needed to answer, if hemodialytic patients are at risk for symptomatic vitamin A toxicity?. Even with normal or low plasma vitamin E, it is needed as an antioxidant accessory therapy in hemodialytic patients.

  14. Vitamin D deficiency in adolescents

    OpenAIRE

    Ashraf T Soliman; Vincenzo De Sanctis; Rania Elalaily; Said Bedair; Islam Kassem

    2014-01-01

    The prevalence of severe vitamin D deficiency (VDD) in adolescents is variable but considerably high in many countries, especially in Middle-east and Southeast Asia. Different factors attribute to this deficiency including lack of sunlight exposure due to cultural dress codes and veiling or due to pigmented skin, and less time spent outdoors, because of hot weather, and lower vitamin D intake. A potent adaptation process significantly modifies the clinical presentation and therefore clinical ...

  15. Iron deficiency and cognitive functions

    OpenAIRE

    Jáuregui-Lobera I

    2014-01-01

    Ignacio Jáuregui-Lobera Department of Nutrition and Bromatology, Pablo de Olavide University, Seville, Spain Abstract: Micronutrient deficiencies, especially those related to iodine and iron, are linked to different cognitive impairments, as well as to potential long-term behavioral changes. Among the cognitive impairments caused by iron deficiency, those referring to attention span, intelligence, and sensory perception functions are mainly cited, as well as those associated with...

  16. Simultaneous quantification of GABAergic 3alpha,5alpha/3alpha,5beta neuroactive steroids in human and rat serum.

    Science.gov (United States)

    Porcu, Patrizia; O'Buckley, Todd K; Alward, Sarah E; Marx, Christine E; Shampine, Lawrence J; Girdler, Susan S; Morrow, A Leslie

    2009-01-01

    The 3alpha,5alpha- and 3alpha,5beta-reduced derivatives of progesterone, deoxycorticosterone, dehydroepiandrosterone and testosterone enhance GABAergic neurotransmission and produce inhibitory neurobehavioral and anti-inflammatory effects. Despite substantial information on the progesterone derivative (3alpha,5alpha)-3-hydroxypregnan-20-one (3alpha,5alpha-THP, allopregnanolone), the physiological significance of the other endogenous GABAergic neuroactive steroids has remained elusive. Here, we describe the validation of a method using gas chromatography-mass spectrometry to simultaneously identify serum levels of the eight 3alpha,5alpha- and 3alpha,5beta-reduced derivatives of progesterone, deoxycorticosterone, dehydroepiandrosterone and testosterone. The method shows specificity, sensitivity and enhanced throughput compared to other methods already available for neuroactive steroid quantification. Administration of pregnenolone to rats and progesterone to women produced selective effects on the 3alpha,5alpha- and 3alpha,5beta-reduced neuroactive steroids, indicating differential regulation of their biosynthetic pathways. Pregnenolone administration increased serum levels of 3alpha,5alpha-THP (+1488%, psteroid was detected only in 3/16 control subjects. Levels of 3alpha,5alpha-A, 3alpha,5beta-A and pregnenolone were not altered. This method can be used to investigate the physiological and pathological role of neuroactive steroids and to develop biomarkers and new therapeutics for neurological and psychiatric disorders.

  17. Radiative Corrections to the Muonium Hyperfine Structure; 2, The $\\alpha (Z\\alpha)^2$ Correction

    CERN Document Server

    Nio, M

    1997-01-01

    This is the second of a series of papers on the radiative corrections of order $\\alpha^2 (Z\\alpha)$, $\\alpha (Z\\alpha )^2$, and various logarithmic terms of order $\\alpha^4$, to the hyperfine structure of the muonium ground state. This paper deals with the $\\alpha (Z\\alpha)^2$ correction. Based on the NRQED bound state theory, we isolated the term of order $\\alpha(Z\\alpha)^2$ exactly. Our result $+16.904~2~(11) \\alpha(Z\\alpha)^2 E_F / \\pi$ for the non-logarithmic part is consistent with the $\\alpha (Z\\alpha)^2$ part of Sapirstein's calculation and the recent result of Pachucki, and reduces the numerical uncertainty in the $\\alpha (Z\\alpha)^2$ term by two orders of magnitude.

  18. 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...

  19. Venus - Alpha Regio

    Science.gov (United States)

    1990-01-01

    The eastern edge of Alpha Regio is shown in this image centered at 30 degrees south latitude and 11.8 degrees east longitude (longitude on Venus is measured from 0 degrees to 360 degrees east). Seven circular, dome-like hills, averaging 25 kilometers (15 miles) in diameter with maximum heights of 750 meters (2,475 feet) dominate the scene. These features are interpreted as very thick lava flows that came from an opening on the relatively level ground, which allowed the lava to flow in an even pattern outward from the opening. The complex fractures on top of the domes suggest that if the domes were created by lava flows, a cooled outer layer formed and then further lava flowing in the interior stretched the surface. The domes may be similar to volcanic domes on Earth. Another interpretation is that the domes are the result of molten rock or magma in the interior that pushed the surface layer upward. The near-surface magma then withdrew to deeper levels, causing the collapse and fracturing of the dome surface. The bright margins possibly indicate the presence of rock debris on the slopes of the domes. Some of the fractures on the plains cut through the domes, while others appear to be covered by the domes. This indicates that active processes pre date and post date the dome-like hills. The prominent black area in the northeast corner of the image is a data gap. North is at the top of the image.

  20. On the Validity of the Geiger-Nuttall Alpha-Decay Law and its Microscopic Basis

    CERN Document Server

    Qi, C; Huyse, M; Liotta, R J; Van Duppen, P; Wyss, R

    2014-01-01

    The Geiger-Nuttall (GN) law relates the partial $\\alpha$-decay half-life with the energy of the escaping $\\alpha$ particle and contains for every isotopic chain two experimentally determined coefficients. The expression is supported by several phenomenological approaches, however its coefficients lack a fully microscopic basis. In this paper we will show that: 1) the empirical coefficients that appear in the GN law have a deep physical meaning and 2) the GN law is successful within the restricted experimental data sets available so far, but is not valid in general. We will show that, when the dependence of logarithm values of the $\\alpha$ formation probability on the neutron number is not linear or constant, the GN law is broken. For the $\\alpha$ decay of neutron-deficient nucleus $^{186}$Po, the difference between the experimental half-life and that predicted by the GN Law is as large as one order of magnitude.

  1. Partitioning $\\alpha$-large sets for $\\alpha<\\varepsilon_{\\omega}$

    CERN Document Server

    De Smet, Michiel

    2010-01-01

    We generalise the results by Bigorajska and Kotlarski about partitioning $\\alpha$-large sets, by extending the domain up to ordinals below $\\varepsilon_{\\omega}$. These results will be very useful to give a miniaturisation of the infinite Ramsey Theorem.

  2. Two alpha, three alpha and multiple heavy-ion radioactivities

    Energy Technology Data Exchange (ETDEWEB)

    Poenaru, D.N.; Ivascu, M. (Institute for Physics and Nuclear Engineering, Bucharest (Romania))

    1985-07-01

    New decay modes by spontaneous emission of two and three ..cap alpha.. particles and two identical or different heavy ions, are predicted. The analytical variant of the superasymmetric fission model is used to estimate the half lives.

  3. 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.

  4. The transcriptional coactivator PGC-1alpha is essential for maximal and efficient cardiac mitochondrial fatty acid oxidation and lipid homeostasis.

    Science.gov (United States)

    Lehman, John J; Boudina, Sihem; Banke, Natasha Hausler; Sambandam, Nandakumar; Han, Xianlin; Young, Deanna M; Leone, Teresa C; Gross, Richard W; Lewandowski, E Douglas; Abel, E Dale; Kelly, Daniel P

    2008-07-01

    High-capacity mitochondrial ATP production is essential for normal function of the adult heart, and evidence is emerging that mitochondrial derangements occur in common myocardial diseases. Previous overexpression studies have shown that the inducible transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha is capable of activating postnatal cardiac myocyte mitochondrial biogenesis. Recently, we generated mice deficient in PGC-1alpha (PGC-1alpha(-/-) mice), which survive with modestly blunted postnatal cardiac growth. To determine if PGC-1alpha is essential for normal cardiac energy metabolic capacity, mitochondrial function experiments were performed on saponin-permeabilized myocardial fibers from PGC-1alpha(-/-) mice. These experiments demonstrated reduced maximal (state 3) palmitoyl-l-carnitine respiration and increased maximal (state 3) pyruvate respiration in PGC-1alpha(-/-) mice compared with PGC-1alpha(+/+) controls. ATP synthesis rates obtained during maximal (state 3) respiration in permeabilized myocardial fibers were reduced for PGC-1alpha(-/-) mice, whereas ATP produced per oxygen consumed (ATP/O), a measure of metabolic efficiency, was decreased by 58% for PGC-1alpha(-/-) fibers. Ex vivo isolated working heart experiments demonstrated that PGC-1alpha(-/-) mice exhibited lower cardiac power, reduced palmitate oxidation, and increased reliance on glucose oxidation, with the latter likely a compensatory response. (13)C NMR revealed that hearts from PGC-1alpha(-/-) mice exhibited a limited capacity to recruit triglyceride as a source for lipid oxidation during beta-adrenergic challenge. Consistent with reduced mitochondrial fatty acid oxidative enzyme gene expression, the total triglyceride content was greater in hearts of PGC-1alpha(-/-) mice relative to PGC-1alpha(+/+) following a fast. Overall, these results demonstrate that PGC-1alpha is essential for the maintenance of maximal, efficient cardiac

  5. Clinical manifestation of myeloperoxidase deficiency.

    Science.gov (United States)

    Lanza, F

    1998-09-01

    Myeloperoxidase (MPO), an iron-containing heme protein localized in the azurophilic granules of neutrophil granulocytes and in the lysosomes of monocytes, is involved in the killing of several micro-organisms and foreign cells, including bacteria, fungi, viruses, red cells, and malignant and nonmalignant nucleated cells. Despite the primary role of the oxygen-dependent MPO system in the destruction of certain phagocytosed microbes, subjects with total or partial MPO deficiency generally do not have an increased frequency of infections, probably because other MPO-independent mechanism(s) for microbicidal activity compensate for the lack of MPO. Infectious diseases, especially with species of Candida, have been observed predominantly in MPO-deficient patients who also have diabetes mellitus, but the frequency of such cases is very low, less than 5% of reported MPO-deficient subjects. Evidence from a number of investigators indicates that individuals with total MPO deficiency show a high incidence of malignant tumors. Since MPO-deficient PMNs exhibit in vitro a depressed lytic action against malignant human cells, it can be speculated that the neutrophil MPO system plays a central role in the tumor surveillance of the host. However, any definitive conclusion on the association between MPO deficiency and the occurrence of cancers needs to be confirmed in further clinical studies. Clinical manifestations of this disorder depend on the nature of the defect; an acquired abnormality associated with other hematological or nonhematological diseases has been occasionally described, but the primary deficiency is the form more commonly reported. Another area of interest pertinent to MPO expression is related to the use of anti-MPO monoclonal antibodies for the lineage assignment of acute leukemic cells, the definition of FAB MO acute myeloid leukemia, the identification of biphenotypic acute leukemias, and their distinction from acute leukemia with minimal phenotypic deviation

  6. HIF1α is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis.

    Science.gov (United States)

    Miyauchi, Yoshiteru; Sato, Yuiko; Kobayashi, Tami; Yoshida, Shigeyuki; Mori, Tomoaki; Kanagawa, Hiroya; Katsuyama, Eri; Fujie, Atsuhiro; Hao, Wu; Miyamoto, Kana; Tando, Toshimi; Morioka, Hideo; Matsumoto, Morio; Chambon, Pierre; Johnson, Randall S; Kato, Shigeaki; Toyama, Yoshiaki; Miyamoto, Takeshi

    2013-10-08

    In women, estrogen deficiency after menopause frequently accelerates osteoclastic bone resorption, leading to osteoporosis, the most common skeletal disorder. However, mechanisms underlying osteoporosis resulting from estrogen deficiency remain largely unknown. Here we show that in bone-resorbing osteoclasts, estrogen-dependent destabilization of hypoxia-inducible factor 1 alpha (HIF1α), which is unstable in the presence of oxygen, plays a pivotal role in promoting bone loss in estrogen-deficient conditions. In vitro, HIF1α was destabilized by estrogen treatment even in hypoxic conditions, and estrogen loss in ovariectomized (Ovx) mice stabilized HIF1α in osteoclasts and promoted their activation and subsequent bone loss in vivo. Osteoclast-specific HIF1α inactivation antagonized bone loss in Ovx mice and osteoclast-specific estrogen receptor alpha deficient mice, both models of estrogen-deficient osteoporosis. Oral administration of a HIF1α inhibitor protected Ovx mice from osteoclast activation and bone loss. Thus, HIF1α represents a promising therapeutic target in osteoporosis.

  7. Molecular basis for H blood group deficiency in Bombay (Oh) and para-Bombay individuals.

    Science.gov (United States)

    Kelly, R J; Ernst, L K; Larsen, R D; Bryant, J G; Robinson, J S; Lowe, J B

    1994-06-21

    The penultimate step in the biosynthesis of the human ABO blood group oligosaccharide antigens is catalyzed by alpha-(1,2)-fucosyltransferase(s) (GDP-L-fucose: beta-D-galactoside 2-alpha-L-fucosyltransferase, EC 2.4.1.69), whose expression is determined by the H and Secretor (SE) blood group loci (also known as FUT1 and FUT2, respectively). These enzymes construct Fuc alpha 1-->2Gal beta-linkages, known as H determinants, which are essential precursors to the A and B antigens. Erythrocytes from individuals with the rare Bombay and para-Bombay blood group phenotypes are deficient in H determinants, and thus A and B determinants, as a consequence of apparent homozygosity for null alleles at the H locus. We report a molecular analysis of a human alpha-(1,2)-fucosyltransferase gene, thought to correspond to the H blood group locus, in a Bombay pedigree and a para-Bombay pedigree. We find inactivating point mutations in the coding regions of both alleles of this gene in each H-deficient individual. These results define the molecular basis for H blood group antigen deficiency in Bombay and para-Bombay phenotypes, provide compelling evidence that this gene represents the human H blood group locus, and strongly support a hypothesis that the H and SE loci represent distinct alpha-(1,2)-fucosyltransferase genes. Candidate sequences for the human SE locus are identified by low-stringency Southern blot hybridization analyses, using a probe derived from the H alpha-(1,2)-fucosyltransferase gene.

