MedWorm: Alpha-1 Antitrypsin Deficiency

Potential New Approach For Treating Graft-Versus-Host-Disease Provided By Natural Enzyme

Health News from Medical News Today — Thu, 19 Jan 2012 08:00:00 +0100

A natural enzyme derived from human blood plasma showed potential in significantly reducing the effects of graft-vs.-host disease, a common and deadly side effect of lifesaving bone marrow transplants. Researchers from the University of Michigan Comprehensive Cancer Center looked at the drug alpha-1-antitrypsin, which is approved by the U.S. Food and Drug Administration for use in people who have a genetic mutation that makes them deficient in a certain enzyme. This drug has been used in many of these patients over extended periods of time and is known to cause minimal side effects... (Source: Health News from Medical News Today)

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How to investigate mildly elevated liver transaminase levels

Clinical Cases and Images — Tue, 17 Jan 2012 13:39:00 +0100

Mild elevations in the liver enzymes alanine transaminase (ALT) and aspartate transaminase (AST) are commonly found in asymptomatic patients. The most common cause is nonalcoholic fatty liver disease (sometimes called nonalcoholic steatohepatitis or NASH), which can affect up to 30% of the U.S. population. Other common liver causes include: - alcoholic liver disease - medication-associated liver injury - viral hepatitis (hepatitis B and C) - hemochromatosis Pale stool and dark urine (click to enlarge the images). This is an example of "obstructive" jaundice with the classic constellation of tea-colored urine and clay-colored stool. Less common liver causes include: - alpha-1-antitrypsin deficiency (AAT) - autoimmune hepatitis - Wilson disease Extrahepatic conditions can also caus...

In vitro and in vivo evidence for the role of elastase shedding of CD163 in human atherothrombosis

European Heart Journal — Sat, 14 Jan 2012 05:00:00 +0100

Conclusion Our results suggest that neutrophil elastase promotes CD163 shedding, resulting in a decreased clearance of Hb by macrophages, which may favour plaque destabilization. This may be reflected by increased plasma levels of sCD163 and elastase/α1-AT complexes which are positively correlated in patients with coronary artery disease. (Source: European Heart Journal)

Alpha-1-antitrypsin monotherapy reduces graft-versus-host disease after experimental allogeneic bone marrow transplantation [Medical Sciences]

Proceedings of the National Academy of Sciences — Tue, 10 Jan 2012 05:00:00 +0100

Acute graft-versus-host disease (GvHD) is a major complication that prevents successful outcomes after allogeneic bone marrow transplantation (BMT), an effective therapy for hematological malignancies. Several studies demonstrate that donor T cells and host antigen-presenting cells along with several proinflammatory cytokines are required for the induction of GvHD and contribute to its severity. Increasing evidence demonstrates that human serum-derived αalpha-1- anti-trypsin (AAT) reduces production of proinflammatory cytokines, induces anti-inflammatory cytokines, and interferes with maturation of dendritic cells. Using well-characterized mouse models of BMT, we have studied the effects of AAT on GvHD severity. Administration of AAT early after BMT decreased mortality in three models of ...

Effect of cigarette smoke exposure and structural modifications on the alpha-1 antitrypsin interaction with caspases.

Molecular Medicine — Tue, 10 Jan 2012 05:00:00 +0100

We reported that A1AT protects lung endothelial cells from apoptosis and inhibits caspase-3 activity. It is not clear if cigarette smoking or A1AT mutations alter the caspase-3 inhibitory activity of A1AT and if this serpin alters the function of other caspases. We tested the hypothesis that the caspase-3 inhibitory activity of A1AT is impaired by cigarette smoking and that the A1AT reactive center loop, the key anti-protease domain of the serpin, is required for its interaction with caspase. We examined the caspase-3 inhibitory activity of human A1AT purified from plasma of actively smoking and non-smoking individuals, either affected or unaffected with COPD. We also tested the caspase inhibitory activity of two mutant forms of A1AT, the recombinant human piZZ and the reactive center loop...

Which Pulmonary Function Tests Best Differentiate Between COPD Phenotypes?

Respiratory Care — Sun, 01 Jan 2012 05:00:00 +0100

Authors: Salzman SH Abstract We are still at the early phase of finding useful phenotypes in COPD that can guide therapy. However, in a simple sense, "sick patients die." Many phenotypic measurements of severity correlate with mortality in COPD: FEV(1), the ratio of inspiratory capacity to total lung capacity (IC/TLC), diffusing capacity of the lung for carbon monoxide (D(LCO)), 6-min walk distance, and maximum oxygen (O(2)) consumption or maximum watts on exercise testing. However, composite parameters, such as the BODE index (body mass index, air flow obstruction, dyspnea, exercise capacity), perform better, likely because they capture different aspects of severity that affect functional impairment and risk of death. Bronchodilator responsiveness is just a relative feature that a...

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Biomarker analysis of Morquio syndrome: Identification of disease state and drug responsive markers

Orphanet Journal of Rare Diseases — Fri, 16 Dec 2011 05:00:00 +0100

Conclusions: Candidate biomarkers alpha-1-antitrypsin, lipoprotein (a), and serum amyloid P may be suitable markers, in addition to urinary KS, to follow the response to ERT in MPS VIA patients. (Source: Orphanet Journal of Rare Diseases)

Probable Dalteparin-Induced Hepatotoxicity in a Man With Alpha-1-Antitrypsin Deficiency.

The Journal of Clinical Pharmacology — Tue, 13 Dec 2011 05:00:00 +0100

Authors: Levinson P, Glaumann H, Söderberg M PMID: 22167567 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)

Alpha-1 Antitrypsin Production by Pro- and Anti-Inflammatory Macrophages and Dendritic Cells.

Am J Respir Cell Mol... — Thu, 08 Dec 2011 05:00:00 +0100

Authors: van 't Wout EF, van Schadewijk A, Savage ND, Stolk J, Hiemstra PS Abstract Alpha-1 antitrypsin (AAT) acts as an important neutrophil elastase inhibitor in the lung. Although the hepatocyte is considered as the primary source of AAT, local production by monocytes, macrophages and epithelial cells may contribute to the formation of an anti-elastase screen. Since monocytes can differentiate into a heterogeneous population of macrophages with subpopulations ranging from pro-inflammatory properties (MΦ-1) to anti-inflammatory properties (MΦ-2) and into dendritic cells (DC), we studied whether lipopolysaccharide (LPS), tumor necrosis factor alpha (TNFα) and oncostatin M (OSM) enhance AAT production differentially in cultured MΦ-1, MΦ-2 and DC. Monocytes from healthy blood d...

SERPINE2 haplotype as a risk factor for panlobular type of emphysema

BMC Medical Genetics - Latest articles — Wed, 07 Dec 2011 05:00:00 +0100

Conclusions: Our results support the previously found association between SERPINE2 polymorphisms and pulmonary emphysema. As a novel finding, our study suggests that the SERPINE2 gene may in particular be involved in the development of panlobular changes, i.e., the same type of changes that are involved in alpha-1-antitrypsin (AAT) -deficiency. (Source: BMC Medical Genetics - Latest articles)

[Role of autophagy in the pathogenesis of liver diseases].

Orvosi Hetilap — Sun, 04 Dec 2011 05:00:00 +0100

Authors: Werling K Abstract Autophagy is a self-digestion process that plays an important role in the development, differentiation and homeostasis of cells, helping their survival during starvation and hypoxia. Accumulated mutant proteins in the endoplasmic reticulum can be degraded by autophagy in alpha-1 antitrypsin deficiency. Hepatitis C and B virus may exploit the autophagy pathway to escape the innate immune response and to promote their own replication. Autophagy is decreased in response to chronic alcohol consumption, likely due to a decrease in 5'-adenosine monophosphate-activated protein kinase, increase in mTOR activity and due to an alteration in vesicle transport in hepatocytes. In obesity and alcoholic liver disease the decreased function of autophagy causes formation...

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Cytokeratin-18 and hyaluronic acid levels predict liver fibrosis in children with non-alcoholic fatty liver disease.

Acta Biochim Pol — Sat, 03 Dec 2011 05:00:00 +0100

Conclusions: Cytokeratin-18 and hyaluronic acid are suitable serum markers predicting liver fibrosis in children with NAFLD. Studying these markers may identify patients at risk of disease progression. PMID: 22140659 [PubMed - as supplied by publisher] (Source: Acta Biochim Pol)

Relation of functional characteristics and serum alpha-1-antitrypsin (AAT) concentration in patients with PiMM phenotype and chronic obstructive pulmonary disease (COPD).

European Journal of Internal Medicine — Wed, 16 Nov 2011 17:59:58 +0100

CONCLUSION: All of the investigated patients with severe COPD were MM type homozygotes with normal plasma level of AAT. There was no significant correlation between the phenotype and severity of COPD. We did not find significant relation of plasma AAT level and lung function impairment. PMID: 22075288 [PubMed - in process] (Source: European Journal of Internal Medicine)

Primary Yolk Sac Tumor of the Urachus

International Journal of Surgical Pathology — Tue, 15 Nov 2011 05:00:00 +0100

Conclusion. An unusual case of a YST in the urachus is presented. This is the first reported adult case based on the authors’ bibliographic search. (Source: International Journal of Surgical Pathology)

A novel model and molecular therapy for Z alpha-1 antitrypsin deficiency

Mammalian Genome — Thu, 10 Nov 2011 16:55:15 +0100

Abstract Animal models that closely resemble human disease can present a challenge. Particularly so in alpha-1 antitrypsin deficiency (α1ATD), as the mouse alpha-1 antitrypsin (α1AT) cluster encodes five highly related genes compared with the one in humans. The mouse PI2 homologue is closest to the α1AT human gene. We have changed the equivalent mouse site that results in the Z variant in man (Glu342Lys) and made both the “M” and “Z” mouse PI2 α1AT proteins. We have tested the ability of a small-molecular-weight compound CG to alleviate polymerisation of these mouse α1AT proteins as it has been shown to reduce aggregates of Z α1AT in man. We found that (1) CG specifically reduces the formation of polymers of recombinant mouse “Z” protein but not “M” pro...