  8. Medical image of the week: panloubular emphysema

    Directory of Open Access Journals (Sweden)

    Mathur A

    2015-08-01

    Full Text Available No abstract available. Article truncated after 150 words. A 60 year old female, non-smoker with a past medical history of chronic rhinosinusitis with nasal polyps presented with an eight year history of productive cough and dyspnea. Previous treatment with inhaled corticosteroids, courses of systemic corticosteroids and antibiotics provided modest improvement in her symptoms. Pulmonary function testing revealed a severe obstructive ventilatory defect without significant bronchodilator response and reduced diffusing capacity (DLCO. Chest x-ray surprisingly revealed lower lobe predominant emphysematous changes (Figure 1. Alpha-1-antitrypsin level was within normal range at 137 mg/dL. Panlobular emphysema represents permanent destruction of the entire acinus distal to the respiratory bronchioles and is more likely to affect the lower lobes compared to centrilobular emphysema (1. Panlobular emphysema is associated with alpha-1-antitrypsin deficiency, intravenous drug abuse specifically with methylphenidate and methadone, Swyer-James syndrome, and obliterative bronchiolitis. Whether this pattern is seen as part of normal senescence in non-smoking individuals remains controversial (2. Panlobular emphysema may ...

  9. [Iron deficiency and iron deficiency anemia are global health problems].

    Science.gov (United States)

    Dahlerup, Jens; Lindgren, Stefan; Moum, Björn

    2015-03-10

    Iron deficiency and iron deficiency anemia are global health problems leading to deterioration in patients' quality of life and more serious prognosis in patients with chronic diseases. The cause of iron deficiency and anemia is usually a combination of increased loss and decreased intestinal absorption and delivery from iron stores due to inflammation. Oral iron is first line treatment, but often hampered by intolerance. Intravenous iron is safe, and the preferred treatment in patients with chronic inflammation and bowel diseases. The goal of treatment is normalisation of hemoglobin concentration and recovery of iron stores. It is important to follow up treatment to ensure that these objectives are met and also long-term in patients with chronic iron loss and/or inflammation to avoid recurrence of anemia.

  10. Iron deficiency in blood donors

    Directory of Open Access Journals (Sweden)

    Armando Cortés

    2005-03-01

    Full Text Available Context: Blood donation results in a substantial loss of iron (200 to 250 mg at each bleeding procedure (425 to 475 ml and subsequent mobilization of iron from body stores. Recent reports have shown that body iron reserves generally are small and iron depletion is more frequent in blood donors than in non-donors. Objective: The aim of this study was to evaluate the frequency of iron deficiency in blood donors and to establish the frequency of iron deficiency in blood donors according to sex, whether they were first-time or multi-time donors. Design: From march 20 to April 5, 2004, three hundred potential blood donors from Hemocentro del Café y Tolima Grande were studied. Diagnostic tests: Using a combination of biochemical measurements of iron status: serum ferritin (RIA, ANNAR and the hemoglobin pre and post-donation (HEMOCUE Vital technology medical . Results: The frequency of iron deficiency in potential blood donors was 5%, and blood donors accepted was 5.1%; in blood donors rejected for low hemoglobin the frequency of iron deficiency was 3.7% and accepted blood donors was 1.7% in male and 12.6% in female. The frequency of iron deficiency was higher in multi-time blood donors than in first-time blood donors, but not stadistic significative. Increase nivel accepted hemoglobina in 1 g/dl no incidence in male; in female increase of 0.5 g/dl low in 25% blood donors accepted with iron deficiency, but increased rejected innecesary in 16.6% and increased is 1 g/dl low blood donors female accepted in 58% (7/12, but increased the rejected innecesary in 35.6%. Conclusions: We conclude that blood donation not is a important factor for iron deficiency in blood donors. The high frequency of blood donors with iron deficiency found in this study suggests a need for a more accurate laboratory trial, as hemoglobin or hematocrit measurement alone is not sufficient for detecting and excluding blood donors with iron deficiency without anemia, and ajustes hacia

  11. Study of the odd-${A}$, high-spin isomers in neutron-deficient trans-lead nuclei with ISOLTRAP

    CERN Multimedia

    Herfurth, F; Blaum, K; Beck, D; Kowalska, M; Schwarz, S; Stanja, J; Huyse, M L; Wienholtz, F

    We propose to measure the excitation energy of the $\\frac{13^{+}}{2}$ isomers in the neutron-deficient isotopes $^{193,195,197}$Po with the ISOLTRAP mass spectrometer. The assignment of the low- and high-spin isomers will be made by measuring the energy of the $\\alpha$- particles emitted in the decay of purified beams implanted in a windmill system. Using $\\alpha$-decay information, it is then also possible to determine the excitation energy of the similar isomers in the $\\alpha$-daughter nuclei $^{189,191,193}$Pb, $\\alpha$-parent nuclei $^{197,199,201}$Rn, and $\\alpha$-grand-parent nuclei $^{201,203,205}$Ra. The polonium beams are produced with a UC$_{\\textrm{x}}$ target and using the RILIS.

  12. The Lyman alpha reference sample

    DEFF Research Database (Denmark)

    Hayes, M.; Östlin, G.; Schaerer, D.

    2013-01-01

    We report on new imaging observations of the Lyman alpha emission line (Lyα), performed with the Hubble Space Telescope, that comprise the backbone of the Lyman alpha Reference Sample. We present images of 14 starburst galaxies at redshifts 0.028 alpha emission line (Lyα), performed with the Hubble Space Telescope, that comprise the backbone of the Lyman alpha Reference Sample. We present images of 14 starburst galaxies at redshifts 0.028 ... with quantities that scale with dust content, in the sense that a low dust abundance is a necessary requirement (although not the only one) in order to spread Lyα photons throughout the interstellar medium and drive a large extended Lyα halo. © 2013. The American Astronomical Society. All rights reserved....

  13. Iron deficiency and cardiovascular disease.

    Science.gov (United States)

    von Haehling, Stephan; Jankowska, Ewa A; van Veldhuisen, Dirk J; Ponikowski, Piotr; Anker, Stefan D

    2015-11-01

    Iron deficiency affects up to one-third of the world's population, and is particularly common in elderly individuals and those with certain chronic diseases. Iron excess can be detrimental in cardiovascular illness, and research has now also brought anaemia and iron deficiency into the focus of cardiovascular medicine. Data indicate that iron deficiency has detrimental effects in patients with coronary artery disease, heart failure (HF), and pulmonary hypertension, and possibly in patients undergoing cardiac surgery. Around one-third of all patients with HF, and more than one-half of patients with pulmonary hypertension, are affected by iron deficiency. Patients with HF and iron deficiency have shown symptomatic improvements from intravenous iron administration, and some evidence suggests that these improvements occur irrespective of the presence of anaemia. Improved exercise capacity has been demonstrated after iron administration in patients with pulmonary hypertension. However, to avoid iron overload and T-cell activation, it seems that recipients of cardiac transplantations should not be treated with intravenous iron preparations.

  14. Almost Redundant Components in the 3 alpha Faddeev Equation for the Buck, Friedlich and Wheatly alpha alpha Potential

    CERN Document Server

    Fujiwara, Y; Kohno, M

    2004-01-01

    The 3 alpha orthogonality condition model using the Pauli-forbidden bound states of the Buck, Friedlich and Wheatly alpha alpha potential can yield a compact 3 alpha ground state with a large binding energy, in which a small admixture of the redundant components can never be eliminated.

  15. Selective predisposition to bacterial infections in IRAK-4-deficient children : IRAK-4-dependent TLRs are otherwise redundant in protective immunity

    NARCIS (Netherlands)

    Ku, Cheng-Lung; von Bernuth, Horst; Picard, Capucine; Zhang, Shen-Ying; Chang, Huey-Hsuan; Yang, Kun; Chrabieh, Maya; Issekutz, Andrew C.; Cunningham, Coleen K.; Gallin, John; Holland, Steven M.; Roifman, Chaim; Ehl, Stephan; Smart, Joanne; Tang, Mimi; Barrat, Franck J.; Levy, Ofer; McDonald, Douglas; Day-Good, Noorbibi K.; Miller, Richard; Takada, Hidetoshi; Hara, Toshiro; Al-Hajjar, Sami; Al-Ghonaium, Abdulaziz; Speert, David; Sanlaville, Damien; Li, Xiaoxia; Geissmann, Frederic; Vivier, Eric; Marodi, Laszlo; Garty, Ben-Zion; Chapel, Helen; Rodriguez-Gallego, Carlos; Bossuyt, Xavier; Abel, Laurent; Puel, Anne; Casanova, Jean-Laurent

    2007-01-01

    Human interleukin ( IL) 1 receptor - associated kinase 4 ( IRAK- 4) deficiency is a recently discovered primary immunodefi ciency that impairs Toll/ IL- 1R immunity, except for the Toll- like receptor ( TLR) 3 - and TLR4 - interferon ( IFN)-alpha/beta pathways. The clinical and immunological phenoty

  16. Total alpha-globin gene cluster deletion has high frequency in Filipinos

    Energy Technology Data Exchange (ETDEWEB)

    Hunt, J.A.; Haruyama, A.Z.; Chu, B.M. [Kapiolani Medical Center, Honolulu, HI (United States)] [and others

    1994-09-01

    Most {alpha}-thalassemias [Thal] are due to large deletions. In Southeast Asians, the (--{sup SEA}) double {alpha}-globin gene deletion is common, 3 (--{sup Tot}) total {alpha}-globin cluster deletions are known: Filipino (--{sup Fil}), Thai (--{sup Thai}), and Chinese (--{sup Chin}). In a Hawaii Thal project, provisional diagnosis of {alpha}-Thal-1 heterozygotes was based on microcytosis, normal isoelectric focusing, and no iron deficiency. One in 10 unselected Filipinos was an {alpha}-Thal-1 heterozygote, 2/3 of these had a (--{sup Tot}) deletion: a {var_sigma}-cDNA probe consistently showed fainter intensity of the constant 5.5 kb {var_sigma}{sub 2} BamHI band, with no heterzygosity for {var_sigma}-globin region polymorphisms; {alpha}-cDNA or {var_sigma}-cDNA probes showed no BamHI or BglII bands diagnostic of the (--{sup SEA}) deletion; bands for the (-{alpha}) {alpha}-Thal-2 single {alpha}-globin deletions were only seen in Hb H cases. A reliable monoclonal anti-{var_sigma}-peptide antibody test for the (--{sup SEA}) deletion was always negative in (--{sup Tot}) samples. Southern digests with the Lo probe, a gift from D. Higgs of Oxford Univ., confirmed that 49 of 50 (--{sup Tot}) chromosomes in Filipinos were (--{sup Fil}). Of 20 {alpha}-Thal-1 hydrops born to Filipinos, 11 were (--{sup Fil}/--{sup SEA}) compound heterozygotes; 9 were (--{sup SEA}/--{sup SEA}) homozygotes, but none was a (--{sup Fil}/--{sup Fil}).

  17. Differential diagnosis of iron deficiency

    OpenAIRE

    2010-01-01

    A deficiência de ferro é considerada a patologia hematológica mais prevalente no homem. Assim, é fundamental a adequada identificação de suas causas, bem como a diferenciação com outras patologias distintas para adequada abordagem da deficiência de ferro. Neste artigo são brevemente descritas outras condições que podem cursar com anemia microcítica, tais como: talassemias, anemia de doença crônica, anemia sideroblástica e envenenamento por chumbo, patologias estas que devem ser afastadas dura...

  18. [Phosphate metabolism and iron deficiency].

    Science.gov (United States)

    Yokoyama, Keitaro

    2016-02-01

    Autosomal dominant hypophosphatemic rickets(ADHR)is caused by gain-of-function mutations in FGF23 that prevent its proteolytic cleavage. Fibroblast growth factor 23(FGF23)is a hormone that inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D biosynthesis. Low iron status plays a role in the pathophysiology of ADHR. Iron deficiency is an environmental trigger that stimulates FGF23 expression and hypophosphatemia in ADHR. It was reported that FGF23 elevation in patients with CKD, who are often iron deficient. In patients with nondialysis-dependent CKD, treatment with ferric citrate hydrate resulted in significant reductions in serum phosphate and FGF23.

  19. Primary Carnitine (OCTN2) Deficiency Without Neonatal Carnitine Deficiency

    NARCIS (Netherlands)

    Boer, L. de; Kluijtmans, L.A.J.; Morava, E.

    2013-01-01

    Although the diagnosis of a primary carnitine deficiency is usually based on a very low level of free and total carnitine (free carnitine: 1-5 muM, normal 20-55 muM) (Longo et al. 2006), we detected a patient via newborn screening with a total carnitine level 67 % of the normal value. At the age of

  20. A P-loop Mutation in G[alpha] Subunits Prevents Transition to the Active State: Implications for G-protein Signaling in Fungal Pathogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Bosch, Dustin E.; Willard, Francis S.; Ramanujam, Ravikrishna; Kimple, Adam J.; Willard, Melinda D.; Naqvi, Naweed I.; Siderovski, David P. (UNC); (Singapore)

    2012-10-23

    Heterotrimeric G-proteins are molecular switches integral to a panoply of different physiological responses that many organisms make to environmental cues. The switch from inactive to active G{alpha}{beta}{gamma} heterotrimer relies on nucleotide cycling by the G{alpha} subunit: exchange of GTP for GDP activates G{alpha}, whereas its intrinsic enzymatic activity catalyzes GTP hydrolysis to GDP and inorganic phosphate, thereby reverting G{alpha} to its inactive state. In several genetic studies of filamentous fungi, such as the rice blast fungus Magnaporthe oryzae, a G42R mutation in the phosphate-binding loop of G{alpha} subunits is assumed to be GTPase-deficient and thus constitutively active. Here, we demonstrate that G{alpha}(G42R) mutants are not GTPase deficient, but rather incapable of achieving the activated conformation. Two crystal structure models suggest that Arg-42 prevents a typical switch region conformational change upon G{alpha}{sub i1}(G42R) binding to GDP {center_dot} AlF{sub 4}{sup -} or GTP, but rotameric flexibility at this locus allows for unperturbed GTP hydrolysis. G{alpha}(G42R) mutants do not engage the active state-selective peptide KB-1753 nor RGS domains with high affinity, but instead favor interaction with G{beta}{gamma} and GoLoco motifs in any nucleotide state. The corresponding G{alpha}{sub q}(G48R) mutant is not constitutively active in cells and responds poorly to aluminum tetrafluoride activation. Comparative analyses of M. oryzae strains harboring either G42R or GTPase-deficient Q/L mutations in the G{alpha} subunits MagA or MagB illustrate functional differences in environmental cue processing and intracellular signaling outcomes between these two G{alpha} mutants, thus demonstrating the in vivo functional divergence of G42R and activating G-protein mutants.