Inhibition of IL-32 activation by {alpha}-1 antitrypsin suppresses alloreactivity and increases survival in an allogeneic murine marrow transplantation model

Blood — Thu, 03 Nov 2011 04:00:00 +0100

Interleukin (IL)–32 was originally identified in natural killer cells and IL-2–activated human T lymphocytes. As T cells are activated in allogeneic transplantation, we determined the role of IL-32 in human mixed lymphocyte cultures (MLCs) and GVHD. In allogeneic MLCs, IL-32 increased two-fold in responding T cells, accompanied by five-fold increases of TNFα, IL-6, and IL-8. After allogeneic hematopoietic cell transplantation, IL-32 mRNA levels in blood leukocytes were statistically significantly higher in patients with acute GVHD (n = 10) than in serial samples from patients who did not develop acute GVHD (n = 5; P = .02). No significant changes in IL-32 levels were present in patients with treated (n = 14) or untreated (n = 8) chronic GVHD, compared with healthy control...

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Correspondence between salivary proteomic pattern and clinical course in primary Sjogren syndrome and non-Hodgkin's lymphoma: a case report

Journal of Translational Medicine — Wed, 02 Nov 2011 04:00:00 +0100

Conclusion: This study suggests that clinical and functional changes of the salivary glands driven by autoimmune and lymphoproliferative processes might be reflected in patients' whole saliva proteins, shedding new light on the potential usefulness of salivary proteomic analysis in the identification of prognostic and therapeutic biomarkers for patients with pSS and non Hodgkin's lymphomas. (Source: Journal of Translational Medicine)

A quantitative method for detection of spliced X-box binding protein-1 (XBP1) mRNA as a measure of endoplasmic reticulum (ER) stress.

Cell Stress and Chaperones — Mon, 31 Oct 2011 04:00:00 +0100

Authors: van Schadewijk A, Van't Wout EF, Stolk J, Hiemstra PS Abstract Endoplasmic reticulum (ER) stress is increasingly recognized as an important mechanism in a wide range of diseases including cystic fibrosis, alpha-1 antitrypsin deficiency, Parkinson's and Alzheimer's disease. Therefore, there is an increased need for reliable and quantitative markers for detection of ER stress in human tissues and cells. Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum can cause ER stress, which leads to the activation of the unfolded protein response (UPR). UPR signaling involves splicing of X-box binding protein-1 (XBP1) mRNA, which is frequently used as a marker for ER stress. In most studies, the splicing of the XBP1 mRNA is visualized by gel electrophoresis whi...

Altered proteomic pattern in platelets of rats with sepsis.

Blood Cells, Molecules and Diseases — Tue, 18 Oct 2011 04:00:00 +0100

Authors: Hu JY, Li CL, Wang YW Abstract Platelet dysfunction and thrombocytopenia are common responses to sepsis, but how sepsis changes platelet function is not completely understood. This is due, in part, to our lack of understanding of how sepsis alters platelet protein patterns. The aim of the present study, accordingly, was to investigate the response of the platelet proteome to sepsis. We applied proteomic technology to analyze platelet samples of rats with sepsis. Rats were divided into two groups: 1) sham surgery and 2) sepsis induced by cecal ligation and puncture (CLP) surgery. Platelet samples were collected from surviving rats 12 and 24h after surgery, and platelet proteins were separated by two-dimensional electrophoresis (2-DE). Differentially expressed proteins were ...

HNF1alpha inhibition triggers epithelial-mesenchymal transition in human liver cancer cell lines

BMC Cancer — Wed, 05 Oct 2011 04:00:00 +0100

Conclusion: Our results suggest that HNF1alpha is not only important for hepatocyte differentiation, but has also a role in the maintenance of epithelial phenotype of hepatocytes. (Source: BMC Cancer)

Identification of Compound Heterozygous Mutation in a Korean Patient with Alpha 1-antitrypsin Deficiency.

The Korean Journal of Laboratory Medicine — Sat, 01 Oct 2011 04:00:00 +0100

Authors: Ko DH, Chang HE, Song SH, Yoon H, Park KU, Song J Abstract Alpha 1-antitrypsin (AAT) deficiency is a genetic disorder that primarily affects the lungs and liver. While AAT deficiency is one of the most common genetic disorders in the Caucasian population, it is extremely rare in Asians. Here, we report the case of a 36-year-old Korean woman with AAT deficiency who visited the emergency department of our hospital for the treatment of progressive dyspnea that had begun 10 years ago. She had never smoked. Chest computed tomography revealed panlobular emphysema in both lungs, which suggested AAT deficiency. The serum AAT level was 33 mg/dL (reference interval: 90-200 mg/dL). Four exons of the SERPINA1 gene, which is responsible for AAT deficiency, and their flanking regions we...

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A Review of Alpha-1 Antitrypsin Deficiency.

American Journal of Respiratory and Critical Care Medicine — Thu, 29 Sep 2011 04:00:00 +0100

Authors: Stoller JK, Aboussouan LS Abstract Alpha-1 antitrypsin (AAT) deficiency is an under-recognized genetic condition, which affects approximately 1 in 2000 to 1 in 5000 individuals and predisposes to liver disease and early-onset emphysema. AAT is mainly produced in the liver and functions to protect the lung against proteolytic damage, e.g., from neutrophil elastase. Among the approximately 120 variant alleles described to date, the Z allele is most commonly responsible for severe deficiency and disease. Z-type AAT molecules polymerize within the hepatocyte, precluding secretion into the blood and causing low serum AAT levels (~3-7 micromolar with normal serum levels 20-53 micromolar). A serum AAT level of 11 micromolar represents the protective threshold value below which th...

The Use of Oral Budesonide in Adolescents and Adults With Protein-Losing Enteropathy After the Fontan Operation [ORIGINAL ARTICLES: PEDIATRIC CARDIAC]

The Annals of Thoracic Surgery — Wed, 28 Sep 2011 04:00:00 +0100

Conclusions CR-budesonide can be used to treat PLE in certain patients, but careful assessment of hepatic function should be performed before initiation of therapy as systemic side effects can limit treatment. Normal serum liver function tests do not preclude hepatic dysfunction in the Fontan patient, and it is important to perform radiographic assessments as well. (Source: The Annals of Thoracic Surgery)

Mice deficient in LMAN1 exhibit FV and FVIII deficiencies and liver accumulation of {alpha}1-antitrypsin

Blood — Thu, 22 Sep 2011 04:00:00 +0100

The type 1-transmembrane protein LMAN1 (ERGIC-53) forms a complex with the soluble protein MCFD2 and cycles between the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment (ERGIC). Mutations in either LMAN1 or MCFD2 cause the combined deficiency of factor V (FV) and factor VIII (FVIII; F5F8D), suggesting an ER-to-Golgi cargo receptor function for the LMAN1-MCFD2 complex. Here we report the analysis of LMAN1-deficient mice. Levels of plasma FV and FVIII, and platelet FV, are all reduced to ~ 50% of wild-type in Lman1–/– mice, compared with the 5%-30% levels typically observed in human F5F8D patients. Despite previous reports identifying cathepsin C, cathepsin Z, and α1-antitrypsin as additional potential cargoes for LMAN1, no differences were observed betw...

Impact of non-linear smoking effects on the identification of gene-by-smoking interactions in COPD genetics studies

Thorax — Tue, 20 Sep 2011 04:00:00 +0100

Conclusion In study samples of subjects with a wide range of COPD severity, a non-linear relationship between pack-years of smoking and FEV1 is likely. In this setting, approaches that account for this non-linearity can be more powerful and less biased than the more common approach of using total pack-years to model the smoking effect. (Source: Thorax)

Polymorphisms of hemochromatosis, and alpha-1 antitrypsin genes in Egyptian HCV patients with and without hepatocellular carcinoma.

Gene — Thu, 08 Sep 2011 04:00:00 +0100

Authors: Gharib AF, Karam RA, Pasha HF, Radwan MI, Elsawy WH Abstract Hereditary hemochromatosis and alpha-1antitrypsin deficiency are genetic diseases characterized by endoplasmic reticulum (ER) stress with subsequent development of liver disease. Our aim was to estimate the frequency of hemochromatosis gene (HFE) mutant alleles (C282Y and H63D) and alpha-1 antitrypsin S/Z variants among Egyptian HCV cirrhotic patients and in hepatocellular carcinoma patients and to evaluate their effects on disease progression. HFE and alpha-1 antitrypsin polymorphisms were characterized in 200 Egyptian patients with HCV infection (100 patients complicated with cirrhosis, 100 patients with HCC) and 100 healthy subjects who had no history of any malignancy. The frequencies of HD genotype of H63D m...

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ANCA-associated vasculitis is linked to carriage of the Z allele of {alpha}1 antitrypsin and its polymers

Annals of the Rheumatic Diseases — Mon, 05 Sep 2011 04:00:00 +0100

Conclusions The Z but not the S deficiency allele is associated with AAV. Polymers of α1AT are present in the serum and glomeruli of at least some patients with the Z allele, which may promote inflammation through priming of neutrophils. (Source: Annals of the Rheumatic Diseases)

What Causes Coughs?

PediatricEducation.org — Mon, 05 Sep 2011 00:22:52 +0100

Discussion “A cough is a voluntary or involuntary explosive expiration. After a deep inspiration, the glottis is closed and the expiratory muscles contract, compressing the lung and raising intrapulmonary pressure above the atmospheric pressure. The glottis then opens, and gas is expelled at a rapid rate.” Acute coughs are commonly due to upper respiratory tract diseases in children of all ages – often because of post-nasal rhinorrhea. Chronic coughs may be more difficult to determine the cause of and may require more investigation, consultation, and/or empiric trials of medication including radiographic imaging of chest or sinuses, spirotometry, sweat chloride, methacholine challenge, bronchoscopy, gastroscopy, immunodeficiency testing, etc. Children with congenital abn...