  1. Human acid alpha-glucosidase from rabbit milk has therapeutic effect in mice with glycogen storage disease type II

    NARCIS (Netherlands)

    A.G.A. Bijvoet (Agnes); A.J.J. Reuser (Arnold); H. van Hirtum (Hans); M.A. Kroos (Marian); E.H. van de Kamp; O. Schoneveld; P. Visser (Pim); J.P. Brakenhoff (Just); M. Weggeman; E.J.J.M. van Corven (Emiel); A.T. van der Ploeg (Ans)

    1999-01-01

    textabstractPompe's disease or glycogen storage disease type II (GSDII) belongs to the family of inherited lysosomal storage diseases. The underlying deficiency of acid alpha-glucosidase leads in different degrees of severity to glycogen storage in heart, skeletal and s

  2. Changes in blood levels of proteinase inhibitors, pregnancy zone protein, steroid carriers and complement factors induced by oral contraceptives

    DEFF Research Database (Denmark)

    Nielsen, C H; Poulsen, H K; Teisner, B

    1993-01-01

    levels of antithrombin III (AT III), alpha 2-macroglobulin (alpha 2M) alpha 1-antitrypsin (alpha 1at), complement factors (factor B, C3, C4), pregnancy zone protein (PZP), corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG) and albumin were measured before treatment and during...

  3. Differential expression of microRNAs in the intervertebral disc of hypoxia-inducible factor-1alpha deficient mice%MicroRNAs在缺氧诱导因子1α缺失椎间盘组织中的差异性表达

    Institute of Scientific and Technical Information of China (English)

    孟祥超; 刘卓超; 王君; 周琦; 齐进; 张兴凯

    2016-01-01

    背景:MicroRNAs在椎间盘退变的疾病中起重要作用,缺氧诱导因子缺失可加速椎间盘的退变。  目的:检测缺氧诱导因子1α后小鼠椎间盘内microRNAs的变化情况,探究microRNAs与椎间盘退变的关系及缺氧诱导因子1α调控椎间盘退变机制和通路。  方法:通过前期构建的条件性敲除髓核细胞缺氧诱导因子1α基因的小鼠,分别取基因敲除组与正常对照组4周龄小鼠的椎间盘组织进行组织学染色观察;通过提取标本的总RNAs,从中分离microRNAs,荧光标记后与微阵列芯片杂交,扫描检测后数据经分析处理,筛选椎间盘组织中microRNA差异表达谱。采用实时荧光定量RT-PCR技术验证在椎间盘组织中均存在显著差异表达的microRNAs。分析差异表达microRNAs的靶基因及通路,预测其在椎间盘退变中的作用。  结果与结论:缺氧诱导因子1α基因缺失小鼠椎间盘髓核细胞数量减少,细胞形态变小,细胞质着色加深;两组小鼠椎间盘中的microRNAs的芯片筛选结果中,10个microRNAs发生了明显的差异表达,其中有7个microRNAs发生上调,3个microRNAs发生下调。结果提示缺氧诱导因子1α缺失后可能引起某些重要的microRNAs调节失衡,引起椎间盘髓核细胞大量的死亡,加速椎间盘的退变。%BACKGROUND:It is confirmed that the absence of hypoxia-inducible factor-1α (HIF-1α) accelerates the degenerative process in the intervertebral discs, and microRNAs have an important role in degeneration of the intervertebral discs. OBJECTIVE:To evaluate the changes of microRNAs in the intervertebral discs of HIF-1α-deficient (HIF-1α-/-) mice which may mediate the signaling pathway of HIF-1α in the intervertebral discs. METHODS: As previously reported, HIF-1α-/- mice were established. HIF-1α-/- mice and HIF-1αflox/flox mice (control mice) aged 4 weeks were used. MRI and histological staining were

  4. Investigation of the Pygmy Dipole Resonance in (alpha, alpha 'gamma) coincidence experiments

    NARCIS (Netherlands)

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

    2007-01-01

    We report on first results from experiments using the (alpha, alpha'gamma) reaction at E alpha = 136 MeV to investigate bound electric dipole (El) excitations building the so-called Pygmy Dipole Resonance (PDR) in the semi-magic nucleus Ce-140. The method of (alpha, alpha'gamma) allows the separatio

  5. Hereditary angioedema type I: a case report.

    Science.gov (United States)

    Muñoz Peralta, Francisca; Buller Vigueira, Eva; Cabello Pulido, Juana

    2016-01-28

    Hereditary angioedema is a rare disease with great heterogeneity of symptoms such as edema of the skin, gastro-intestinal mucosa and larynx or pharynx. Even though there are three types, the most frequent is type I, which is a result from a deficiency of the complement C1 inhibitor. The severity of its symptoms along with the low prevalence of the disease and the need for appropriate specific treatment make the diagnosis and treatment of the pathology an outstanding subject for the family physician. The present is the case of a male teenager with alpha-1 antitrypsin deficiency since he was six months old, angioedema on arms and legs since 11 years old and diagnosed with hereditary angioedema type I one year after. The definitive diagnosis of the disease enabled an appropriate treatment which consists in preventing outbreaks that may compromise the patient's life and, if they occur, administration of complement C1 inhibitor.

  6. Assessment of regional progression of pulmonary emphysema with CT densitometry

    DEFF Research Database (Denmark)

    Bakker, M Els; Putter, Hein; Stolk, Jan;

    2008-01-01

    with general emphysema (general emphysema without phenotype PiZZ [non-PiZ] group) were scanned with CT at baseline and after 30 months. Densitometry was performed in 12 axial partitions of equal volumes. To indicate predominant location, craniocaudal locality was defined as the slope in the plot of densities......BACKGROUND: Lung densitometry is an effective method to assess overall progression of emphysema, but generally the location of the progression is not estimated. We hypothesized that progression of emphysema is the result of extension from affected areas toward less affected areas in the lung....... To test this hypothesis, a method was developed to assess emphysema severity at different levels in the lungs in order to estimate regional changes. METHODS: Fifty subjects with emphysema due to alpha(1)-antitrypsin deficiency (AATD) [AATD deficiency of phenotype PiZZ (PiZ) group] and 16 subjects...

  7. Omigapil ameliorates the pathology of muscle dystrophy caused by laminin-α2 deficiency

    OpenAIRE

    Erb, M.; Meinen, S.; Barzaghi, P.; Sumanovski, L. T.; Courdier-Fruh, I; Ruegg, M A; T. Meier

    2009-01-01

    Laminin alpha2-deficient Congenital Muscular Dystrophy, called MDC1A, is a rare, devastating genetic disease characterized by severe neonatal hypotonia ("floppy infant syndrome"), peripheral neuropathy, inability to stand or walk, respiratory distress and premature death in early life. Transgenic overexpression of the apoptosis inhibitor protein BCL-2, or deletion of the pro-apoptotic Bax gene in a mouse model for MDC1A prolong survival and mitigate pathology, indicating that apoptotic events...

  8. Dopamine beta-hydroxylase deficiency

    Directory of Open Access Journals (Sweden)

    Senard Jean-Michel

    2006-03-01

    Full Text Available Abstract Dopamine beta-hydroxylase (DβH deficiency is a very rare form of primary autonomic failure characterized by a complete absence of noradrenaline and adrenaline in plasma together with increased dopamine plasma levels. The prevalence of DβH deficiency is unknown. Only a limited number of cases with this disease have been reported. DβH deficiency is mainly characterized by cardiovascular disorders and severe orthostatic hypotension. First symptoms often start during a complicated perinatal period with hypotension, muscle hypotonia, hypothermia and hypoglycemia. Children with DβH deficiency exhibit reduced ability to exercise because of blood pressure inadaptation with exertion and syncope. Symptoms usually worsen progressively during late adolescence and early adulthood with severe orthostatic hypotension, eyelid ptosis, nasal stuffiness and sexual disorders. Limitation in standing tolerance, limited ability to exercise and traumatic morbidity related to falls and syncope may represent later evolution. The syndrome is caused by heterogeneous molecular alterations of the DBH gene and is inherited in an autosomal recessive manner. Restoration of plasma noradrenaline to the normal range can be achieved by therapy with the synthetic precursor of noradrenaline, L-threo-dihydroxyphenylserine (DOPS. Oral administration of 100 to 500 mg DOPS, twice or three times daily, increases blood pressure and reverses the orthostatic intolerance.

  9. Educational paper: Primary antibody deficiencies

    NARCIS (Netherlands)

    G.J.A. Driessen (Gertjan); M. van der Burg (Mirjam)

    2011-01-01

    textabstractPrimary antibody deficiencies (PADs) are the most common primary immunodeficiencies and are characterized by a defect in the production of normal amounts of antigen-specific antibodies. PADs represent a heterogeneous spectrum of conditions, ranging from often asymptomatic selective IgA a

  10. Epigenetic Deficiencies and Replicative Stress

    DEFF Research Database (Denmark)

    Shoaib, Muhammad; Sørensen, Claus Storgaard

    2015-01-01

    Cancer cell-specific synthetic lethal interactions entail promising therapeutic possibilities. In this issue of Cancer Cell, Pfister et al. describe a synthetic lethal interaction where cancer cells deficient in H3K36me3 owing to SETD2 loss-of-function mutation are strongly sensitized to inhibiti...

  11. Deferasirox in pyruvate kinase deficiency

    OpenAIRE

    Deeren, Dries

    2008-01-01

    Deferasirox in pyruvate kinase deficiency phone: +32-51-237437 (Deeren, Dries) (Deeren, Dries) Department of Haematology, Heilig-Hartziekenhuis Roeselare-Menen vzw - Wilgenstraat 2 - B-8800 - Roeselare - BELGIUM (Deeren, Dries) BELGIUM Registration: 2008-09-10 Received: 2008-09-05 Accepted: 2008-09-10 ePublished: 2008-09-23

  12. Management of Iron Deficiency Anemia

    Science.gov (United States)

    Jimenez, Kristine; Kulnigg-Dabsch, Stefanie

    2015-01-01

    Anemia affects one-fourth of the world’s population, and iron deficiency is the predominant cause. Anemia is associated with chronic fatigue, impaired cognitive function, and diminished well-being. Patients with iron deficiency anemia of unknown etiology are frequently referred to a gastroenterologist because in the majority of cases the condition has a gastrointestinal origin. Proper management improves quality of life, alleviates the symptoms of iron deficiency, and reduces the need for blood transfusions. Treatment options include oral and intravenous iron therapy; however, the efficacy of oral iron is limited in certain gastrointestinal conditions, such as inflammatory bowel disease, celiac disease, and autoimmune gastritis. This article provides a critical summary of the diagnosis and treatment of iron deficiency anemia. In addition, it includes a management algorithm that can help the clinician determine which patients are in need of further gastrointestinal evaluation. This facilitates the identification and treatment of the underlying condition and avoids the unnecessary use of invasive methods and their associated risks. PMID:27099596

  13. Congenital β-lipoprotein deficiency

    NARCIS (Netherlands)

    Buchem, F.S.P. van; Pol, G.; Gier, J. de; Böttcher, C.J.F.; Pries, C.

    1966-01-01

    There are several degrees of β-lipoprotein deficiency. If there is no β-lipoprotein present, or if there are only traces of it, the Bassen-Kornzweig syndrome develops. A constant feature of this syndrome is disturbed fat absorption with accumulation of fat in the epithelium of intestinal mucosa and

  14. 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.

  15. Scale Setting for $\\alpha_{s}$ Beyond Leading Order

    CERN Document Server

    Hornbostel, K; Morningstar, C J

    2001-01-01

    We present a general procedure for applying the scale-setting prescription of Brodsky, Lepage and Mackenzie to higher orders in the strong coupling constant $\\alphas$. In particular, we show how to apply this prescription when the leading coefficient or coefficients in a series in $\\alphas$ are anomalously small. We give a general method for computing an optimum scale numerically, within dimensional regularization, and in cases when the coefficients of a series are known. We find significant corrections to the scales for $R_{e^+ e^-}$, $\\Gamma(B \\to X_u e \\bar{\

  16. Proxima's orbit around Alpha Centauri

    CERN Document Server

    Kervella, P

    2016-01-01

    Proxima and Alpha Centauri AB have almost identical distances and proper motions with respect to the Sun. Although the probability of such similar parameters is in principle very low, the question whether they actually form a single gravitationally bound triple system has been open since the discovery of Proxima one century ago. Owing to recent high precision radial velocity measurements and the revision of the parameters of the Alpha Cen pair, we show that Proxima and Alpha Cen are gravitationally bound with a high degree of confidence. The orbital period of Proxima is approximately 600 000 years, with a moderate excentricity of 0.42 +0.07 -0.08. Proxima comes within 5.3 -0.9 +1.2 kAU of Alpha Cen at periastron, and the apastron occurs at 12.9 +0.3 -0.1 kAU. This orbital motion may have influenced the formation or evolution of the recently discovered planet orbiting Proxima as well as circumbinary planet formation around Alpha Cen.

  17. Viral infection causes rapid sensitization to lipopolysaccharide: central role of IFN-alpha beta

    DEFF Research Database (Denmark)

    Nansen, A; Randrup Thomsen, A

    2001-01-01

    LPS is the major active agent in the pathogenesis of Gram-negative septic shock. In this report we have studied the influence of concurrent viral infection on the outcome of LPS-induced shock. We find that infection with vesicular stomatitis virus sensitizes mice to LPS at an early time point......-depleted and gene-targeted mice. Our results revealed that while NK cell depletion and elimination of IFN-gamma partially protected against the sensitizing effects of vesicular stomatitis virus and polyinosinic:polycytidylic acid, the most striking effect was observed in IFN-alphabetaR-deficient mice. Thus...... hyperproduction of TNF-alpha was completely abrogated in IFN-alphabetaR-deficient mice, indicating that the principal mechanism underlying rapid virus-induced sensitization to LPS is an IFN-alphabeta-mediated priming of mice for an augmented production of TNF-alpha in response to LPS. This conclusion was further...

  18. Ageing Fxr deficient mice develop increased energy expenditure, improved glucose control and liver damage resembling NASH.

    Directory of Open Access Journals (Sweden)

    Mikael Bjursell

    Full Text Available Nuclear receptor subfamily 1, group H, member 4 (Nr1h4, FXR is a bile acid activated nuclear receptor mainly expressed in the liver, intestine, kidney and adrenal glands. Upon activation, the primary function is to suppress cholesterol 7 alpha-hydroxylase (Cyp7a1, the rate-limiting enzyme in the classic or neutral bile acid synthesis pathway. In the present study, a novel Fxr deficient mouse line was created and studied with respect to metabolism and liver function in ageing mice fed chow diet. The Fxr deficient mice were similar to wild type mice in terms of body weight, body composition, energy intake and expenditure as well as behaviours at a young age. However, from 15 weeks of age and onwards, the Fxr deficient mice had almost no body weight increase up to 39 weeks of age mainly because of lower body fat mass. The lower body weight gain was associated with increased energy expenditure that was not compensated by increased food intake. Fasting levels of glucose and insulin were lower and glucose tolerance was improved in old and lean Fxr deficient mice. However, the Fxr deficient mice displayed significantly increased liver weight, steatosis, hepatocyte ballooning degeneration and lobular inflammation together with elevated plasma levels of ALT, bilirubin and bile acids, findings compatible with non-alcoholic steatohepatitis (NASH and cholestasis. In conclusion, ageing Fxr deficient mice display late onset leanness associated with elevated energy expenditure and improved glucose control but develop severe NASH-like liver pathology.

  19. Bioisosteric phentolamine analogs as selective human alpha(2)- versus alpha(1)-adrenoceptor ligands.

    Science.gov (United States)

    Bavadekar, Supriya A; Hong, Seoung-Soo; Lee, Sang-Ii; Miller, Duane D; Feller, Dennis R

    2008-08-20

    Phentolamine is known to act as a competitive, non-subtype-selective alpha-adrenoceptor antagonist. In an attempt to improve alpha(2)- versus alpha(1)-adrenoceptor selectivity and alpha(2)-adrenoceptor subtype-selectivity, two new chemical series of bioisosteric phentolamine analogs were prepared and evaluated. These compounds were evaluated for binding affinities on alpha(1)- (alpha(1A)-, alpha(1B)-, alpha(1D)-) and alpha(2)- (alpha(2A)-, alpha(2B)-, alpha(2C)-) adrenoceptor subtypes that had been stably expressed in human embryonic kidney and Chinese hamster ovary cell lines, respectively. Methylation of the phenolic hydroxy group and replacement of the 4-methyl group of phentolamine with varying lipophilic substituents yielded bioisosteric analogs selective for the alpha(2)- versus alpha(1)-adrenoceptors. Within the alpha(2)-adrenoceptors, these analogs bound with higher affinity at the alpha(2A)- and alpha(2C)-subtypes as compared to the alpha(2B)-subtype. In particular, the t-butyl analog was found to be the most selective, its binding at the alpha(2C)-adrenoceptor (Ki=3.6 nM) being 37- to 173-fold higher than that at the alpha(1)-adrenoceptors, and around 2- and 19-fold higher than at the alpha(2A)- and alpha(2B)-adrenoceptors, respectively. Data from luciferase reporter gene assays confirmed the functional antagonist activities of selected compounds from the bioisosteric series on human alpha(1A)- and alpha(2C)-adrenoceptors. Thus, the results with these bioisosteric analogs of phentolamine provide a lead to the rational design of potent and selective alpha(2)-adrenoceptor ligands that may be useful in improving the therapeutic profile of this drug class for human disorders.

  20. Low doses of alpha particles do not induce sister chromatid exchanges in bystander Chinese hamster cells defective in homologous recombination

    Energy Technology Data Exchange (ETDEWEB)

    Nagasawa, H; Wilson, P F; Chen, D J; Thompson, L H; Bedford, J S; Little, J B

    2007-10-26

    We reported previously that the homologous recombinational repair (HRR)-deficient Chinese hamster mutant cell line irs3 (deficient in the Rad51 paralog Rad51C) showed only a 50% spontaneous frequency of sister chromatid exchange (SCE) as compared to parental wild-type V79 cells. Furthermore, when irradiated with very low doses of alpha particles, SCEs were not induced in irs3 cells, as compared to a prominent bystander effect observed in V79 cells (Nagasawa et al., Radiat. Res. 164, 141-147, 2005). In the present study, we examined additional Chinese hamster cell lines deficient in the Rad51 paralogs Rad51C, Rad51D, Xrcc2, and Xrcc3 as well as another essential HRR protein, Brca2. Spontaneous SCE frequencies in non-irradiated wild-type cell lines CHO, AA8 and V79 were 0.33 SCE/chromosome, whereas two Rad51C-deficient cell lines showed only 0.16 SCE/chromosome. Spontaneous SCE frequencies in cell lines defective in Rad51D, Xrcc2, Xrcc3, and Brca2 ranged from 0.23-0.33 SCE/chromosome, 0-30% lower than wild-type cells. SCEs were induced significantly 20-50% above spontaneous levels in wild-type cells exposed to a mean dose of 1.3 mGy of alpha particles (<1% of nuclei traversed by an alpha particle). However, induction of SCEs above spontaneous levels was minimal or absent after {alpha}-particle irradiation in all of the HRR-deficient cell lines. These data suggest that Brca2 and the Rad51 paralogs contribute to DNA damage repair processes induced in bystander cells (presumably oxidative damage repair in S-phase cells) following irradiation with very low doses of alpha particles.

  1. Identifying Causes of Job Performance Deficiencies.

    Science.gov (United States)

    Herem, Maynard A.

    1979-01-01

    A model to guide the search for types of performance deficiencies is set forth within the general framework of systems theory. Five types of problems, singly or in combination, are discussed as causes of deficiencies. (Author)

  2. Genetics Home Reference: congenital leptin deficiency

    Science.gov (United States)

    ... Obesity? National Institute of Diabetes and Digestive and Kidney Diseases: Active at Any Size! Educational Resources (6 links) Centers for Disease Control and Prevention: Obesity and Genetics MalaCards: congenital leptin deficiency Orphanet: Obesity due to congenital leptin deficiency ...

  3. Genetics Home Reference: protein S deficiency

    Science.gov (United States)

    ... my area? Other Names for This Condition hereditary thrombophilia due to protein S deficiency Related Information How are ... Merck Manual Home Edition for Patients and Caregivers: Thrombophilia Orphanet: Hereditary thrombophilia due to congenital protein S deficiency ...

  4. Genetics Home Reference: corticosterone methyloxidase deficiency

    Science.gov (United States)

    ... levels of potassium in the blood (hyponatremia and hyperkalemia, respectively). Individuals with corticosterone methyloxidase deficiency can also ... acid in the blood (metabolic acidosis). The hyponatremia, hyperkalemia, and metabolic acidosis associated with corticosterone methyloxidase deficiency ...

  5. Cobalamin deficiency, hyperhomocysteinemia, and dementia

    Directory of Open Access Journals (Sweden)

    Steven F Werder

    2010-04-01

    Full Text Available Steven F Werder1,21Kansas University School of Medicine – Wichita, Wichita, KS, USA; 2Community Health Center of Southeast Kansas, Pittsburg, KS, USAIntroduction: Although consensus guidelines recommend checking serum B12 in patients with dementia, clinicians are often faced with various questions: (1 Which patients should be tested? (2 What test should be ordered? (3 How are inferences made from such testing? (4 In addition to serum B12, should other tests be ordered? (5 Is B12 deficiency compatible with dementia of the Alzheimer’s type? (6 What is to be expected from treatment? (7 How is B12 deficiency treated?Methods: On January 31st, 2009, a Medline search was performed revealing 1,627 citations related to cobalamin deficiency, hyperhomocysteinemia, and dementia. After limiting the search terms, all abstracts and/or articles and other references were categorized into six major groups (general, biochemistry, manifestations, associations and risks, evaluation, and treatment and then reviewed in answering the above questions.Results: The six major groups above are described in detail. Seventy-five key studies, series, and clinical trials were identified. Evidence-based suggestions for patient management were developed.Discussion: Evidence is convincing that hyperhomocysteinemia, with or without hypovitaminosis B12, is a risk factor for dementia. In the absence of hyperhomocysteinemia, evidence is less convincing that hypovitaminosis B12 is a risk factor for dementia. B12 deficiency manifestations are variable and include abnormal psychiatric, neurological, gastrointestinal, and hematological findings. Radiological images of individuals with hyperhomocysteinemia frequently demonstrate leukoaraiosis. Assessing serum B12 and treatment of B12 deficiency is crucial for those cases in which pernicious anemia is suspected and may be useful for mild cognitive impairment and mild to moderate dementia. The serum B12 level is the standard initial test

  6. NACA Physicist Studying Alpha Rays

    Science.gov (United States)

    1957-01-01

    NACA Physicits studying Alpha Rays in a continuous cloud chamber. A cloud chamber is used by Lewis scientists to obtain information aimed at minimizing undesirable effects of radiation on nuclear-powered aircraft components. Here, alpha particles from a polonium source emit in a flower-like pattern at the cloud chamber's center. The particles are made visible by means of alcohol vapor diffusing from an area at room temperature to an area at minus -78 deg. Centigrade. Nuclear-powered aircraft were never developed and aircraft nuclear propulsion systems were canceled in the early 1960s.

  7. Simulating the Lyman Alpha Forest

    CERN Document Server

    Machacek, M E; Anninos, P; Meiksin, A; Norman, M L; Machacek, Marie E.; Bryan, Greg L.; Anninos, Peter; Meiksin, Avery; Norman, Michael L.

    1998-01-01

    In this paper we review the importance of the Lyman alpha forest as a probe of structure formation in the universe. We first discuss the statistics used to describe the Lyman alpha forest and the numerical techniques used to produce simulated spectra of the forest from a given cosmological model. We then discuss the physical picture of the absorbing structures that emerges from these numerical simulations. Finally, we comment on how two of the statistics, the slope of the column density distribution and the b parameter distribution, may be used to constrain competing cosmologies.

  8. Loss of skeletal muscle HIF-1alpha results in altered exercise endurance.

    Directory of Open Access Journals (Sweden)

    Steven D Mason

    2004-10-01

    Full Text Available The physiological flux of oxygen is extreme in exercising skeletal muscle. Hypoxia is thus a critical parameter in muscle function, influencing production of ATP, utilization of energy-producing substrates, and manufacture of exhaustion-inducing metabolites. Glycolysis is the central source of anaerobic energy in animals, and this metabolic pathway is regulated under low-oxygen conditions by the transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha. To determine the role of HIF-1alpha in regulating skeletal muscle function, we tissue-specifically deleted the gene encoding the factor in skeletal muscle. Significant exercise-induced changes in expression of genes are decreased or absent in the skeletal-muscle HIF-1alpha knockout mice (HIF-1alpha KOs; changes in activities of glycolytic enzymes are seen as well. There is an increase in activity of rate-limiting enzymes of the mitochondria in the muscles of HIF-1alpha KOs, indicating that the citric acid cycle and increased fatty acid oxidation may be compensating for decreased flow through the glycolytic pathway. This is corroborated by a finding of no significant decreases in muscle ATP, but significantly decreased amounts of lactate in the serum of exercising HIF-1alpha KOs. This metabolic shift away from glycolysis and toward oxidation has the consequence of increasing exercise times in the HIF-1alpha KOs. However, repeated exercise trials give rise to extensive muscle damage in HIF-1alpha KOs, ultimately resulting in greatly reduced exercise times relative to wild-type animals. The muscle damage seen is similar to that detected in humans in diseases caused by deficiencies in skeletal muscle glycogenolysis and glycolysis. Thus, these results demonstrate an important role for the HIF-1 pathway in the metabolic control of muscle function.

  9. Cobalamin deficiency in children: A literature review

    OpenAIRE

    Moen, Synne Helland

    2013-01-01

    Objective: The aim of this review is to present cobalamin deficiency in children with a specific focus on infants. Background: Cobalamin deficiency is caused by inadequate intake, malabsorption or inborn errors of vitamin B12 metabolism. Cobalamin deficiency in infants is usually caused by deficiency in the mother. There is often a diagnostic delay among infants because the most frequent symptoms are unspecific, e.g., developmental delay, apathy, hypotonia, anorexia and failure to thrive. Chi...

  10. Experimental investigation of decay properties of neutron deficient $^{116-118}$Ba isotopes and test of $^{112-115}$Ba beam counts

    CERN Multimedia

    We propose to study decay of neutron deficient isotopes $^{116-118}$Ba using Double Sided Silicon Strip Detector (DSSSD). To study delayed-proton and $\\alpha$-decay branching ratios of $^{116-118}$Ba are of special interest because of their vicinity to the proton drip line. The nuclear life-times and properties of the proton unstable states of Cs isotopes, populated through decay of $^{116-118}$Ba isotopes will be measured. In addition to that we propose beam development of $^{112-115}$Ba to study exotic decay properties of these neutron deficient nuclei and to search for super-allowed $\\alpha$-decay in future.

  11. Iron-induced nickel deficiency in pecan

    Science.gov (United States)

    Economic loss due to nickel (Ni) deficiency can occur in horticultural and agronomic crops. This study assesses impact of excessive iron (Fe) on expression of Ni deficiency in pecan [Carya illinoinensis (Wangenh.) K. Koch]. Field and greenhouse experiments found Ni deficiency to be inducible by ei...

  12. Iron Deficiency in Autism and Asperger Syndrome.

    Science.gov (United States)

    Latif, A.; Heinz, P.; Cook, R.

    2002-01-01

    Retrospective analysis of the full blood count and, when available, serum ferritin measurements of 96 children (52 with autism and 44 with Asperger syndrome) found six autistic children had iron deficiency and 12 of the 23 autistic children with serum ferritin measures were iron deficient. Far fewer Asperger children were iron deficient. Results…

  13. Alpha-nucleus potential for alpha-decay and sub-barrier fusion

    CERN Document Server

    Denisov, V Y

    2005-01-01

    The set of parameters for alpha-nucleus potential is derived by using the data for both the alpha-decay half-lives and the fusion cross-sections around the barrier for reactions alpha+40Ca, alpha+59Co, alpha+208Pb. The alpha-decay half-lives are obtained in the framework of a cluster model using the WKB approximation. The evaluated alpha-decay half-lives and the fusion cross-sections agreed well with the data. Fusion reactions between alpha-particle and heavy nuclei can be used for both the formation of very heavy nuclei and spectroscopic studies of the formed compound nuclei.

  14. Alpha-nucleus potential for alpha-decay and sub-barrier fusion

    OpenAIRE

    Denisov, V. Yu.; Ikezoe, H.

    2005-01-01

    The set of parameters for alpha-nucleus potential is derived by using the data for both the alpha-decay half-lives and the fusion cross-sections around the barrier for reactions alpha+40Ca, alpha+59Co, alpha+208Pb. The alpha-decay half-lives are obtained in the framework of a cluster model using the WKB approximation. The evaluated alpha-decay half-lives and the fusion cross-sections agreed well with the data. Fusion reactions between alpha-particle and heavy nuclei can be used for both the f...

  15. Growth hormone regulation of p85alpha expression and phosphoinositide 3-kinase activity in adipose tissue: mechanism for growth hormone-mediated insulin resistance.