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

Annales de Biologie Clinique — Thu, 01 Sep 2011 04:00:00 +0100

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. PMID: 22008137 [PubMed - in process] (Source: Annales de Biologie Clinique)

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

Respiratory Medicine — Mon, 29 Aug 2011 04:00:00 +0100

Conclusions: AAT in EBC was detectable and quantifiable. AAT measured in EBC was significantly increased during exacerbations of COPD and can potentially be used as a biomarker in exacerbations. (Source: Respiratory Medicine)

Combination therapy utilizing shRNA knockdown and an optimized resistant transgene for rescue of diseases caused by misfolded proteins [Medical Sciences]

Proceedings of the National Academy of Sciences — Mon, 22 Aug 2011 23:00:00 +0100

In this study we used alpha-1 antitrypsin (AAT) deficiency with the piZZ mutant phenotype as a model system to evaluate the efficiency of gene-delivery approaches that both silence the piZZ transcript (e.g., shRNA) and restore circulating wild-type AAT expression from resistant codon-optimized AAT (AAT-opt) transgene cassette using adeno-associated virus (AAV) vector delivery. After systemic injection of a self-complimentary AAV serotype 8 (scAAV8) vector encoding shRNA in piZZ transgenic mice, both mutant AAT mRNA in the liver and defected serum protein level were inhibited by 95%, whereas liver pathology, as monitored by dPAS and fibrosis staining, reversed. To restore blood AAT levels in AAV8/shRNA-treated mice, several strategies to restore functional AAT levels were tested, including ...

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Alpha 1 antitrypsin phenotypes and obstructive airway disease in subjects over 65 years of age: QUID R Cohort

Age and Ageing — Wed, 10 Aug 2011 23:00:00 +0100

(Source: Age and Ageing)

Kamada Was Granted New Orphan Drug Designation by the FDA, for the Treatment of Type 1 Diabetes

Pharmaceutical Online News — Thu, 04 Aug 2011 13:00:00 +0100

Kamada LTD., a bio-pharmaceutical company engaged in the development, manufacturing and marketing of specialty life-saving therapeutics, was granted an Orphan Drug Designation for its Alpha-1 Antitrypsin (AAT) product to treat type 1 diabetes. Kamada is currently undergoing a Phase I/II clinical trial with its FDA approved AAT by IV route of administration, for the treatment of type 1 diabetes, also known as juvenile diabetes. Kamada plans to publish an interim and/or the final reports (Source: Pharmaceutical Online News)

Role of Malectin in Glc2Man9GlcNAc2-dependent quality control of {alpha}1-antitrypsin.

Mol Biol Cell — Tue, 02 Aug 2011 23:00:00 +0100

Authors: Chen Y, Hu D, Yabe R, Tateno H, Qin SY, Matsumoto N, Hirabayashi J, Yamamoto K Abstract Malectin was first discovered as a novel endoplasmic reticulum (ER)-resident lectin from Xenopus laevis that exhibits structural similarity to bacterial glycosylhydrolases (Mol. Biol. Cell 19, 3404-3414, 2008). Like other intracellular lectins involved in glycoprotein quality control, malectin was found to be highly conserved in animals. Here, results from in vitro membrane-based binding assays and frontal affinity chromatography confirmed that human malectin binds specifically to Glc(2)Man(9)GlcNAc(2) (G2M9) N-glycan, with a K(a) of 1.97 × 10(5) M(-1), whereas binding to Glc(1)Man(9)GlcNAc(2) (G1M9), Glc(3)Man(9)GlcNAc(2) (G3M9) and other N-glycans was barely detectable. Metabolic lab...

Neutrophil Elastase Regulator Needed in Systemic SclerosisNeutrophil Elastase Regulator Needed in Systemic Sclerosis

Medscape Today Headlines — Tue, 02 Aug 2011 18:10:41 +0100

Patients with SSc have normal amounts of serum neutrophil elastase, but low levels of alpha-1-antitrypsin lead to excess elastase activity. This might be treatable. Medscape Medical News (Source: Medscape Today Headlines)

Simultaneous Phenotyping and Quantification of {alpha}-1-Antitrypsin by Liquid Chromatography-Tandem Mass Spectrometry [Proteomics and Protein Markers]

Clinical Chemistry — Wed, 27 Jul 2011 23:00:00 +0100

CONCLUSIONS: The LC-MS/MS method correlates well with current phenotyping and nephelometric assays and has the potential to improve the laboratory diagnosis of genetic A1AT deficiency. (Source: Clinical Chemistry)

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Factors Associated with the Evolution of Lung Function in Patients With Alpha-1 Antitrypsin Deficiency in the Spanish Registry.

Archivos de Bronconeumologia — Mon, 25 Jul 2011 23:00:00 +0100

CONCLUSION: Being a smoker or ex-smoker, greater baseline lung function, and low BMI were the main risk factors associated with an accelerated rate of decline in FEV1. This finding warrants the close observation of younger patients with a better-preserved FEV1. PMID: 21798656 [PubMed - as supplied by publisher] (Source: Archivos de Bronconeumologia)

The fibrinogen cleavage product A{alpha}-Val360, a specific marker of neutrophil elastase activity in vivo

Thorax — Tue, 19 Jul 2011 23:00:00 +0100

Conclusions Aα-Val360 represents the first specific footprint of pre-inhibition NE activity and is a potential biomarker of disease activity and progression in subjects with elastase-dependent COPD. Trial registration The EXACTLE study was registered in ClinicalTrials.gov as ‘Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients’; ClinicalTrials.gov Identifier: NCT00263887. (Source: Thorax)

The prevalence of alpha-1 antitrypsin deficiency in Ireland.

BioMed Central — Tue, 12 Jul 2011 23:00:00 +0100

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. (Source: BioMed Central)

The IDDEA project: a strategy for the detection of alpha-1 antitrypsin deficiency in COPD patients in the primary care setting

Therapeutic Advances in Respiratory Disease — Mon, 04 Jul 2011 04:00:00 +0100

Conclusions: Results confirm that ATT deficiency is still underdiagnosed. The IDDEA system appears to be a useful tool for the detection of AAT deficiency in the primary care setting. (Source: Therapeutic Advances in Respiratory Disease)

Differences in acute lung response to elastase instillation in two rodent species may determine differences in severity of emphysema development

AJP: Regulatory, Integrative and Comparative Physiology — Thu, 30 Jun 2011 23:00:00 +0100

In conclusion, several components of the initial lung response showed species differences. Cytokine release pattern and functional inhibition of α1-AT were the most significant components differing among species and could account for differences in susceptibility to elastase. (Source: AJP: Regulatory, Integrative and Comparative Physiology)

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Acquired alpha 1-antitrypsin deficiency in tropical pulmonary eosinophilia.

The Indian Journal of Medical Research — Thu, 30 Jun 2011 23:00:00 +0100

In this study, we have done Pi (Protease inhibitor) phenotyping to investigate the possibility of association of any heterozygous (or homozygous) α1-AT deficiency in patients with TPE. Methods: Serum a1antitrypsin (α1-AT) was measured in 103 patients (Group A) with TPE, 99 patients with pulmonary eosinophilia who had associated intestinal worm infestation (Group B) and 43 healthy volunteers who served as controls. In 19 α1-AT deficient patients (9 of Group A and 10 of Group B), α1-AT level was measured before and after treatment. In 58 patients with TPE and in 5 controls, phenotyping was done. Results : Fifteen patients of Group A and 16 from Group B showed intermediate α1-AT deficiency (150 mg % or less. None of the control subjects had α1-AT deficiency (<200 mg%). After treatmen...

The use of SDS-PAGE scanning of spent dialysate to assess uraemic toxin removal by dialysis

Nephrology Dialysis Transplantation — Sun, 26 Jun 2011 23:00:00 +0100

Conclusions. SDS–PAGE scanning provided a good characterization of protein patterns in the spent dialysate; it extended and agreed with protein determinations and allowed a better assessment of dialyser performance in removing 10 to 80 kDa molecular weight substances. It also identified differences between the three mainly filtrating polysulfone dialysers that were not detected with blood measurements. (Source: Nephrology Dialysis Transplantation)

Dilatation of the ascending aorta and serum alpha 1-antitrypsin level in patients with bicuspid aortic valve

Heart and Vessels — Wed, 22 Jun 2011 15:59:19 +0100

This study sought to examine the relationship between proximal aortic dilatation and matrix metalloproteinase-9 (MMP-9) and alpha 1-antitrypsin (α1AT) levels in patients with BAV. All patients underwent echocardiography using a standard protocol, and aortic measurements were taken in end-diastole. We studied 82 patients with BAV and categorized them into two groups according to aortic dimensions corrected for body surface area and age. The plasma level of α1AT was routinely determined using a BN ProSpec analyzer (Siemens Healthcare Diagnostics, Marburg, Germany), and that of MMP-9 were determined by ELISA (RayBiotech Inc. Norcross, GA, USA). Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS; SPSS Inc., Chicago, IL, USA) software for Windows...

Severe ulcerative panniculitis caused by alpha 1-antitrypsin deficiency: Remission induced and maintained with intravenous alpha 1-antitrypsin

Journal of the American Academy of Dermatology — Sat, 18 Jun 2011 16:31:42 +0100

We present a case of a boy who developed extremely tender and debilitating recalcitrant panniculitis secondary to PiZZ phenotype A1AT deficiency requiring regular intravenous infusions of A1AT enzymes (Prolastin; Talecris Biotherapeutics, Research Triangle Park, NC) to maintain remission. (Source: Journal of the American Academy of Dermatology)

Human neutrophil chemotaxis regulation by {alpha}-1 antitrypsin

Thorax — Tue, 14 Jun 2011 23:00:00 +0100

α-1 Antitrypsin (AAT) has anti-inflammatory roles beyond regulation of proteases. Chronic lung disease in α-1 antitrypsin deficiency (AATD) is characterised by neutrophilic inflammation. This series of experiments investigated the effects of AAT on neutrophil chemotaxis by comparing neutrophils from patients with AATD with controls, both in vitro and in vivo. Chemotaxis to both IL-8 and soluble immune complexes was increased in neutrophils from AATD patients when compared with controls, but chemotaxis was inhibited by exogenous AAT, with a dose–response effect. Similarly, in vivo, the increased chemotaxis of neutrophils from patients with AATD was normalised when they were treated with AAT augmentation therapy. To investigate the mechanism behind this, further experiments...