    Science.gov (United States)

    del Rincon, Juan-Pablo; Iida, Keiji; Gaylinn, Bruce D; McCurdy, Carrie E; Leitner, J Wayne; Barbour, Linda A; Kopchick, John J; Friedman, Jacob E; Draznin, Boris; Thorner, Michael O

    2007-06-01

    Phosphoinositide (PI) 3-kinase is involved in insulin-mediated effects on glucose uptake, lipid deposition, and adiponectin secretion from adipocytes. Genetic disruption of the p85alpha regulatory subunit of PI 3-kinase increases insulin sensitivity, whereas elevated p85alpha levels are associated with insulin resistance through PI 3-kinase-dependent and -independent mechanisms. Adipose tissue plays a critical role in the antagonistic effects of growth hormone (GH) on insulin actions on carbohydrate and lipid metabolism through changes in gene transcription. The objective of this study was to assess the role of the p85alpha subunit of PI 3-kinase and PI 3-kinase signaling in GH-mediated insulin resistance in adipose tissue. To do this, p85alpha mRNA and protein expression and insulin receptor substrate (IRS)-1-associated PI 3-kinase activity were measured in white adipose tissue (WAT) of mice with GH excess, deficiency, and sufficiency. Additional studies using 3T3-F442A cells were conducted to confirm direct effects of GH on free p85alpha protein abundance. We found that p85alpha expression 1) is decreased in WAT from mice with isolated GH deficiency, 2) is increased in WAT from mice with chronic GH excess, 3) is acutely upregulated in WAT from GH-deficient and -sufficient mice after GH administration, and 4) is directly upregulated by GH in 3T3-F442A adipocytes. The insulin-induced increase in PI 3-kinase activity was robust in mice with GH deficiency, but not in mice with GH excess. In conclusion, GH regulates p85alpha expression and PI 3-kinase activity in WAT and provides a potential explanation for 1) the insulin hypersensitivity and associated obesity and hyperadiponectinemia of GH-deficient mice and 2) the insulin resistance and associated reduced fat mass and hypoadiponectinemia of mice with GH excess.

  16. Inflaton Decay in an Alpha Vacuum

    CERN Document Server

    Naidu, S; Naidu, Siddartha; Holman, Richard

    2004-01-01

    We study the alpha vacua of de Sitter space by considering the decay rate of the inflaton field coupled to a scalar field placed in an alpha vacuum. We find an {\\em alpha dependent} Bose enhancement relative to the Bunch-Davies vacuum and, surprisingly, no non-renormalizable divergences. We also consider a modified alpha dependent time ordering prescription for the Feynman propagator and show that it leads to an alpha independent result. This result suggests that it may be possible to calculate in any alpha vacuum if we employ the appropriate causality preserving prescription.

  17. Iron deficiency anemia in pregnancy.

    Science.gov (United States)

    Di Renzo, Gian Carlo; Spano, Filippo; Giardina, Irene; Brillo, Eleonora; Clerici, Graziano; Roura, Luis Cabero

    2015-11-01

    Anemia is the most frequent derailment of physiology in the world throughout the life of a woman. It is a serious condition in countries that are industrialized and in countries with poor resources. The main purpose of this manuscript is to give the right concern of anemia in pregnancy. The most common causes of anemia are poor nutrition, iron deficiencies, micronutrients deficiencies including folic acid, vitamin A and vitamin B12, diseases like malaria, hookworm infestation and schistosomiasis, HIV infection and genetically inherited hemoglobinopathies such as thalassemia. Depending on the severity and duration of anemia and the stage of gestation, there could be different adverse effects including low birth weight and preterm delivery. Treatment of mild anemia prevents more severe forms of anemia, strictly associated with increased risk of fetal-maternal mortality and morbidity.

  18. Vitamin D deficiency in Europe

    DEFF Research Database (Denmark)

    Cashman, Kevin D.; Dowling, Kirsten G; Škrabáková, Zuzana

    2016-01-01

    BACKGROUND: Vitamin D deficiency has been described as being pandemic, but serum 25-hydroxyvitamin D [25(OH)D] distribution data for the European Union are of very variable quality. The NIH-led international Vitamin D Standardization Program (VDSP) has developed protocols for standardizing existing...... 25(OH)D values from national health/nutrition surveys. OBJECTIVE: This study applied VDSP protocols to serum 25(OH)D data from representative childhood/teenage and adult/older adult European populations, representing a sizable geographical footprint, to better quantify the prevalence of vitamin D...... sera. These data were combined with standardized serum 25(OH)D data from 4 previously standardized studies (for a total n = 55,844). Prevalence estimates of vitamin D deficiency [using various serum 25(OH)D thresholds] were generated on the basis of standardized 25(OH)D data. RESULTS: An overall pooled...

  19. DNA repair deficiency in neurodegeneration

    DEFF Research Database (Denmark)

    Jeppesen, Dennis Kjølhede; Bohr, Vilhelm A; Stevnsner, Tinna V.

    2011-01-01

    : homologous recombination and non-homologous end-joining. Ataxia telangiectasia and related disorders with defects in these pathways illustrate that such defects can lead to early childhood neurodegeneration. Aging is a risk factor for neurodegeneration and accumulation of oxidative mitochondrial DNA damage......Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive...... neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative...

  20. Osteoblastic regulation of B lymphopoiesis is mediated by Gs{alpha}-dependent signaling pathways.

    Science.gov (United States)

    Wu, Joy Y; Purton, Louise E; Rodda, Stephen J; Chen, Min; Weinstein, Lee S; McMahon, Andrew P; Scadden, David T; Kronenberg, Henry M

    2008-11-04

    Osteoblasts play an increasingly recognized role in supporting hematopoietic development and recently have been implicated in the regulation of B lymphopoiesis. Here we demonstrate that the heterotrimeric G protein alpha subunit G(s)alpha is required in cells of the osteoblast lineage for normal postnatal B lymphocyte production. Deletion of G(s)alpha early in the osteoblast lineage results in a 59% decrease in the percentage of B cell precursors in the bone marrow. Analysis of peripheral blood from mutant mice revealed a 67% decrease in the number of circulating B lymphocytes by 10 days of age. Strikingly, other mature hematopoietic lineages are not decreased significantly. Mice lacking G(s)alpha in cells of the osteoblast lineage exhibit a reduction in pro-B and pre-B cells. Furthermore, interleukin (IL)-7 expression is attenuated in G(s)alpha-deficient osteoblasts, and exogenous IL-7 is able to restore B cell precursor populations in the bone marrow of mutant mice. Finally, the defect in B lymphopoiesis can be rescued by transplantation into a WT microenvironment. These findings confirm that osteoblasts are an important component of the B lymphocyte niche and demonstrate in vivo that G(s)alpha-dependent signaling pathways in cells of the osteoblast lineage extrinsically regulate bone marrow B lymphopoiesis, at least partially in an IL-7-dependent manner.

  1. Molecular Genetics of Lactase Deficiencies

    OpenAIRE

    Kuokkanen, Mikko

    2006-01-01

    Congenital lactase deficiency (CLD) (MIM 223000) is a rare autosomal recessive gastrointestinal disorder characterized by watery diarrhea in infants fed with breast milk or other lactose-containing formulas. The CLD locus was previously assigned by linkage and linkage disequilibrium analyses on 2q21 in 19 Finnish families. In this study, the molecular background of this disorder is reported. The CLD locus was refined in 32 CLD patients in 24 families by using microsatellite and single nucleot...

  2. Iron refractory iron deficiency anemia

    OpenAIRE

    De Falco, Luigia; Sanchez, Mayka; Silvestri, Laura; Kannengiesser, Caroline; Muckenthaler, Martina U; Iolascon, Achille; Gouya, Laurent; Camaschella, Clara; Beaumont, Carole

    2013-01-01

    Iron refractory iron deficiency anemia is a hereditary recessive anemia due to a defect in the TMPRSS6 gene encoding Matriptase-2. This protein is a transmembrane serine protease that plays an essential role in down-regulating hepcidin, the key regulator of iron homeostasis. Hallmarks of this disease are microcytic hypochromic anemia, low transferrin saturation and normal/high serum hepcidin values. The anemia appears in the post-natal period, although in some cases it is only diagnosed in ad...

  3. Congenital deficiency of factor VII.

    Science.gov (United States)

    Sikka, M; Gomber, S; Madan, N; Rusia, U; Sharma, S

    1996-01-01

    A case of congenital factor VII deficiency in a five-year-old child is reported. The patient, born of a non-consanguineous marriage, presented with repeated bouts of epistaxis since childhood. The prothrombin time (PT) was markedly prolonged with a normal bleeding time (BT), partial thromboplastin time with Kaolin (PTTK) and platelet count. The patient has been on follow up for the last four years and is doing apparently well.

  4. What Powers Lyman alpha Blobs?

    CERN Document Server

    Ao, 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; Weiss, A; Zheng, Z

    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 radio with fluxes of 67+/-17 microJy and 77+/-16 microJy, respectively, and B5 is marginally detected at 3 sigma (51+/-16 microJy). For all detected sources, their radio positions are consistent with the central positions of the LABs. B6 and B7 are obviously also detected in the FIR. By fitting the data with different templates, we obtained redshifts of 2.20$^{+0.30}_{-0.35}$ for B6 and 2.20$^{+0.45}_{-0.30}$ for B7 which are consistent with the redshift of the lyman alpha emission within uncertainties, indicating that both ...

  5. Alpha proton x ray spectrometer

    Science.gov (United States)

    Rieder, Rudi; Waeke, H.; Economou, T.

    1994-01-01

    Mars Pathfinder will carry an alpha-proton x ray spectrometer (APX) for the determination of the elemental chemical composition of Martian rocks and soils. The instrument will measure the concentration of all major and some minor elements, including C, N, and O at levels above typically 1 percent.

  6. Sparse Coding for Alpha Matting.

    Science.gov (United States)

    Johnson, Jubin; Varnousfaderani, Ehsan; Cholakkal, Hisham; Rajan, Deepu

    2016-04-21

    Existing color sampling based alpha matting methods use the compositing equation to estimate alpha at a pixel from pairs of foreground (F) and background (B) samples. The quality of the matte depends on the selected (F,B) pairs. In this paper, the matting problem is reinterpreted as a sparse coding of pixel features, wherein the sum of the codes gives the estimate of the alpha matte from a set of unpaired F and B samples. A non-parametric probabilistic segmentation provides a certainty measure on the pixel belonging to foreground or background, based on which a dictionary is formed for use in sparse coding. By removing the restriction to conform to (F,B) pairs, this method allows for better alpha estimation from multiple F and B samples. The same framework is extended to videos, where the requirement of temporal coherence is handled effectively. Here, the dictionary is formed by samples from multiple frames. A multi-frame graph model, as opposed to a single image as for image matting, is proposed that can be solved efficiently in closed form. Quantitative and qualitative evaluations on a benchmark dataset are provided to show that the proposed method outperforms current state-of-the-art in image and video matting.

  7. Mitochondrial cytochrome c oxidase deficiency.

    Science.gov (United States)

    Rak, Malgorzata; Bénit, Paule; Chrétien, Dominique; Bouchereau, Juliette; Schiff, Manuel; El-Khoury, Riyad; Tzagoloff, Alexander; Rustin, Pierre

    2016-03-01

    As with other mitochondrial respiratory chain components, marked clinical and genetic heterogeneity is observed in patients with a cytochrome c oxidase deficiency. This constitutes a considerable diagnostic challenge and raises a number of puzzling questions. So far, pathological mutations have been reported in more than 30 genes, in both mitochondrial and nuclear DNA, affecting either structural subunits of the enzyme or proteins involved in its biogenesis. In this review, we discuss the possible causes of the discrepancy between the spectacular advances made in the identification of the molecular bases of cytochrome oxidase deficiency and the lack of any efficient treatment in diseases resulting from such deficiencies. This brings back many unsolved questions related to the frequent delay of clinical manifestation, variable course and severity, and tissue-involvement often associated with these diseases. In this context, we stress the importance of studying different models of these diseases, but also discuss the limitations encountered in most available disease models. In the future, with the possible exception of replacement therapy using genes, cells or organs, a better understanding of underlying mechanism(s) of these mitochondrial diseases is presumably required to develop efficient therapy.

  8. [Iodine deficiency in cardiovascular diseases].

    Science.gov (United States)

    Molnár, I; Magyari, M; Stief, L

    1998-08-30

    The thyroid hormone deficiency on cardiovascular function can be characterized with decreased myocardial contractility and increased peripheral vascular resistance as well as with the changes in lipid metabolism. 42 patients with cardiovascular disease (mean age 65 +/- 13 yr, 16 males) were investigated if iodine insufficiency can play a role as a risk factor for the cardiovascular diseases. The patients were divided in 5 subgroups on the ground of the presence of hypertension, congestive heart failure, cardiomyopathy, coronary disfunction and arrhythmia. Urine iodine concentration (5.29 +/- 4.52 micrograms/dl) was detected with Sandell-Kolthoff colorimetric reaction. The most decreased urine iodine concentration was detected in the subgroups with arrhythmia and congestive heart failure (4.7 +/- 4.94 micrograms/dl and 4.9 +/- 4.81 micrograms/dl, respectively). An elevated TSH level was found by 3 patients (5.3 +/- 1.4 mlU/l). An elevation in lipid metabolism (cholesterol, triglyceride) associated with all subgroups without arrhythmia. In conclusion, the occurrence of iodine deficiency in cardiovascular disease is frequent. Iodine supplementation might prevent the worsing effect of iodine deficiency on cardiovascular disease.

  9. Zinc Deficiency in Humans and its Amelioration

    OpenAIRE

    Yashbir Singh Shivay

    2015-01-01

    Zinc (Zn) deficiency in humans has recently received considerable attention. Global mortality in children under 5 years of age in 2004 due to Zn deficiency was estimated at 4,53,207 as against 6,66,771 for vitamin A deficiency; 20,854 for iron deficiency and 3,619 for iodine deficiency. In humans 2800-3000 proteins contain Zn prosthetic group and Zn is an integral component of zinc finger prints that regulate DNA transcription. Zinc is a Type-2 nutrient, which means that its concentration in ...

  10. Biological activity of 1. cap alpha. -hydroxyvitamin D/sub 2/ in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Reeve, L.E.; Schnoes, H.K.; DeLuca, H.F.

    1978-01-01

    The biological activity of 1..cap alpha..-hydroxyvitamin D/sub 2/ has been determined in vitamin D-deficient rats. In the calcification of the rachitic epiphyseal plate, 1..cap alpha..-hydroxyvitamin D/sub 2/ is more active than 25-hydroxyvitamin D/sub 3/, while it is equally active in stimulating intestinal calcium absorption. On the other hand, it is much less active (one-third to one-fifth) than 25-hydroxyvitamin D/sub 3/ in the mobilization of calcium from bone. In both the intestinal and bone responses, 1..cap alpha..-hydroxyvitamin D/sub 2/ (312 pmol) is active in nephrectomized rats while 15-hydroxyvitamin D/sub 3/ is not.

  11. Correlation of vitamin A nutritional status on alpha-tocopherol in the colostrum of lactating women.

    Science.gov (United States)

    de Lira, Larissa Queiroz; Lima, Mayara Santa Rosa; de Medeiros, Jovilma Maria Soares; da Silva, Isabelle Ferreira; Dimenstein, Roberto

    2013-01-01

    The adequate supply of vitamins A and E to newborns is essential. However, factors such as maternal nutritional status and nutrient interaction may limit its bioavailability. The aim of this study was to establish nutritional status for vitamins A and E and evaluate the correlation of retinol on colostrum alpha-tocopherol in lactating women. A total of 103 lactating women were recruited at a Brazilian public maternity hospital. Fasting serum and colostrum samples were collected in the immediate post-partum. Retinol and alpha-tocopherol levels were determined by high-performance liquid chromatography and nutritional status for these vitamins was defined from specific cut-off points for serum and colostrum. Mean serum and colostrum retinol (1.49 µmol L(-1) , 2.18 µmol L(-1) ) and alpha-tocopherol (26.4 µmol L(-1) , 26.1 µmol L(-1) ) indicated satisfactory biochemical status. However, we found a prevalence of subclinical deficiency of vitamin A and vitamin E in serum (15.5% and 16%) and colostrum (50% and 60%). Lactating women with serum retinol ≥ 1.05 µmol L(-1) showed an inverse correlation between serum retinol and alpha-tocopherol concentration in the colostrum (P = 0.008, r = -0.28). This association was not observed in serum level nutritional status of lactating women for vitamins A and E was adequate, although there is a risk of subclinical deficiency. The negative correlation of serum retinol on alpha-tocopherol concentration in the colostrum must be carefully evaluated in situations of vitamin A supplementation, because alpha-tocopherol bioavailability in maternal milk may be compromised.

  12. Deficiencies in the Management of Iron Deficiency Anemia During Childhood.

    Science.gov (United States)

    Powers, Jacquelyn M; Daniel, Catherine L; McCavit, Timothy L; Buchanan, George R

    2016-04-01

    Limited high-quality evidence supports the management of iron deficiency anemia (IDA). To assess our institutional performance in this area, we retrospectively reviewed IDA treatment practices in 195 consecutive children referred to our center from 2006 to mid-2010. The majority of children were ≤4 years old (64%) and had nutritional IDA (74%). In 11- to 18-year-old patients (31%), the primary etiology was menorrhagia (42%). Many were referred directly to the emergency department and/or prescribed iron doses outside the recommended range. Poor medication adherence and being lost-to-follow-up were common. Substantial improvements are required in the management of IDA.

  13. Primary Carnitine (OCTN2) Deficiency Without Neonatal Carnitine Deficiency

    OpenAIRE

    Boer, L.; Kluijtmans, L.A.J.; Morava, E.

    2012-01-01

    Although the diagnosis of a primary carnitine deficiency is usually based on a very low level of free and total carnitine (free carnitine: 1–5 μM, normal 20–55 μM) (Longo et al. 2006), we detected a patient via newborn screening with a total carnitine level 67 % of the normal value. At the age of 1 year, after interruption of carnitine supplementation for a 4-week period the carnitine profile was assessed and the free carnitine level had dropped to 10.4 μmol/l (normal: 20–55 μM) and total car...

  14. Evolution and seismology of alpha Centauri

    CERN Document Server

    Montalban, J; Montalban, Josefina; Miglio, Andrea

    2005-01-01

    Solar-like oscillations detected in both components of the binary system alpha Centauri provide strong constraints on the fundamental parameters of the stellar system. We model alpha Centauri by means of a Levenberg-Marquardt minimization algorithm including seismic and classical constraints. Computations, that were perfomed decreasing significanly the weight of alpha Cen B seismic data in the calibration procedure, predict small separations in good agreement with new observations of solar-like oscillations in alpha Cen B by Bedding (these proceedings).

  15. Astrophysical reaction rate for $\\alpha(\\alpha n,\\gamma)$

    CERN Document Server

    Sumiyoshi, K; Goko, S; Kajino, T

    2002-01-01

    We study the astrophysical reaction rate for the formation of $^{9}$Be through the three body reaction $\\alpha(\\alpha n,\\gamma)$. This reaction is one of the key reactions which could bridge the mass gap at A = 8 nuclear systems to produce intermediate-to-heavy mass elements in alpha- and neutron-rich environments such as r-process nucleosynthesis in supernova explosions, s-process nucleosynthesis in asymptotic giant branch (AGB) stars, and primordial nucleosynthesis in baryon inhomogeneous cosmological models. To calculate the thermonuclear reaction rate in a wide range of temperatures, we numerically integrate the thermal average of cross sections assuming a two-steps formation through a metastable $^{8}$Be. Off-resonant and on-resonant contributions from the ground state in $^{8}$Be are taken into account. As input cross section, we adopt the latest experimental data by photodisintegration of $^{9}$Be with laser-electron photon beams, which covers all relevant resonances in $^{9}$Be. We provide the reactio...

  16. 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

    1992-01-01

    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

  17. Effectiveness of Alpha Biofeedback Therapy: Negative Results.

    Science.gov (United States)

    Watson, Charles G.; Herder, Joseph

    1980-01-01

    Assessed the utility of alpha biofeedback training in the treatment of patients (N=66). Biofeedback and placebo biofeedback groups were given alpha or mock-alpha training sessions. Improvement on 54 variables was compared to that of no-treatment controls. Only a chance number of significant changes appeared among the groups. (Author)

  18. Refinement of the $n-\\alpha$ and $p-\\alpha$ fish-bone potential

    CERN Document Server

    Smith, E; Papp, Z

    2012-01-01

    The fishbone potential of composite particles simulates the Pauli effect by nonlocal terms. We determine the $n-\\alpha$ and $p-\\alpha$ fish-bone potential by simultaneously fitting to the experimental phase shifts. We found that with a double Gaussian parametrization of the local potential can describe the $n-\\alpha$ and $p-\\alpha$ phase shifts for all partial waves.

  19. 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.; Wortche, 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 allo

  20. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency).

    Science.gov (United States)

    Mills, Philippa B; Footitt, Emma J; Mills, Kevin A; Tuschl, Karin; Aylett, Sarah; Varadkar, Sophia; Hemingway, Cheryl; Marlow, Neil; Rennie, Janet; Baxter, Peter; Dulac, Olivier; Nabbout, Rima; Craigen, William J; Schmitt, Bernhard; Feillet, François; Christensen, Ernst; De Lonlay, Pascale; Pike, Mike G; Hughes, M Imelda; Struys, Eduard A; Jakobs, Cornelis; Zuberi, Sameer M; Clayton, Peter T

    2010-07-01

    Pyridoxine-dependent epilepsy was recently shown to be due to mutations in the ALDH7A1 gene, which encodes antiquitin, an enzyme that catalyses the nicotinamide adenine dinucleotide-dependent dehydrogenation of l-alpha-aminoadipic semialdehyde/L-Delta1-piperideine 6-carboxylate. However, whilst this is a highly treatable disorder, there is general uncertainty about when to consider this diagnosis and how to test for it. This study aimed to evaluate the use of measurement of urine L-alpha-aminoadipic semialdehyde/creatinine ratio and mutation analysis of ALDH7A1 (antiquitin) in investigation of patients with suspected or clinically proven pyridoxine-dependent epilepsy and to characterize further the phenotypic spectrum of antiquitin deficiency. Urinary L-alpha-aminoadipic semialdehyde concentration was determined by liquid chromatography tandem mass spectrometry. When this was above the normal range, DNA sequencing of the ALDH7A1 gene was performed. Clinicians were asked to complete questionnaires on clinical, biochemical, magnetic resonance imaging and electroencephalography features of patients. The clinical spectrum of antiquitin deficiency extended from ventriculomegaly detected on foetal ultrasound, through abnormal foetal movements and a multisystem neonatal disorder, to the onset of seizures and autistic features after the first year of life. Our relatively large series suggested that clinical diagnosis of pyridoxine dependent epilepsy can be challenging because: (i) there may be some response to antiepileptic drugs; (ii) in infants with multisystem pathology, the response to pyridoxine may not be instant and obvious; and (iii) structural brain abnormalities may co-exist and be considered sufficient cause of epilepsy, whereas the fits may be a consequence of antiquitin deficiency and are then responsive to pyridoxine. These findings support the use of biochemical and DNA tests for antiquitin deficiency and a clinical trial of pyridoxine in infants and

  1. Separation of the subtypes of type V collagen molecules, [alpha 1(V)]2 alpha 2(V) and alpha 1(V) alpha 2(V) alpha 3(V), by chain composition-dependent affinity for heparin: single alpha 1(V) chain shows intermediate heparin affinity between those of the type V collagen subtypes composed of [alpha 1(V)]2 alpha 2(V) and of alpha 1(V) alpha 2(V) alpha 3(V).

    Science.gov (United States)

    Mizuno, K; Hayashi, T

    1996-11-01

    The heparin affinities of heat-treated type V collagen alpha-chains and the triple-helical molecules were evaluated in terms of the NaCl concentration required for prevention of binding to a heparin-Sepharose column. After heat treatment, alpha 1(V) chain required approximately two-fold higher NaCl concentration to pass through the column than the other two chains, alpha 2(V) and alpha 3(V). Thus, the heparin affinity of alpha 1(V) may be approximately two-fold higher than those of the other alpha (V)-chains. The type V collagen molecules in triple-helical conformation were separated into two fractions at 170 mM NaCl in 20 mM phosphate buffer, pH 7.2, containing 2 M urea; bound and non-bound. The ratio of the three alpha-chains, alpha 1(V): alpha 2(V): alpha 3(V) was 2 : 1 : 0 and 1 : 1 : 1 in the bound and flow-through fractions, respectively, on analysis by SDS-PAGE. The differential affinity of the two fractions could be accounted for by the number of alpha 1(V) chains in the triple-helical molecule, if these fractions contained triple-helical subtypes with the chain compositions of [alpha 1(V)]2 alpha 2(V) and alpha 1(V) alpha 2(V) alpha 3(V), respectively. From the comparison of the NaCl concentration required for prevention of the binding, [alpha 1(V)]2, alpha 2(V) had about two-fold higher affinity than alpha 1(V) alpha 2(V) alpha 3(V), and the separated alpha 1(V) chain showed an intermediate affinity. A possible explanation for difference in heparin affinity among the subtypes of molecules and the separated alpha-chains is that the heparin affinity of type V collagen molecule is governed by the number of alpha 1(V) chains contained in the molecule and that steric restraint in a triple-helical conformation weakens the binding of alpha 1(V) chain to heparin.

  2. Skin wound healing in MMP2-deficient and MMP2 / plasminogen double-deficient mice

    DEFF Research Database (Denmark)

    Frøssing, Signe; Rønø, Birgitte; Hald, Andreas;

    2010-01-01

    -sensitive MMPs during wound healing. To address whether MMP2 is accountable for the galardin-induced healing deficiency in wildtype and Plg-deficient mice, incisional skin wounds were generated in MMP2 single-deficient mice and in MMP2/Plg double-deficient mice and followed until healed. Alternatively, tissue...... was isolated 7 days post wounding for histological and biochemical analyses. No difference was found in the time from wounding to overt gross restoration of the epidermal surface between MMP2-deficient and wildtype control littermate mice. MMP2/Plg double-deficient mice were viable and fertile, and displayed...... an unchallenged general phenotype resembling that of Plg-deficient mice, including development of rectal prolapses. MMP2/Plg double-deficient mice displayed a slight increase in the wound length throughout the healing period compared with Plg-deficient mice. However, the overall time to complete healing...

  3. Genetics Home Reference: 17 alpha-hydroxylase/17,20-lyase deficiency

    Science.gov (United States)

    ... hypertension), low levels of potassium in the blood (hypokalemia), and abnormal sexual development. The severity of the ... these salt-regulating hormones leads to hypertension and hypokalemia. Loss of 17,20-lyase activity impairs sex ...

  4. Alcoholic Myelopathy and Nutritional Deficiency

    Science.gov (United States)

    Koike, Haruki; Nakamura, Tomohiko; Ikeda, Shohei; Takahashi, Mie; Kawagashira, Yuichi; Iijima, Masahiro; Katsuno, Masahisa; Sobue, Gen

    2017-01-01

    A patient with chronic alcoholism presented with myelopathy and low serum folate and cobalamin levels. A 42-year-old alcoholic man had gait disturbance for 4 months. A neurological examination revealed marked spasticity with increased deep tendon reflexes and extensor plantar responses of the lower limbs. His cobalamin level was decreased and his serum folate level was particularly low. His plasma ammonia level was not increased. Abstinence and folic acid and cobalamin supplementation stopped the progression of his neurological deficits. This case indicates that nutritional deficiency should be monitored closely in patients with chronic alcoholism who present with myelopathy. PMID:28049986

  5. Muscle phosphoglycerate mutase deficiency revisited

    DEFF Research Database (Denmark)

    Naini, Ali; Toscano, Antonio; Musumeci, Olimpia;

    2009-01-01

    storage disease type X and novel mutations in the gene encoding the muscle subunit of PGAM (PGAM2). DESIGN: Clinical, pathological, biochemical, and molecular analyses. SETTING: Tertiary care university hospitals and academic institutions. Patients A 37-year-old Danish man of Pakistani origin who had...... PGAM deficiency, and molecular studies revealed 2 novel homozygous mutations, a nonsense mutation and a single nucleotide deletion. Pathological studies of muscle showed mild glycogen accumulation but prominent tubular aggregates in both patients. CONCLUSIONS: We found that glycogen storage disease...