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Significance of Circulating Hepatocyte Growth Factor in Protein-Losing Enteropathy After Fontan Operation

Pediatric Cardiology — Sat, 11 Jun 2011 06:04:22 +0100

Abstract The purpose of this study was to measure serum hepatocyte growth factor (HGF) and elucidate the relationship between HGF and protein-losing enteropathy (PLE) after Fontan operation (FO). Ten patients with PLE (mean age 15.7 ± 8.7 years) who underwent FO were enrolled. Control group 1 comprised 20 patients without PLE after FO, and control group 2 comprised 10 patients with nephrotic syndrome (NS). Serum HGF, vascular endothelial growth factor, albumin, and random stool alpha-1 antitrypsin concentration were measured. Transthoracic echocardiography was completed. Serum HGF level was significantly greater in the PLE patients (0.61 ± 0.27 ng/ml) after FO than in the two control groups (0.41 ± 0.12 ng/ml [P = 0....

Safe drugs to fight mutant protein overload and alpha-1-antitrypsin deficiency

Journal of Hepatology — Fri, 10 Jun 2011 04:00:00 +0100

We read with interest the commentary, “Drug enhanced autophagy to fight mutant protein overload”, by Mehrpour and Codogno . The authors discuss recent experimental findings by Hidvegi et al., in a in vitro and in an animal model of alpha-1-antitrypsin (AT) deficiency, which raise the interesting possibility that the iminostilbene derivative carbamazepine (CBZ) could be used to treat this severe liver disease in humans . The authors correctly conclude that these findings have provided the rationale for studies on CBZ in patients with AT deficiency . However, in our opinion, they overlooked that at least one crucial, open question remains to be clarified, before application of these findings in clinical practice. This concerns the fact that in the preclinical mouse model of AT deficiency...

Alpha-1-antitrypsin gene delivery reduces inflammation, increases T-regulatory cell population size and prevents islet allograft rejection.

Molecular Medicine — Tue, 07 Jun 2011 23:00:00 +0100

Authors: Galit S, Hadas M, Eyal O, Mark M, Avishag A, Lewis EC Anti-inflammatory clinical-grade, plasma-derived human alpha-1 antitrypsin (hAAT) protects islets from allorejection, as well as from autoimmune destruction. hAAT was also shown to interfere with disease progression in experimental autoimmune encephalomyelitis (EAE) and in collagen-induced arthritis (CIA) mouse models. hAAT increases IL-1 receptor antagonist expression in human mononuclear cells, and T-regulatory cell population size in animal models. Clinical-grade hAAT contains plasma impurities, multiple hAAT isoforms and various states of inactive hAAT. We thus wished to establish islet-protective activities and effect on Tregs of plasmid-derived circulating hAAT in whole animals. The previously reported plasmid, pEF-hA...

Alpha-1 antitrypsin is a potential biomarker for hepatitis B

BioMed Central — Sat, 04 Jun 2011 23:00:00 +0100

Conclusion: These results suggest the possibility of AAT as a potential biomarker for hepatitis B in diagnosis. (Source: BioMed Central)

Proteomic analysis of peritoneal fluid of patients treated by peritoneal dialysis: effect of glucose concentration

Nephrology Dialysis Transplantation — Thu, 02 Jun 2011 23:00:00 +0100

Conclusions. This study provides a possible platform for future diagnostic and therapeutic applications in the field of PD and allowed the identification of potential targets to be used in preventing inflammatory processes induced by the exposure to dialysis solutions. (Source: Nephrology Dialysis Transplantation)

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Protease activity in the multi-layered intra-luminal thrombus of abdominal aortic aneurysms

Atherosclerosis — Wed, 01 Jun 2011 04:00:00 +0100

Conclusions: In AAA thick ILTs with multiple layers contain substantial amounts of proteases, but their activity is limited to the luminal layer. Proteases in the abluminal layer are mostly inactive, probably due to excess amounts of inhibitors and are consequently unable to directly participate in the pathogenesis of AAA. (Source: Atherosclerosis)

The diagnosis and outcomes of persistent diarrhea in infants aged 0-24 months A Turkish cohort study.

The Turkish Journal of Gastroenterology — Tue, 31 May 2011 23:00:00 +0100

Conclusions: Reviewing the literature, these cases represent the largest non-infectious infantile group of persistent diarrheas. A practical diagnostic algorithm for persistent diarrheas has been constituted. PMID: 21805416 [PubMed - in process] (Source: The Turkish Journal of Gastroenterology)

Respiratory disease registries in Spain: fundamentals and organization.

Archivos de Bronconeumologia — Thu, 19 May 2011 23:00:00 +0100

Authors: Lara B, Morales P, Blanco I, Vendrell M, Monreal M, Orriols R, Isidro I, Abú-Shams K, Escribano P, Villena V, Rodrigo T, García-Yuste M This present paper describes the general characteristics, objectives and organizational aspects of the respiratory disease registries in Spain with the aim to report their activities and increase their diffusion. The document compiles information on the following registries: the Spanish Registry of Patients with Alpha-1 Antitrypsin Deficiency, Spanish Registry of Bronchiectasis, International Registry of Thromboembolic Disease, Spanish Registry of Occupational Diseases, Spanish Registry of Pulmonary Artery Hypertension, Registry of Pleural Mesothelioma, Spanish Registry of Tuberculosis and Spanish Multi-center Study of Neuroendocrine Pulmona...

Alpha-1 antitrypsin inhibits caspase-1 and protects from acute myocardial ischemia–reperfusion injury

Journal of Molecular and Cellular Cardiology — Sun, 15 May 2011 23:00:00 +0100

In conclusion, exogenous administration of clinical grade AAT reduces caspase-1 activity in the ischemic myocardium leading to preservation of viable myocardium and prevention of adverse cardiac remodeling.Research Highlights: ► Alpha 1 anti trypsin is a naturally occurring anti-inflammatory protein inhibiting caspase-1. ► Alpha 1 anti trypsin blunts ischemia–reperfusion driven caspase-1 activation. ► Alpha 1 anti trypsin prevents cell death during acute myocardial infarction. (Source: Journal of Molecular and Cellular Cardiology)

Alpha-1 antitrypsin deficiency

Respiratory Medicine CME — Thu, 05 May 2011 22:58:37 +0100

Discussion and conclusions: AAT deficiency is an autosomal co-dominantly inherited disease which affects the lungs and liver predominantly. The clinical manifestations, prevalence, genetics, molecular pathophysiology, screening and treatment recommendations are summarised in this review. (Source: Respiratory Medicine CME)

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Reversible severe pulmonary hypertension in obesity hypoventilation and Mohr syndrome

Respiratory Medicine CME — Thu, 05 May 2011 22:58:37 +0100

Abstract: A young overweight patient with Mohr–Claussen Syndrome was admitted to our department with the clinical diagnosis of pulmonary hypertension complaining about dyspnea at rest and excessive daytime sleepiness. Pulmonary function testing indicated severe airflow limitation and respiratory insufficiency. Pulmonary artery (PA) pressure was markedly increased. Pulmonary embolism, Alpha-1-antitrypsin-deficiency, emphysema and anatomical obstructions were excluded. Polysomnography showed recurrent oxygen desaturations compatible with alveolar hypoventilations. Hypercapnic ventilatory response testing (HCVR) indicated a missing increase in minute ventilation when exposed to hypercapnia. After 6 weeks of nocturnal non-invasive ventilation therapy, her clinical condition markedly improved...

Site-specific enzymatic polysialylation of therapeutic proteins using bacterial enzymes [Biochemistry]

Proceedings of the National Academy of Sciences — Mon, 02 May 2011 23:00:00 +0100

The posttranslational modification of therapeutic proteins with terminal sialic acids is one means of improving their circulating half-life, thereby improving their efficiency. We have developed a two-step in vitro enzymatic modification of glycoproteins, which has previously only been achieved by chemical means [Gregoriadis G, Jain S, Papaioannou I, Laing P (2005) Int J Pharm 300:125–130). This two-step procedure uses the Campylobacter jejuni Cst-II α2,8-sialyltransferase to provide a primer on N-linked glycans, followed by polysialylation using the Neisseria meningitidis α2,8-polysialyltransferase. Here, we have demonstrated the ability of this system to modify three glycoproteins with varying N-linked glycan compositions: the human therapeutic proteins alpha-1-antitrypsin (A1AT) and...

Autologous Carotid Artery Reconstruction for the Extracranial Internal Carotid Artery Aneurysm in a Patient Combined with Pulmonary Bulla

European Journal of Vascular and Endovascular Surgery — Sun, 24 Apr 2011 23:00:00 +0100

Conclusion: The possibility of a relationship between AEICA and bullous lung disease is discussed about the level of alpha 1-antitrypsin (α1-AT). The using of external carotid artery (ECA) replace of the internal carotid artery (ICA) combined with resection of the AEICA is an autologous reconstruction to restore arterial continuity and avoiding the use of synthetic or vein graft with their potential complications. (Source: European Journal of Vascular and Endovascular Surgery)

Autologous Carotid Artery Reconstruction for the Extracranial Internal Carotid Artery Aneurysm in a Patient Combined with Pulmonary Bulla.

PubMed: Eur J Vasc Endovasc ... — Wed, 20 Apr 2011 23:00:00 +0100

CONCLUSION: The possibility of a relationship between AEICA and bullous lung disease is discussed about the level of alpha 1-antitrypsin (α1-AT). The using of external carotid artery (ECA) replace of the internal carotid artery (ICA) combined with resection of the AEICA is an autologous reconstruction to restore arterial continuity and avoiding the use of synthetic or vein graft with their potential complications. PMID: 21514853 [PubMed - as supplied by publisher] (Source: PubMed: Eur J Vasc Endovasc ...)

Spontaneous hepatic repopulation in transgenic mice expressing mutant human {alpha}1-antitrypsin by wild-type donor hepatocytes

Journal of Clinical Investigation — Wed, 20 Apr 2011 13:52:09 +0100

α1-Antitrypsin deficiency is an inherited condition that causes liver disease and emphysema. The normal function of this protein, which is synthesized by the liver, is to inhibit neutrophil elastase, a protease that degrades connective tissue of the lung. In the classical form of the disease, inefficient secretion of a mutant α1-antitrypsin protein (AAT-Z) results in its accumulation within hepatocytes and reduced protease inhibitor activity, resulting in liver injury and pulmonary emphysema. Because mutant protein accumulation increases hepatocyte cell stress, we investigated whether transplanted hepatocytes expressing wild-type AAT might have a competitive advantage relative to AAT-Z–expressing hepatocytes, using transgenic mice expressing human AAT-Z. Wild-type don...

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SERPINA1 11478G->A variant, serum {alpha}1-antitrypsin, exacerbation frequency and FEV1 decline in COPD

Thorax — Mon, 18 Apr 2011 23:00:00 +0100

Conclusion The 11478G->A α1-antitrypsin polymorphism is not associated with increased risk of developing COPD, nor accelerated lung function decline. Serum α1-antitrypsin may not be upregulated early at COPD exacerbation. In patients with the 11478G->A polymorphism there was no relationship between the serum α1-antitrypsin and serum IL-6 concentrations. (Source: Thorax)

BSA-tetraphenylethene derivative conjugates with aggregation-induced emission properties: Fluorescent probes for label-free and homogeneous detection of protease and [small alpha]1-antitrypsin

RSC - Analyst latest articles — Wed, 13 Apr 2011 23:00:00 +0100

The construction of BSA-tetraphenylethene derivative conjugates are described and used as fluorescent AIE probes for label-free and homogenous detection of protease and [small alpha]1-antitrypsin.Jian-Ping Xu, Yuan Fang, Zhe-Gang Song, Ju Mei, Lan Jia, An Jun Qin, Jing Zhi Sun, Jian Ji, Ben Zhong Tang ( from Analyst) Jian-Ping Xu, Analyst, 2011, DOI: 10.1039/C0AN00813C To cite this article before page numbers are assigned, use the DOI form of citation above. The content of this RSS Feed (c) The Royal Society of Chemistry (Source: RSC - Analyst latest articles)

Is it Asthma, is it Bronchiectasis…or is it an Alpha-1-Antitrypsin Deficiency?

Archivos de Bronconeumologia — Tue, 12 Apr 2011 23:00:00 +0100

Authors: Amaro R, Huerta A, Miravitlles M PMID: 21497005 [PubMed - as supplied by publisher] (Source: Archivos de Bronconeumologia)

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

Orphanet Journal of Rare Diseases — Mon, 11 Apr 2011 23:00:00 +0100

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 (Source: Orphanet Journal of Rare Diseases)

Misclassification of an apparent alpha 1-antitrypsin "Z" deficiency variant by melting analysis.

International Journal of Clinical Chemistry — Thu, 07 Apr 2011 23:00:00 +0100

CONCLUSIONS: Laboratories utilizing melt-curve analysis to diagnose patients should be aware of the potential for false positive results caused by polymorphisms located in the binding region of the genotyping probes. Alternatively, the probes should be designed to be specific to the mutation, rather than to the WT sequence. PMID: 21497588 [PubMed - as supplied by publisher] (Source: International Journal of Clinical Chemistry)

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Diagnosis of Alpha-1 Antitrypsin Deficiency: Limitations of Rapid Diagnostic Laboratory Tests.

Archivos de Bronconeumologia — Sun, 03 Apr 2011 23:00:00 +0100

The objective of this study is to demonstrate the limitations of some laboratory methods used in the study of the deficiency, and which may produce errors in interpretation and detection of uncommon alleles. Two clinical cases are described: the index patient, who had pulmonary emphysema with α1-AT levels less than 12mg/dL, was erroneously classified as a homozygote of the normal allelic variant PI MM using a rapid genotype method; the mother of the patient, asymptomatic, with low levels (60mg/dL), was also classified as PI MM. The gene sequencing classified the index patient as a carrier of the PI Clayton null allele and PI Mmalton deficient. The mother was a PI Clayton/PI heterozygote carrier. These results highlight the difficulties in diagnosing the deficiency, as the well as the need...

Urinary Glycoprotein Biomarker Discovery for Bladder Cancer Detection using LC-MS/MS and Label-free Quantification.

Clinical Cancer Research — Thu, 31 Mar 2011 23:00:00 +0100

CONCLUSIONS: The described strategy can enable higher resolution profiling of the proteome in biological fluids by reducing complexity. Application of glycoprotein enrichment provided novel candidates for further investigation as biomarkers for the non-invasive detection of bladder cancer. PMID: 21459797 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)

Alteration of Elastin Metabolism in Women With Pelvic Organ Prolapse

The Journal of Urology — Fri, 18 Mar 2011 00:00:00 +0100

Conclusions: After menopause increased elastolytic protease has a significant role in the development of pelvic organ prolapse. (Source: The Journal of Urology)

Plasma hepcidin correlates positively with interleukin-6 in patients undergoing pulmonary endarterectomy.

Physiological Research — Mon, 14 Mar 2011 00:00:00 +0100

Authors: Maruna P, Vokurka M, Lindner J Hepcidin, a recently discovered antimicrobial peptide synthesized in the liver, was identified to be the key mediator of iron metabolism and distribution. Despite our knowledge of hepcidin increased in recent years, there are only limited data on hepcidin regulation during systemic inflammatory response in human subjects. In a prospective study, the time course of plasma hepcidin was analyzed in relations to six inflammatory parameters - plasma cytokines and acute-phase proteins in patients undergoing uncomplicated pulmonary endarterectomy. 24 patients, males, age 52.6 +/-10.2 yr., treated with pulmonary endarterectomy in a deep hypothermic circulatory arrest, were enrolled into study. Hepcidin, interleukin (IL)-6, IL-8, tumor necrosis factor-alp...

Alpha 1-antitrypsin retention in an ectopic liver

BioMed Central — Mon, 28 Feb 2011 00:00:00 +0100

Ectopic livers are infrequently reported in the literature. The reported size for ectopic livers range from a few millimeters up to several centimeters. They are often clinically silent and incidentally discovered during imaging of the hepatobiliary tract, regional surgical procedures or autopsy. They are predestined for benign liver diseases otherwise observed in normal livers like fatty change or develop malignancies such as hepatocellular carcinoma, in a manner analogous to the parent orthotopic liver. The presence of abnormal alpha 1-antitrypsin retention in an ectopic liver has, to our knowledge, not been reported in the literature. Hereby, we present the first reported case featuring alpha 1-antitrypsin retention in an ectopic liver attached to the fundus of the gallbladder and prese...

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Lupus protein-losing enteropathy (LUPLE): A systematic review

Rheumatology International — Thu, 24 Feb 2011 00:11:06 +0100

Abstract Lupus protein-losing enteropathy (LUPLE) is a well reported but a rare manifestation of systemic lupus erythematosus (SLE). The main objectives of this study are to raise awareness of LUPLE that can be easily missed by internist, rheumatologist, gastroenterologist and nephrologist, and then to be considered in any patient with unexplained edema, ascites, and hypoalbuminemia. A systematic review was performed with 112 patients who met the eligibility criteria and were critically appraised. The LUPLE was ultimately diagnosed by either Tc-99m albumin scintography (99mTc-HAS) or fecal alpha-1-antitrypsin clearance test. Clinical features of patients, at the time of LUPLE diagnosis, were as follows: age was 34 ± 14.2 years; the female to male ratio was 5...

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

Journal of Translational Medicine — Thu, 24 Feb 2011 00:00:00 +0100

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. (Source: Journal of Translational Medicine)

Vitamin D-binding protein contributes to COPD by activation of alveolar macrophages

Thorax — Fri, 18 Feb 2011 00:00:00 +0100

Conclusions The genetic association of DBP with COPD may be mediated by effects on macrophage activation, since DBP relates to FEV1, and affects macrophage activation. Vitamin D effects may be independent of this, relating more strongly to innate immunity. (Source: Thorax)

Novel peptides as potential treatment of systemic lupus erythematosus.

Lupus — Fri, 18 Feb 2011 00:00:00 +0100

Authors: Shapira I, Proscura E, Brodsky B, Wormser U Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a loss of immunologic tolerance, production of auto-antibodies, and inflammatory damage in multiple organs. We have tested the effect of anti-inflammatory peptide, a H2A histone fragment, termed IIIM1, on MRL/lpr mice, animal model of SLE. Oral administration of IIIM1 at early stage of disease caused reduction in proteinuria and serum anti-dsDNA antibodies. Starting the treatment at advanced stage of disease resulted in prolonged animal survival, decreased lymphadenosis and reduced levels of pathogenic or abnormal double negative CD4(-)CD8(-) cells and B220(+) cells in lymph nodes and spleen. We discovered that IIIM1 induces the production of an additional p...