  6. Crystalline anhydrous {alpha},{alpha}-trehalose (polymorph {beta}) and crystalline dihydrate {alpha},{alpha}-trehalose: A calorimetric study

    Energy Technology Data Exchange (ETDEWEB)

    Pinto, Susana S. [Centro de Quimica Estrutural, Complexo Interdisciplinar, Instituto Superior Tecnico, 1049-001 Lisbon (Portugal)]. E-mail: susanapinto@ist.utl.pt; Diogo, Herminio P. [Centro de Quimica Estrutural, Complexo Interdisciplinar, Instituto Superior Tecnico, 1049-001 Lisbon (Portugal)]. E-mail: hdiogo@ist.utl.pt; Moura-Ramos, Joaquim J. [Centro de Quimica-Fisica Molecular, Complexo Interdisciplinar, Instituto Superior Tecnico, 1049-001 Lisbon (Portugal)]. E-mail: mouraramos@ist.utl.pt

    2006-09-15

    The mean values of the standard massic energy of combustion of crystalline anhydrous {alpha},{alpha}-trehalose (C{sub 12}H{sub 22}O{sub 11}, polymorph {beta}) and crystalline dihydrate {alpha},{alpha}-trehalose (C{sub 12}H{sub 26}O{sub 13}) measured by static-bomb combustion calorimetry in oxygen, at the temperature T=298.15K, are {delta}{sub c}u{sup o}=-(16434.05+/-4.50)J.g{sup -1} and {delta}{sub c}u{sup o}=-(14816.05+/-3.52)J.g{sup -1}, respectively. The standard (p{sup o}=0.1MPa) molar enthalpy of formation of these compounds were derived from the corresponding standard molar enthalpies of combustion, respectively, {delta}{sub f}H{sub m}{sup o} (C{sub 12}H{sub 22}O{sub 11},cr)=-(2240.9+/-3.9)kJ.mol{sup -1}, and {delta}{sub f}H{sub m}{sup o} (C{sub 12}H{sub 26}O{sub 13},cr)=-(2832.6+/-3.6)kJ.mol{sup -1}. The values of the standard enthalpies of formation obtained in this work, together with data on enthalpies of solution at infinite dilution ({delta}{sub sol}H{sup {approx}}) for crystalline dihydrate and amorphous anhydrous trehalose, allow a better insight on the thermodynamic description of the trehalose system which can provide, together with the future research on the subject, a contribution for understanding the metabolism in several organisms, as well as the phase transition between the different polymorphs.

  7. Radioimmunotherapy Using Vascular Targeted 213Bi: The Role of TNF-Alpha in the Development of Pulmonary Fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Davis, I.A.; Kennel, S.J.

    1998-10-14

    A monoclonal antibody (201B) specific to murine thrombomodulin, covalently linked to CHX-b-DTPA, successfully delivers chelated 213Bi, an {alpha}-particle emitter, (213Bi-201B) rapidly to lungvascular endothelium. When injected at doses of l MBq/mouse, 213Bi-201B destroyed most of the 100 colonies of EMT-6 mammary carcinomas growing as lung tumors of up to 2000 cells/colony. Some mice were cured of lung tumors and others had extended life-spans compared to untreated control animals but eventually succumbed to tumor recurrence. At injected doses of 4-6 MBq/mouse, 100% of lung tumor colonies were eliminated; however, 3-4 months later these mice developed pulmonary fibrosis and died. The mechanisms leading to the fibrotic response in other pulmonary irradiation models strongly implicate tumor necrosis factor-alpha (TNF-{alpha}), released from damaged tissues, as the pivotal inflammatory cytokine in a cascade of events which culminate in fibrosis. Attempts to prevent the development of pulmonary fibrosis, by using antibodies or soluble receptor (Enbrel{trademark}) as inhibitors of TNF-{alpha}, were unsuccessful. Additionally, mice genetically deficient for TNF-{alpha} production developed pulmonary fibrosis following 213Bi-201B treatment. Interestingly, non-tumor bearing BALB/c mice receiving Enbrel{trademark} or mice genetically deficient in TNF-{alpha} production and treated with 213Bi-201B, had significantly reduced life spans compared to mice receiving no treatment or 213Bi-201B alone. We speculate that, in normal mice, while TNF-{alpha} may induce an inflammatory response following {alpha}-particle radiation mediated tumor clearance and pulmonary damage, its effects in the post-tumor clearance time period may actually retard the development of fibrosis.

  8. Alpha voltaic batteries and methods thereof

    Science.gov (United States)

    Raffaelle, Ryne P. (Inventor); Jenkins, Phillip (Inventor); Wilt, David (Inventor); Scheiman, David (Inventor); Chubb, Donald (Inventor); Castro, Stephanie (Inventor)

    2011-01-01

    An alpha voltaic battery includes at least one layer of a semiconductor material comprising at least one p/n junction, at least one absorption and conversion layer on the at least one layer of semiconductor layer, and at least one alpha particle emitter. The absorption and conversion layer prevents at least a portion of alpha particles from the alpha particle emitter from damaging the p/n junction in the layer of semiconductor material. The absorption and conversion layer also converts at least a portion of energy from the alpha particles into electron-hole pairs for collection by the one p/n junction in the layer of semiconductor material.

  9. Collagen IV alpha 3, alpha 4, and alpha 5 chains in rodent basal laminae: sequence, distribution, association with laminins, and developmental switches

    OpenAIRE

    1994-01-01

    Collagen IV is a major component of vertebrate basal laminae (BLs). Studies in humans have revealed a family of genes encoding alpha 1- alpha 6 collagen IV chains and implicated alpha 3-alpha 6 in disease processes (Goodpasture and Alport syndromes and diffuse leiomyomatosis). To extend studies of these components to an experimentally accessible animal, we cloned cDNAs encoding partial collagen alpha 3, alpha 4, and alpha 5(IV) chains from the mouse. Ribonuclease protection assays showed that...

  10. Vitamin D deficiency and stroke

    Directory of Open Access Journals (Sweden)

    2012-12-01

    Full Text Available Vitamin D comprises a group of fat-soluble pro-hormones, obtained from sun exposure, food, and supplements, and it must undergo two hydroxylation reactions to be activated in the body. Several studies have shown the role of vitamin D in mineral metabolism regulation, especially calcium, phosphorus, and bone metabolism. Some factors such as inadequate vitamin intake and liver or kidney disorders can lead to vitamin D deficiency. Furthermore, vitamin D malnutrition may also be linked to susceptibility to chronic diseases such as heart failure, peripheral artery disease, high blood pressure, cognitive impairment including foggy brain and memory loss, and autoimmune diseases including diabetes type I. Recent research has revealed that low levels of vitamin D increase the risk of cardiovascular-related morbidity (Sato et al., 2004 and mortality (Pilz et al., 2008. Also, hypertension contributes to a reduction in bone mineral density and increase in the incidence of stroke and death. This article reviews the function and physiology of vitamin D and examines the effects of vitamin D deficiency on susceptibility to stroke, as a cardiovascular event, and its morbidity and subsequent mortality.

  11. New insights into iron deficiency and iron deficiency anemia.

    Science.gov (United States)

    Camaschella, Clara

    2017-02-13

    Recent advances in iron metabolism have stimulated new interest in iron deficiency (ID) and its anemia (IDA), common conditions worldwide. Absolute ID/IDA, i.e. the decrease of total body iron, is easily diagnosed based on decreased levels of serum ferritin and transferrin saturation. Relative lack of iron in specific organs/tissues, and IDA in the context of inflammatory disorders, are diagnosed based on arbitrary cut offs of ferritin and transferrin saturation and/or marker combination (as the soluble transferrin receptor/ferritin index) in an appropriate clinical context. Most ID patients are candidate to traditional treatment with oral iron salts, while high hepcidin levels block their absorption in inflammatory disorders. New iron preparations and new treatment modalities are available: high-dose intravenous iron compounds are becoming popular and indications to their use are increasing, although long-term side effects remain to be evaluated.

  12. Further Precise Determinations of $\\alpha_s$ from Lattice QCD

    CERN Document Server

    Davies, C T H; Lepage, G P; McCallum, P; Shigemitsu, J; Sloan, J

    1997-01-01

    We present a new determination of the strong coupling constant from lattice QCD simulations. We use four different short-distance quantities to obtain the coupling, three different (infrared) meson splittings to tune the simulation parameters, and a wide range of lattice spacings, quark masses, and lattice volumes to test for systematic errors. Our final result consists of ten different determinations of $\\alpha^{(3)}_{P}(8.2 GeV)$, which agree well with each other and with our previous results. The most accurate of these, when evolved perturbatively to the $Z^0$ mass, gives obtained from other recent lattice simulations.

  13. Double-real corrections at O(alpha alpha_s) to single gauge boson production

    CERN Document Server

    Bonciani, Roberto; Mondini, Roberto; Vicini, Alessandro

    2016-01-01

    We consider the O(alpha alpha_s) corrections to single on-shell gauge boson production at hadron colliders. We concentrate on the contribution of all the subprocesses where the gauge boson is accompanied by the emission of two additional real partons and we evaluate the corresponding total cross sections. The latter are divergent quantities, because of soft and collinear emissions, and are expressed as Laurent series in the dimensional regularization parameter. The total cross sections are evaluated by means of reverse unitarity, i.e. expressing the phase-space integrals in terms of two-loop forward box integrals with cuts on the final state particles. The results are reduced to a combination of Master Integrals, which eventually are evaluated in terms of Generalized Polylogarithms. The presence of internal massive lines in the Feynman diagrams, due to the exchange of electroweak gauge bosons, causes the appearance of 14 Master Integrals which were not previously known in the literature and have been evaluate...

  14. Cryptosporidiosis in the acquired immune deficiency syndrome.

    Science.gov (United States)

    Cooper, D A; Wodak, A; Marriot, D J; Harkness, J L; Ralston, M; Hill, A; Penny, R

    1984-10-01

    Cryptosporidiosis was found in a patient with the acquired immune deficiency syndrome. The microbiological and morphological features of this newly recognized opportunistic infection are distinctive and diagnostic.

  15. Vitamin C deficiency in weanling guinea pigs

    DEFF Research Database (Denmark)

    Lykkesfeldt, Jens; Trueba, Gilberto Perez; Poulsen, Henrik E.

    2007-01-01

    Neonates are particularly susceptible to malnutrition due to their limited reserves of micronutrients and their rapid growth. In the present study, we examined the effect of vitamin C deficiency on markers of oxidative stress in plasma, liver and brain of weanling guinea pigs. Vitamin C deficiency...... increased, while protein oxidation decreased (P¼0003). The results show that the selective preservation of brain ascorbate and induction of DNA repair in vitamin C-deficient weanling guinea pigs is not sufficient to prevent oxidative damage. Vitamin C deficiency may therefore be particularly adverse during...

  16. Genetics Home Reference: factor X deficiency

    Science.gov (United States)

    ... deficiency occurs in approximately 1 per million individuals worldwide. Related Information What information about a genetic condition can statistics provide? Why are some genetic conditions more common ...

  17. Iron deficiency anemia in heart failure.

    Science.gov (United States)

    Arora, Natasha P; Ghali, Jalal K

    2013-07-01

    Anemia and iron deficiency are quite prevalent in patients with heart failure (HF) and may overlap. Both anemia and iron deficiency are associated with worse symptoms and adverse clinical outcomes. In the past few years, there has been an enormous interest in the subject of iron deficiency and its management in patients with HF. In this review, the etiology and relevance of iron deficiency, iron metabolism in the setting of HF, studies on iron supplementation in patients with HF and potential cardiovascular effects of subclinical iron overload are discussed.

  18. Reduced prostasin (CAP1/PRSS8) activity eliminates HAI-1 and HAI-2 deficiency-associated developmental defects by preventing matriptase activation

    DEFF Research Database (Denmark)

    Szabo, Roman; Uzzun Sales, Katiuchia; Kosa, Peter;

    2012-01-01

    to placental labyrinth failure, and neural tube defects in HAI-2-deficient embryos. Inactivation of genes encoding c-Met, protease-activated receptor-2 (PAR-2), or the epithelial sodium channel (ENaC) alpha subunit all failed to rescue embryonic lethality, suggesting that deregulated matriptase...

  19. Phytanic acid oxidation: normal activation and transport yet defective alpha-hydroxylation of phytanic acid in peroxisomes from Refsum disease and rhizomelic chondrodysplasia punctata.

    Science.gov (United States)

    Pahan, K; Khan, M; Singh, I

    1996-05-01

    In humans the oxidation of phytanic acid is a peroxisomal function. To understand the possible mechanisms for the pathognomic accumulation of phytanic acid in plasma and body fluids of Refsum disease (RD) and rhizomelic chondrodysplasia punctata (RCDP), we investigated activities of various steps (activation, transport, and oxidation) in the metabolism of phytanic acid in peroxisomes isolated from cultured skin fibroblasts from control, RD, and RCDP subjects. Activation of phytanic acid was normal in peroxisomes from both RD and RCDP. Transport of phytanic acid or phytanoyl-CoA in the absence or presence of fatty acid activating cofactors (ATP, MgCl2, and CoASH) into peroxisomes isolated from RD and RCDP skin fibroblasts was also similar to that of peroxisomes from control fibroblasts. Defective oxidation of [(2,3)-3H]- or [1-14C]phytanic acid, or [1-14C]phytanoyl-CoA (substrate for the first step of alpha-oxidation) but normal oxidation of [1-14C] alpha-hydroxyphytanic acid (substrate for the second step of the alpha-oxidation pathway) in peroxisomes from RD clearly demonstrates that excessive accumulation of phytanic acid in plasma and body fluids of RD is due to the deficiency of phytanic acid alpha-hydroxylase in peroxisomes. However, in RCDP peroxisomes, in addition to deficient oxidation of [1-14C]phytanic acid or phytanoyl-CoA or [(2,3)-3H]phytanic acid, the oxidation of [1-14C] alpha-hydroxyphytanic acid was also deficient, indicating that in RCDP the activities both of alpha-hydroxylation of phytanic acid and decarboxylation of alpha-hydroxyphytanic acid are deficient. These observations indicate that peroxisomal membrane functions (phytanic acid activation and transport) in phytanic acid metabolism are normal in both RD and RCDP. The defect in RD is in the alpha-hydroxylation of phytanic acid; whereas in RCDP both alpha-hydroxylation of phytanic acid as well as decarboxylation of alpha-hydroxyphytanic acid are deficient.

  20. Fatty acid composition, eicosanoid production and permeability in skin tissues of rainbow trout (Oncorhynchus mykiss) fed a control or an essential fatty acid deficient diet.

    Science.gov (United States)

    Ghioni, C; Bell, J G; Bell, M V; Sargent, J R

    1997-06-01

    4 (LTC4) and leukotriene C5 (LTC5) in skin cells challenged with the calcium ionophore A23187, and of prostaglandin F2alpha (PGF2alpha), 12-HETE and 12-HEPE in gill cells challenged similarly. Prostaglandin F3alpha (PGF3alpha) production by ionophore stimulated gill cells was significantly reduced in fish fed the EFA-deficient diet. 14-HDHE produced by gill cells was 3.3 fold higher in EFA deficient fish compared to controls.