Kamada Announces Successful Interim Report Of The Phase 2-3 Clinical Trial With Its Inhaled Alpha-1 Antitrypsin

Health News from Medical News Today — Thu, 17 Feb 2011 08:00:00 +0100

Kamada, a bio-pharmaceutical company engaged in the development, manufacturing and marketing of specialty life-saving therapeutics, announced that it received the interim report of its phase 2-3 trial to treat Alpha-1 deficiency with its flag product, Alpha-Antitrypsin, delivered by inhalation. The report, which includes information on 13 months treatment of dozens of patients, shows an excellent safety and tolerability profile... (Source: Health News from Medical News Today)

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Proteomics in sepsis: a pilot study

Revista Brasileira de Terapia Intensiva — Tue, 25 Jan 2011 08:30:52 +0100

This study was aimed to advance the insight into the molecular foundations of sepsis. It employed proteomic techniques to identify and analyze differential serum protein expressions taken from a patient throughout the stages of sepsis (sepsis, severe sepsis and septic shock). Serum samples were collected at each stage of sepsis and submitted to one-dimensional electrophoresis, on gradient strips of immobilized pH, followed by two-dimensional 12.5% polyacrylamide gel electrophoresis. The gels obtained were stained, scanned and analyzed by the ImageMasterPlatinum program. Proteins that were differentially expressed in the gels were excised, digested with trypsin and identified through mass spectrometry. Fourteen differentially expressed proteins were identified throughout the stages of sepsi...

Errata

Revista Brasileira de Terapia Intensiva — Tue, 25 Jan 2011 08:30:52 +0100

Cutoff level to detect heterozygous alpha 1 antitrypsin deficiency in Turkish population

Journal of Clinical Laboratory Analysis — Sat, 01 Jan 2011 00:00:00 +0100

AbstractBackground: Alpha 1 antitrypsin (AT) deficiency is a hereditary disorder leading to the defective defence system against neutrophil elastasis in lung and accumulation of insoluble heterodimer AT molecules in hepatocytes. Knowledge of the prevalence of AT deficiency in each country is important to organize the public health policy. The aim of this study is to determine the prevalence of AT deficiency in Turkish population and to define the cutoff value of AT level in serum to detect heterozygous AT deficient subjects. Materials and Methods: Serum samples from 1,203 healthy blood donors were used, attending the Blood Bank of Hacettepe Medical Faculty. Isoelectric focusing method for determining PIM, PIS, and PIZ alleles and rate immune nephelometry for measuring the level of AT in se...

Impact of a Clinical Decision Support System in an Electronic Health Record to Enhance Detection of Alpha-1 Antitrypsin Deficiency.

Chest — Thu, 30 Dec 2010 00:00:00 +0100

CONCLUSIONS: Issuing an alert within an EHR was associated with a several-fold increased frequency of testing for AAT without a higher rate of diagnosing severe AATD. While the lack of more frequent diagnosis of AATD may reflect a high rate of baseline detection, these results prompt consideration of additional strategies to enhance detection of AATD. PMID: 21193532 [PubMed - as supplied by publisher] (Source: Chest)

Preclinical Evaluation of a Recombinant Adeno-Associated Virus Vector Expressing Human Alpha-1 Antitrypsin Made Using a Recombinant Herpes Simplex Virus Production Method

Human Gene Therapy — Sun, 12 Dec 2010 17:44:35 +0100

Human Gene Therapy , Vol. 0, No. 0. (Source: Human Gene Therapy)

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Talecris Biotherapeutics Enrolls Patients In Clinical Trial Evaluating Two Doses Of PROLASTIN®-C

Health News from Medical News Today — Fri, 10 Dec 2010 14:00:00 +0100

Talecris Biotherapeutics, Inc. (Nasdaq: TLCR) announced the initiation of a clinical trial evaluating the safety and the pharmacokinetic profile of two doses of PROLASTIN®-C (Alpha(1)-Proteinase Inhibitor [Human]) (A1PI), a therapy indicated for chronic augmentation and maintenance in adults with emphysema due to alpha(1)-antitrypsin (AAT) deficiency. AAT deficiency is a rare, genetic disorder in which low levels of the alpha(1) protein circulating in the lungs can increase an individual's risk of developing emphysema... (Source: Health News from Medical News Today)

HIV infection is associated with reduced serum alpha-1-antitrypsin concentrations.

Clinical and Investigative Medicine — Fri, 10 Dec 2010 10:20:04 +0100

Conclusion: The association between reduced serum AAT concentration and HIV infection is consistent with a role for AAT as an endogenous HIV suppressor. PMID: 21134340 [PubMed - in process] (Source: Clinical and Investigative Medicine)

Adipose tissue-derived mesenchymal stem cell-based liver gene delivery

Journal of Hepatology — Thu, 09 Dec 2010 00:00:00 +0100

Conclusions: These results demonstrated that AT-MSCs can be transduced by rAAV vectors, engrafted into recipient livers, contribute to liver regeneration, and serve as a platform for transgene expression without eliciting an immune response. AT-MSC-based gene therapy presents a novel approach for the treatment of liver diseases, such as AAT deficiency. (Source: Journal of Hepatology)

Increased expression of carbonic anhydrase I in the synovium of patients with ankylosing spondylitis

BMC Musculoskeletal Disorders — Wed, 08 Dec 2010 00:00:00 +0100

Conclusion: In vitro experiments by other groups indicated that CA1 catalyzes the generation of HCO3- through the hydration of CO2, which then combines with Ca2+ to form a CaCO3 precipitate. Calcification is an essential step of bone formation. Substantial evidence indicates that carbonic anhydrase also stimulates bone resorption. Hence, overexpression of CA1 in the synovial tissues of AS patients may promote improper calcification and bone resorption in AS. (Source: BMC Musculoskeletal Disorders)

Cardiovascular and Musculoskeletal Co-morbidities in Patients with Alpha 1 Antitrypsin Deficiency

Respiratory Research — Tue, 07 Dec 2010 00:00:00 +0100

Background Determining the presence and extent of co-morbidities is fundamental in assessing patients with chronic respiratory disease, where increased cardiovascular risk, presence of osteoporosis and low muscle mass have been recognised in several disease states. We hypothesised that the systemic consequences are evident in a further group of subjects with COPD due to Alpha-1 Antitrypsin Deficiency (A1ATD), yet are currently under-recognised.Methods We studied 19 patients with PiZZ A1ATD COPD and 20 age, sex and smoking matched controls, all subjects free from known cardiovascular disease. They underwent spirometry, haemodynamic measurements including aortic pulse wave velocity (aPWV), an independent predictor or cardiovascular risk, dual energy X-ray absorptiometry to determine body com...

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Alpha- 1 antitrypsin deficiency related liver disease: is it worth a search in India?

Indian Pediatrics — Tue, 07 Dec 2010 00:00:00 +0100

Authors: Yachha SK, Srivastava A PMID: 21220797 [PubMed - in process] (Source: Indian Pediatrics)

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

Journal of Genetics — Wed, 01 Dec 2010 00:00:00 +0100

Authors: Mikelsaar R, Lissitsina J, Ausmees K, Punab M, Korrovits P, Vaidla E PMID: 21273701 [PubMed - in process] (Source: Journal of Genetics)

Alpha-1 Antitrypsin: Its Role in Health and Disease

Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry — Sun, 28 Nov 2010 01:19:32 +0100

(Source: Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry)

Alpha-1-Antitrypsin Deficiency and Mechanisms of Liver Disease

Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry — Sun, 28 Nov 2010 01:19:32 +0100

(Source: Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry)

Role of Alpha-1 Antitrypsin (AAT) in Ocular Allergy and Uveitis

Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry — Sun, 28 Nov 2010 01:19:32 +0100

(Source: Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry)

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New Strategies in Drug Development Focusing on the Anti-Protease-Protease Balance in Alpha-1 Antitrypsin Deficiency

Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry — Sun, 28 Nov 2010 01:19:32 +0100

(Source: Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry)

Alpha-1 Antitrypsin Deficiency: Treatment Beyond Augmentation Therapy

Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry — Sun, 28 Nov 2010 01:19:32 +0100

(Source: Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry)

Gain of Function Effects of Z Alpha-1 Antitrypsin

Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry — Sun, 28 Nov 2010 01:19:32 +0100

(Source: Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry)

Editorial [Hot topic: Alpha-1 Antitrypsin Deficiency: A Disease with Numerous Adverse Effects on Humans (Guest Editors: S. Ghavami, A.J. Halayko and F.J. de Serres)]

Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry — Sat, 27 Nov 2010 02:24:24 +0100

This article is currently available as a free download on ingentaconnect (Source: Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry)

Integrated Analysis Demonstrates Alpha(1)-Augmentation Therapy Significantly Reduces Loss Of Lung Tissue In Patients With Deficiency-related Emphysema

Health News from Medical News Today — Tue, 16 Nov 2010 11:00:00 +0100

Talecris Biotherapeutics (Nasdaq: TLCR) announced the publication of combined data from two studies demonstrating that augmentation therapy with Alpha(1)-Proteinase Inhibitor (Human) (A1PI) significantly reduces lung tissue loss in patients with emphysema related to Alpha(1)-antitrypsin (AAT) deficiency. Results of the studies, published as an integrated analysis of the raw data from two similar pilot trials, were published in the journal Respiratory Research... (Source: Health News from Medical News Today)

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Streptococcal pyrogenic exotoxin B (SpeB) boosts the contact system via binding of alpha-1 antitrypsin

BJ Cell — Tue, 16 Nov 2010 00:00:00 +0100

The Streptococcus pyogenes cysteine protease, SpeB, 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 systemic spreading. Addition of SpeB to human plasma increased plasma-mediated bacterial killing and prolonged coagulation time through the intrinsic pathway of coagulation. This effect was independent of the enzymatic activity of SpeB and was mediated by a non-covalent medium-affinity binding and modification of the serpin alpha-1 antitrypsin. Consequently, supplement of alpha-1 antitrypsin to plasma increased bacterial survival. Sequestration of alpha-1 antitrypsin by SpeB led to enhanced contact system activation, supported by incre...

Streptococcal pyrogenic exotoxin B (SpeB) boosts the contact system via binding of alpha-1 antitrypsin.

The Biochemical Journal — Tue, 16 Nov 2010 00:00:00 +0100

Authors: Meinert Niclasen L, Olsen JG, Dagil R, Qing Z, Sørensen OE, Kragelund BB The Streptococcus pyogenes cysteine protease, SpeB, 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 systemic spreading. Addition of SpeB to human plasma increased plasma-mediated bacterial killing and prolonged coagulation time through the intrinsic pathway of coagulation. This effect was independent of the enzymatic activity of SpeB and was mediated by a non-covalent medium-affinity binding and modification of the serpin alpha-1 antitrypsin. Consequently, supplement of alpha-1 antitrypsin to plasma increased bacterial survival. Sequestration of al...

{alpha}-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8

Journal of Clinical Investigation — Wed, 10 Nov 2010 15:51:50 +0100

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....

Diagnostic Delay and Clinical Modifiers in Alpha-1 Antitrypsin Deficiency

Medscape Today Headlines — Wed, 03 Nov 2010 10:38:31 +0100

AATD is one of the most prevalent inherited diseases, but identification of affected patients and establishment of the diagnosis is still unsatisfactory. Therapeutic Advances in Respiratory Disease (Source: Medscape Today Headlines)

Proteostasis Strategies for Restoring {alpha}1-Antitrypsin Deficiency.

Annual Review of Biochemistry — Mon, 01 Nov 2010 00:00:00 +0100

Authors: Bouchecareilh M, Conkright JJ, Balch WE The function of the human proteome is defined by the proteostasis network (PN) (Science 2008;319:916; Science 2010;329:766), a biological system that generates, protects, and, where necessary, degrades a protein to optimize the cell, tissue, and organismal response to diet, stress, and aging. Numerous human diseases result from the failure of proteins to fold properly in response to mutation, disrupting the proteome. In the case of the exocytic pathway, this includes proteostasis components that direct folding, and export of proteins from the endoplasmic reticulum (ER). Included here are serpin deficiencies, a class of related diseases that result in a significant reduction of secretion of serine proteinase inhibitors from the liver into...

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Baxter Launches GLASSIATM In The U.S.

Health News from Medical News Today — Tue, 26 Oct 2010 10:00:00 +0100

Baxter International Inc. (NYSE: BAX) announced the commercial launch of GLASSIATM [Alpha1-Proteinase Inhibitor (Human)] in the United States. GLASSIATM is the first available ready-to-use liquid alpha1-proteinase inhibitor (Alpha1-PI) and is indicated as a chronic augmentation and maintenance therapy in adults with emphysema due to congenital deficiency of alpha-1 antitrypsin (AAT), an under-diagnosed hereditary condition characterized by a low level of alpha-1 protein in the blood... (Source: Health News from Medical News Today)

Oxidation of Z {alpha}1-antitrypsin by Cigarette Smoke Induces Polymerization: A Novel Mechanism of Early-onset Emphysema.

American Journal of Respiratory Cell and Molecular Biology — Thu, 21 Oct 2010 23:00:00 +0100

Conclusion Our data show that cigarette smoke accelerates polymerization of Z-AT by oxidative modification, which in so doing further reduces pulmonary defense and increases neutrophil influx into the lungs. These novel findings provide a molecular explanation for the striking observation of premature emphysema in ZZ homozygotes who smoke, and raise the prospect of anti-oxidant therapy in Z-AT related COPD. PMID: 20971880 [PubMed - as supplied by publisher] (Source: American Journal of Respiratory Cell and Molecular Biology)

[COPD and alpha-1-antitrypsin deficiency]

Archivos de Bronconeumologia — Thu, 07 Oct 2010 00:20:02 +0100

Authors: Lara B Alpha-1-antitrypsin deficiency (AATD) is the main genetic factor related to the development of emphysema. This protein has numerous variants, some of which are clinically relevant because their anomalous conformation implies that they fail to reach the target organs as they are polymerized in the hepatocyte. The main abnormal variant is PiZ. In a small percentage of individuals, the accumulation of Z polymers in the liver leads to the development of liver disease. The lack of AATD in the lung favors the development of emphysema, since the proteolytic effect of elastases - the main biological function of AATD - is not counteracted. In Spain, approximately 400 persons are diagnosed with severe AATD deficiency, representing less than 10 % of those expected by epidemiologic...

Reply to: Kelly et al. Alpha-1-antitrypsin deficiency

Respiratory Medicine — Wed, 06 Oct 2010 00:00:00 +0100

I recently read the Alpha-1-antitrypsin review in press by Kelly and colleagues (Kelly E et al, Alpha-1-antitrypsin deficiency. Respir Med 2010; 104:763–772). Interest in this genetic predisposition to COPD and especially the processes that lead to emphysema has received a welcomed increase. (Source: Respiratory Medicine)

Therapeutic efficacy of alpha-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry

Respiratory Research — Mon, 04 Oct 2010 23:00:00 +0100

Conclusions: The overall results of the combined analysis of 2 separate trials of comparable design, and the only 2 controlled clinical trials completed to date, has confirmed that IV AAT augmentation therapy significantly reduces the decline in lung density and may therefore reduce the future risk of mortality in patients with AAT deficiency-related emphysema.Trial registration: The EXACTLE study was registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887. (Source: Respiratory Research)

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Heterozygous Alpha-1-Antitrypsin Deficiency (PiMZ): Risk Factor in the Development of Primary Liver Carcinoma in Non-Cirrhotic Liver?

Zeitschrift fur Gastroenterologie — Thu, 30 Sep 2010 23:00:00 +0100

Authors: Manekeller S, Sauerbruch T, Fischer HP, Propping P, Hirner A Here we report on a patient with a primary hepatocellular carcinoma in a non-cirrhotic liver, in whom heterozygosity for an AAT-deficiency allele was found (PiMZ). Based on this observation and the current literature, the possible mechanisms for an eventual contribution of a heterozygosity of a heterozygous AAT-deficiency for a hepatocellular carcinoma are discussed. Alpha-1-antitrypsin (AAT)-deficiency (Laurell-Eriksson syndrome) is a genetic disorder, in which individuals who are homozygous for a deficiency allele are at an increased lifetime risk for pulmonary emphysema, liver cirrhosis, and primary hepatocellular carcinoma. It has been controversially discussed whether the heterozygous form (PiMZ) is also associa...

The ubiquitin ligase Hrd1 promotes degradation of the Z variant alpha 1-antitrypsin and increases its solubility.

Molecular and Cellular Biochemistry — Thu, 30 Sep 2010 23:00:00 +0100

Authors: Wang H, Li Q, Shen Y, Sun A, Zhu X, Fang S, Shen Y Alpha 1-antitrypsin (AAT) deficiency is an autosomal recessive disorder that is characterized by the retention of misfolded AAT in the endoplasmic reticulum (ER) of hepatocytes and a significant decrease in the serum levels of AAT. Previous studies have demonstrated that the ubiquitin-proteasome pathway is involved in the degradation of the Z variant of AAT (ATZ). However, the detailed mechanisms of ATZ degradation are not fully understood. We investigated whether the ER membrane-embedded ubiquitin ligase (E3) Hrd1 promotes the removal of ATZ through ER-associated degradation (ERAD). Our results indicate that Hrd1 decreases intracellular levels of ATZ, especially the detergent-insoluble fraction, in cells transfected with a pl...

Alpha-1-antitrypsin deficiency

Best Practice and Research. Clinical Gastroenterology — Thu, 30 Sep 2010 23:00:00 +0100

(AATD) is a rare genetic disorder associated with the development of liver and lung disease. AAT is a 52-kD glycoprotein, produced mainly by hepatocytes and secreted into the blood. Agglomeration of the AAT-protein in hepatocytes can result in liver disease. Exposure to smoke is the major risk factor for the development of lung disease characterised as early chronic obstructive lung disease (COPD). Diagnosis is based on the analysis of the AAT genotype and phenotype. The measurement of the AAT serum level is useful as screening test. Liver biopsy is not necessary to establish the diagnosis. Therapy for AAT-related liver disease is supportive, a specific therapy is not available. AATD is a rare condition (1:5000–10000) and, as a consequence, data and information on diagnosis and treatmen...

Plasma levels of TIMP-1 are higher in 34-year-old individuals with severe {alpha}1-antitrypsin deficiency

Thorax — Wed, 22 Sep 2010 15:12:25 +0100

(No abstract is available for this citation) (Source: Thorax)

AGTC Receives Second Grant From Food And Drug Administration For Clinical Study Of Genetic Respiratory Disease

Health News from Medical News Today — Sun, 19 Sep 2010 08:00:00 +0100

Applied Genetic Technologies Corporation, a privately-held, clinical stage biotechnology company developing novel systems to deliver human therapeutics, announces that it has received a grant of $1 million from the Food and Drug Administration (FDA Orphan Drugs Program) to fund a Phase II Human Clinical Trial evaluating the safety and efficacy of a treatment for Alpha 1 Antitrypsin Deficiency (AAT), a genetic disease known to result in serious lung and/or liver disease. The clinical trial is being coordinated by AGTC at The University of Massachusetts by Dr. Terrence R... (Source: Health News from Medical News Today)

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Cochrane meta-analysis on alpha-1 antitrypsin prompts furor

Nature Biotechnology — Fri, 10 Sep 2010 11:21:22 +0100

Nature Biotechnology 28, 885 (2010). doi:10.1038/nbt0910-885a Author: Mark Ratner (Source: Nature Biotechnology)

Brush border enzymes and absorptive capacity in extrahepatic portal venous obstruction in children

Hepatology International — Tue, 07 Sep 2010 17:24:22 +0100

Conclusion EHPVO leads to decrease in levels of brush border enzymes in small bowel but their absorption capacity remains normal. Content Type Journal ArticleDOI 10.1007/s12072-010-9211-5Authors Gurbakhshish Singh Sidhu, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Gastroenterology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012 IndiaB. R. Thapa, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Gastroenterology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012 IndiaPawan Rawal, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Gastroenterology, Post Graduate Institute of Medical Education and Resear...