  1. Ablation of phosphoinositide-3-kinase class II alpha suppresses hepatoma cell proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Ng, Stanley K.L. [Singapore Immunology Network A-STAR (Singapore); Neo, Soek-Ying, E-mail: neo_soek_ying@sics.a-star.edu.sg [Singapore Immunology Network A-STAR (Singapore); Yap, Yann-Wan [Singapore Immunology Network A-STAR (Singapore); Karuturi, R. Krishna Murthy; Loh, Evelyn S.L. [Genome Institute of Singapore A-STAR (Singapore); Liau, Kui-Hin [Department of General Surgery, Tan Tock Seng Hospital (Singapore); Ren, Ee-Chee, E-mail: ren_ee_chee@immunol.a-star.edu.sg [Singapore Immunology Network A-STAR (Singapore); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (Singapore)

    2009-09-18

    Cancer such as hepatocellular carcinoma (HCC) is characterized by complex perturbations in multiple signaling pathways, including the phosphoinositide-3-kinase (PI3K/AKT) pathways. Herein we investigated the role of PI3K catalytic isoforms, particularly class II isoforms in HCC proliferation. Among the siRNAs tested against the eight known catalytic PI3K isoforms, specific ablation of class II PI3K alpha (PIK3C2{alpha}) was the most effective in impairing cell growth and this was accompanied by concomitant decrease in PIK3C2{alpha} mRNA and protein levels. Colony formation ability of cells deficient for PIK3C2{alpha} was markedly reduced and growth arrest was associated with increased caspase 3 levels. A small but significant difference in gene dosage and expression levels was detected between tumor and non-tumor tissues in a cohort of 19 HCC patients. Taken together, these data suggest for the first time that in addition to class I PI3Ks in cancer, class II PIK3C2{alpha} can modulate HCC cell growth.

  2. Regulation of homocysteine homeostasis through the transcriptional coactivator PGC-1alpha.

    Science.gov (United States)

    Li, Siming; Arning, Erland; Liu, Chang; Vitvitsky, Victor; Hernandez, Carlos; Banerjee, Ruma; Bottiglieri, Teodoro; Lin, Jiandie D

    2009-03-01

    Plasma homocysteine (Hcy) is an independent risk factor for cardiovascular disease. Hcy is a nonprotein amino acid derivative that is generated from the methionine cycle, which provides the methyl group for essentially all biological methylation reactions. Although plasma Hcy levels are elevated in patients with cardiovascular disease, the mechanisms that regulate Hcy homeostasis remain poorly defined. In this study, we found that the expression of key enzymes involved in Hcy metabolism is induced in the liver in response to fasting. This induction coincides with increased expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha, a transcriptional coactivator that regulates hepatic gluconeogenesis and mitochondrial function. PGC-1alpha stimulates the expression of genes involved in Hcy metabolism in cultured primary hepatocytes as well as in the liver. Adenoviral-mediated expression of PGC-1alpha in vivo leads to elevated plasma Hcy levels. In contrast, mice deficient in PGC-1alpha have lower plasma Hcy concentrations. These results define a novel role for the PGC-1alpha coactivator pathway in the regulation of Hcy homeostasis and suggest a potential pathogenic mechanism that contributes to hyperhomocysteinemia.

  3. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha.

    Science.gov (United States)

    Rius, Jordi; Guma, Monica; Schachtrup, Christian; Akassoglou, Katerina; Zinkernagel, Annelies S; Nizet, Victor; Johnson, Randall S; Haddad, Gabriel G; Karin, Michael

    2008-06-05

    The hypoxic response is an ancient stress response triggered by low ambient oxygen (O2) (ref. 1) and controlled by hypoxia-inducible transcription factor-1 (HIF-1), whose alpha subunit is rapidly degraded under normoxia but stabilized when O2-dependent prolyl hydroxylases (PHDs) that target its O2-dependent degradation domain are inhibited. Thus, the amount of HIF-1alpha, which controls genes involved in energy metabolism and angiogenesis, is regulated post-translationally. Another ancient stress response is the innate immune response, regulated by several transcription factors, among which NF-kappaB plays a central role. NF-kappaB activation is controlled by IkappaB kinases (IKK), mainly IKK-beta, needed for phosphorylation-induced degradation of IkappaB inhibitors in response to infection and inflammation. IKK-beta is modestly activated in hypoxic cell cultures when PHDs that attenuate its activation are inhibited. However, defining the relationship between NF-kappaB and HIF-1alpha has proven elusive. Using in vitro systems, it was reported that HIF-1alpha activates NF-kappaB, that NF-kappaB controls HIF-1alpha transcription and that HIF-1alpha activation may be concurrent with inhibition of NF-kappaB. Here we show, with the use of mice lacking IKK-beta in different cell types, that NF-kappaB is a critical transcriptional activator of HIF-1alpha and that basal NF-kappaB activity is required for HIF-1alpha protein accumulation under hypoxia in cultured cells and in the liver and brain of hypoxic animals. IKK-beta deficiency results in defective induction of HIF-1alpha target genes including vascular endothelial growth factor. IKK-beta is also essential for HIF-1alpha accumulation in macrophages experiencing a bacterial infection. Hence, IKK-beta is an important physiological contributor to the hypoxic response, linking it to innate immunity and inflammation.

  4. Myeloid differentiation factor 88 (MyD88-deficiency increases risk of diabetes in mice.

    Directory of Open Access Journals (Sweden)

    Toru Hosoi

    Full Text Available BACKGROUND: Multiple lines of evidence suggest innate immune response pathways to be involved in the development of obesity-associated diabetes although the molecular mechanism underling the disease is unknown. Recent observations suggest that saturated fatty acids can act as a ligand for toll-like receptor (TLR 4, which is thought to mediate obesity-associated insulin resistance. Myeloid differentiation factor 88 (MyD88 is an adapter protein for TLR/IL-1 receptor signaling, which is involved in the activation of inflammatory pathways. To evaluate molecular mechanisms linking obesity-associated diabetes down-stream of TLR4, we investigated physiological role of MyD88 in high-fat diet (HFD-induced obesity. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we found MyD88-deficient mice fed a HFD had increased circulating levels of insulin, leptin and cholesterol, as well as liver dysfunction (increased induction of ALT levels, increased activation of JNK and cleavage of PARP, which were linked to the onset of severe diabetes. On the other hand, TNF-alpha would not be involved in HFD-induced diabetes in MyD88-deficient mice, because TNF-alpha level was attenuated in MyD88-deficient mice fed with HFD. CONCLUSIONS/SIGNIFICANCE: The present finding of an unexpected role for MyD88 in preventing diabetes may provide a potential novel target/strategy for treating metabolic syndrome.

  5. Folding model study of the elastic $\\alpha + \\alpha$ scattering at low energies

    CERN Document Server

    Tan, Ngo Hai; Khoa, Dao T

    2014-01-01

    The folding model analysis of the elastic $\\alpha + \\alpha$ scattering at the incident energies below the reaction threshold of 34.7 MeV (in the lab system) has been done using the well-tested density dependent versions of the M3Y interaction and realistic choices for the $^4$He density. Because the absorption is negligible at the energies below the reaction threshold, we were able to probe the $\\alpha + \\alpha$ optical potential at low energies quite unambiguously and found that the $\\alpha + \\alpha$ overlap density used to construct the density dependence of the M3Y interaction is strongly distorted by the Pauli blocking. This result gives possible explanation of a long-standing inconsistency of the double-folding model in its study of the elastic $\\alpha + \\alpha$ and $\\alpha$-nucleus scattering at low energies using the same realistic density dependent M3Y interaction.

  6. 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...

  7. 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...

  8. The impact of maternal iron deficiency and iron deficiency anemia on child’s health

    OpenAIRE

    Abu-Ouf, Noran M.; Jan, Mohammed M.

    2015-01-01

    Iron deficiency anemia is extremely common, particularly in the developing world, reaching a state of global epidemic. Iron deficiency during pregnancy is one of the leading causes of anemia in infants and young children. Many women go through the entire pregnancy without attaining the minimum required intake of iron. This review aims to determine the impact of maternal iron deficiency and iron deficiency anemia on infants and young children. Extensive literature review revealed that iron def...

  9. Scale setting for alpha_s beyond leading order

    CERN Document Server

    Hornbostel, K; Morningstar, C J

    2003-01-01

    We present a general procedure for incorporating higher-order information into the scale-setting prescription of Brodsky, Lepage and Mackenzie. In particular, we show how to apply this prescription when the leading coefficient or coefficients in a series in the strong coupling alpha_s are anomalously small and the original prescription can give an unphysical scale. We give a general method for computing an optimum scale numerically, within dimensional regularization, and in cases when the coefficients of a series are known. We apply it to the heavy quark mass and energy renormalization in lattice NRQCD, and to a variety of known series. Among the latter, we find significant corrections to the scales for the ratio of e+e- to hadrons over muons, the ratio of the quark pole to MSbar mass, the semi-leptonic B-meson decay width, and the top decay width. Scales for the latter two decay widths, expressed in terms of MSbar masses, increase by factors of five and thirteen, respectively, substantially reducing the size...

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

    CERN Document Server

    Forsberg, U; Andersson, L -L; Di Nitto, A; 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

    2015-01-01

    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 recoil-alpha-fission and five recoil-alpha-alpha-fission events were observed. The latter are similar to four such events reported from experiments performed at the Dubna gas-filled separator. Contrary to their interpretation, we propose an alternative view, namely to assign eight of these eleven decay chains of recoil-alpha(-alpha)-fission type to start from the 3n-evaporation channel 115-288. The other three decay chains remain viable candidates for the 2n-evaporation channel 115-289.

  11. 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

  12. Linearized Bekenstein Varying Alpha Models

    CERN Document Server

    Pina-Avelino, P; Oliveira, J C

    2004-01-01

    We study the simplest class of Bekenstein-type, varying $\\alpha$ models, in which the two available free functions (potential and gauge kinetic function) are Taylor-expanded up to linear order. Any realistic model of this type reduces to a model in this class for a certain time interval around the present day. Nevertheless, we show that no such model is consistent with all existing observational results. We discuss possible implications of these findings, and in particular clarify the ambiguous statement (often found in the literature) that ``the Webb results are inconsistent with Oklo''.

  13. The Alpha Magnetic Spectrometer (AMS)

    Energy Technology Data Exchange (ETDEWEB)

    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. E-mail: contin@bo.infn.it; 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.

    2002-02-01

    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.

  14. 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.

  15. Salivary morning androstenedione and 17alpha-OH progesterone levels in childhood and puberty in patients with classic congenital adrenal hyperplasia

    NARCIS (Netherlands)

    Groot, M.J. de; Pijnenburg-Kleizen, K.J.; Thomas, C.M.G.; Sweep, F.C.; Stikkelbroeck, N.; Otten, B.J.; Claahsen-van der Grinten, H.L.

    2015-01-01

    BACKGROUND: Treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency can be monitored by salivary androstenedione (A-dione) and 17alpha-hydroxyprogesterone (17OHP) levels. There are no objective criteria for setting relevant target values or data on changes of 17OHP and A-dione d

  16. Genetic causes for iron deficiency

    OpenAIRE

    Saad,Sara Teresinha O.

    2010-01-01

    As causas genéticas de deficiência de ferro, real ou funcional, ocorrem por defeitos em muitas proteínas envolvidas na absorção e metabolismo de ferro. Neste capítulo descreveremos sucintamente causas genéticas de carência de ferro para a síntese de hemoglobina, que cursa então com anemia microcítica e hipocrômica. Ressalto que estas são alterações raras, com poucas descrições na literatura. Em alguns casos, o ferro funcional não está disponível para os eritroblastos sintetizarem hemoglobina,...

  17. [Iron deficiency in the elderly].

    Science.gov (United States)

    Helsen, Tuur; Joosten, Etienne

    2016-06-01

    Anemia is a common diagnosis in the geriatric population, especially in institutionalized and hospitalized elderly. Most common etiologies for anemia in elderly people admitted to a geriatric ward are iron-deficiency anemia and anemia associated with chronic disease. Determination of serum ferritin is the most used assay in the differential diagnosis, despite low sensitivity and moderate specificity. New insights into iron homeostasis lead to new diagnostic assays such as serum hepcidin, serum transferrin receptor and reticulocyte hemoglobin equivalent.Importance of proper diagnosis and treatment for this population is large since there is a correlation between anemia and morbidity - mortality. Anemia is usually defined as hemoglobin less than 12 g/dl for women and less than 13 g/dl for men. There is no consensus for which hemoglobinvalue an investigation into underlying pathology is obligatory. This needs to be evaluated depending on functional condition of the patient.

  18. Photodissociation of neutron deficient nuclei

    Energy Technology Data Exchange (ETDEWEB)

    Sonnabend, K.; Babilon, M.; Hasper, J.; Mueller, S.; Zarza, M.; Zilges, A. [TU Darmstadt, Institut fuer Kernphysik, Darmstadt (Germany)

    2006-03-15

    The knowledge of the cross sections for photodissociation reactions like e.g. ({gamma}, n) of neutron deficient nuclei is of crucial interest for network calculations predicting the abundances of the so-called p nuclei. However, only single cross sections have been measured up to now, i.e., one has to rely nearly fully on theoretical predictions. While the cross sections of stable isotopes are accessible by experiments using real photons, the bulk of the involved reactions starts from unstable nuclei. Coulomb dissociation (CD) experiments in inverse kinematics might be a key to expand the experimental database for p-process network calculations. The approach to test the accuracy of the CD method is explained. (orig.)

  19. [delta-Aminolevulinate dehydratase deficiency].

    Science.gov (United States)

    Fujita, H; Ishida, N; Akagi, R

    1995-06-01

    delta-Aminolevulinate dehydratase (ALAD: E. C. 4.2.1.24), the second enzyme in the heme biosynthetic pathway, condenses two moles of delta-aminolevulinic acid to form porphobilinogen. ALAD deficiency is well known to develop signs and symptoms of typical hepatic porphyria, and classified into three categories as follows: (i) ALAD porphyria, a genetic defect of the enzyme, (ii) tyrosinemia type I, a genetic defect of fumarylacetoacetase in the tyrosine catabolic pathway, producing succinylacetone (a potent inhibitor of ALAD), and (iii) ALAD inhibition by environmental hazards, such as lead, trichloroethylene, and styrene. In the present article, we will describe molecular and biochemical mechanisms to cause the enzyme defect to discuss the significance of ALAD defect on human health.

  20. B12 Deficiency with Children

    Directory of Open Access Journals (Sweden)

    Selahattin Katar

    2007-01-01

    Full Text Available Aim of the study: to rewieved the clinical and laboratory properties of seven cases with megaloblastic anemia. Clinical and laboratory findings of seven cases with megaloblastic anemia are described. İt is determined that all of the patients received little or no animal products by nutritional history. Clinically apatite, malasia, headeche, otism, and parestheia in the lower extremities and foods were present in patients. On physical examination; four patients had glossit, four had hyporeflexia, one had ataxia. Folat level was normal and B12 vitamin level was low in all patients. The MCV (mean corpuscular volume was normal in three patients. Hypersegmentation of neutrophil was observed in all patients, leukopenia in two, and trombocytopenia was observed in one patient.Conclusion: it is suggested B12 vitamin deficiency in the patients that received little or no animal products by nutritional history. However, hypersegmentation of neutrophil in peripheral blood sample is an important finding for diagnosis of megaloblastic anemia.