Diagnosis of alpha-1-antitrypsin deficiency in bleeding disorder-related neonatal death

European Journal of Pediatrics — Thu, 02 Sep 2010 14:56:47 +0100

In conclusion, AAT deficiency is a rare genetic disorder that can lead to a serious bleeding disorder in the neonatal period if not recognised on time. Pathological diagnosis together with verifying molecular analysis can be used to identify index patients. Content Type Journal ArticleDOI 10.1007/s00431-010-1280-xAuthors Gursah Kats-Ugurlu, Department of Pathology, Radboud University Nijmegen Medical Centre, 824, PO Box 9101, 6500 HB Nijmegen, The NetherlandsMarije Hogeveen, Department of Paediatrics, Radboud University Nijmegen Medical Centre, PO Box 9101 6500 HB Nijmegen, The NetherlandsAnn Driessen, Department of Pathology, University Hospital of Maastricht, PO Box 5800, 6202 AZ Maastricht, The NetherlandsAns M. W. van den Ouweland, Department of Clinical Genetics, Erasmus M...

Emerging drugs for alpha-1-antitrypsin deficiency

Expert Opinion: Expert Opinion on Emerging Drugs: Table of Contents — Wed, 18 Aug 2010 11:27:33 +0100

Expert Opinion on Emerging Drugs, Volume 0, Issue 0, Page 1-10, Early Online. (Source: Expert Opinion: Expert Opinion on Emerging Drugs: Table of Contents)

Plasma Clusterin Levels in Predicting the Occurrence of Coronary Artery Lesions in Patients With Kawasaki Disease

Pediatric Cardiology — Sat, 14 Aug 2010 16:49:57 +0100

Abstract Kawasaki disease (KD) is the leading cause of acquired heart disease during childhood in the developed countries. Coronary artery lesions (CAL) are the major complications of KD. A unique proteomic profiling with increased or decreased fibrinogen, alpha-1-antitrypsin, clusterin, and immunoglobulin free light chains were noted in KD in our previous study. The purpose of this study was to evaluate relations between these biomarkers and CAL in KD and to establish within the markers the appropriate cut-off value with which to predict the occurrence of CAL. A total of 47 KD patients were enrolled, including 14 with CAL and 33 without CAL. Plasma samples from patients with KD before intravenous immunoglobulin administration were indicated for measurement of these biomar...

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Effect of sialic acid content on glycoprotein pI analyzed by two-dimensional electrophoresis

Electrophoresis — Wed, 04 Aug 2010 23:00:00 +0100

2-DE is broadly used for quantitative analysis of differential protein expression in complex mixtures such as serum samples or cell lysates. PTMs directly influence the 2-DE pattern, and knowledge of the rules of protein separation is required in order to understand the protein distribution in a 2-DE gel. Glycosylation is the most common PTM and can modify both the molecular weight and the pI of a protein. In particular, the effect of charged monosaccharides (mainly sialic acids, SAs) on the 2-DE pattern of a protein is of major interest since changes in sialylation are regularly observed in comparative studies. Little is known about the pI shift of a glycoprotein induced by the presence of SAs, or whether this shift is the same for all glycoproteins. To address this issue, this study exam...

CT lung densitometry in young adults with alpha-1-antitrypsin deficiency

Respiratory Medicine — Mon, 02 Aug 2010 00:00:00 +0100

Summary: Background: Severe (PiZZ) and moderate (PiSZ) alpha-1-antitrypsin (AAT) deficiency predispose to lung emphysema, especially in smokers. We hypothesized that multi-slice computed tomography (CT) might be superior to pulmonary function tests (PFT) to detect lung emphysema in AAT-deficient individuals at the age of 32 years.Methods: A subgroup of PiZZ and PiSZ individuals identified during the Swedish newborn screening programme in 1972–74 underwent multi-slice CT and PFT at the age of 32 years. From the CT scans the percentile density at 15% (PD15) and the relative area below –910 Hounsfield Units (RA−910 HU) were calculated. The results of PFT and CT were compared between the AAT-deficient individuals and an age-matched control group.Results: Twenty-five PiZZ, 11 PiSZ and 17 ...

Metabolic panniculitis: alpha-1 antitrypsin deficiency panniculitis and pancreatic panniculitis

Dermatologic Therapy — Tue, 27 Jul 2010 23:00:00 +0100

Panniculitis can be the initial presentation of both alpha-1 antitrypsin deficiency and pancreatic disease. They can both present with abscess-like draining nodules, but may present like other forms of panniculitis with erythematous nodules. It is important to consider these in the differential diagnosis of patients presenting with panniculitis. Alpha-1 antitrypsin deficiency is a relatively common disorder mainly affecting the lungs and liver. It frequently goes undiagnosed, yet critical interventions can be made to minimize disease progression. Panniculitis associated with alpha-1 antitrypsin deficiency can be difficult to treat. Pancreatic panniculitis occurs in less than 3% of patients with underlying pancreatic disease and is often associated with arthritis. Diagnosis and treatment of...

Exploring a Link Between Fatigue and Intestinal Injury During Pelvic Radiotherapy.

The Oncologist — Tue, 27 Jul 2010 23:00:00 +0100

Conclusion. The present study indicates a link between fatigue and intestinal injury during pelvic radiotherapy. This observation should be considered as a preliminary finding because of the small sample size but may serve as a rationale for therapeutic interventions aimed at alleviating both fatigue and gastrointestinal symptoms during pelvic radiotherapy. PMID: 20667967 [PubMed - as supplied by publisher] (Source: The Oncologist)

Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung disease

NeLM - Drug Specific Reviews — Mon, 26 Jul 2010 23:00:00 +0100

Source: Cochrane Library Area: Evidence > Drug Specific Reviews Background Alpha-1 antitrypsin deficiency is an inherited disorder that can cause lung disease. People who smoke are more seriously affected and have a greater risk of dying from the disease. Objectives To review the benefits and harms of augmentation therapy with alpha-1 antitrypsin in patients with alpha-1 antitrypsin deficiency and lung disease. Search strategy PubMed, the Cochrane Trials Register and ClinicalTrials.gov (7 January 2010), and the Cochrane Cystic Fibrosis & Genetic Disorders Group's Trials Register (13 March 2009). Selection criteria Randomised trials of augmentation therapy with alpha-1 antitrypsin compared with placebo or no treatment. Data collect...

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Augmentation therapy for alpha-1 antitrypsin deficiency ‘ineffective’

MedWire News - Respiratory — Thu, 22 Jul 2010 06:58:31 +0100

Intravenous augmentation therapy for patients with alpha-1 antitrypsin deficiency cannot be recommended as it has no proven clinical benefit, say researchers who conducted a systematic review of published studies. (Source: MedWire News - Respiratory)

Outdoor air pollution is associated with rapid decline of lung function in {alpha}-1-antitrypsin deficiency

Occupational and Environmental Medicine — Tue, 20 Jul 2010 14:48:35 +0100

Conclusions Exposure to ozone and PM10 predicts decline of lung function in AATD. (Source: Occupational and Environmental Medicine)

Accelerated Spirometric Decline In Alpha-1 Antitrypsin Deficient New York City Firefighters.

Chest — Wed, 14 Jul 2010 23:00:00 +0100

CONCLUSIONS: AAT-deficient FDNY rescue workers had significant spirometric decline accelerations and persistent airway symptoms during the first 4 years after the WTC exposure. This represents a novel gene-by-environment interaction. Clinically meaningful decline acceleration occurred even with the mild serum AAT level reductions associated with PiS heterozygosity (without concomitant PiZ heterozygosity). PMID: 20634282 [PubMed - as supplied by publisher] (Source: Chest)

Cochrane Study Poorly Designed, Ignores Wealth Of Data, Does Disservice To Rare Disease Patients, Says Alpha-1 Foundation

Health News from Medical News Today — Mon, 12 Jul 2010 11:00:00 +0100

The Alpha-1 Foundation challenged a newly published review which questions the value of augmentation therapy for Alpha-1 Antitrypsin Deficiency (Alpha-1). The article, "Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung disease" by Peter C. Gotzsche and Helle Krogh Johansen, was published this week by the Cochrane Library. "The Cochrane Library has been respected in the scientific community for carefully performed reviews based on solid evidence," said Foundation President and CEO John Walsh... (Source: Health News from Medical News Today)

Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung disease.

Cochrane Database of Systematic Reviews — Fri, 09 Jul 2010 23:18:04 +0100

CONCLUSIONS: Augmentation therapy with alpha-1 antitrypsin cannot be recommended, in view of the lack of evidence of clinical benefit and the cost of treatment. PMID: 20614465 [PubMed - in process] (Source: Cochrane Database of Systematic Reviews)

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Pricey Lung Disease Drugs Have No Benefit: Study

Medscape Medical News Headlines — Thu, 08 Jul 2010 16:19:53 +0100

Recommendations for expensive treatments for alpha-1 antitrypsin deficiency should be withdrawn because the drugs have no benefit, scientists said on Wednesday. Reuters Health Information (Source: Medscape Medical News Headlines)

Treating Inherited Lung Disease By Replacement Therapy No Longer Recommended

Health News from Medical News Today — Wed, 07 Jul 2010 09:00:00 +0100

An expensive treatment recommended for a genetic disorder called alpha-1 antitrypsin deficiency has no proven clinical benefit, according to a systematic review by Cochrane Researchers. The disorder causes chronic lung disease and the review concludes that considering the lack of evidence for its benefits, and possible adverse effects, the treatment should not be recommended. Alpha-1 antitrypsin deficiency affects less than one in 1,600 people... (Source: Health News from Medical News Today)

U.S. FDA Approves New Drug for Alpha-1 Antitrypsin Deficiency

Medscape Medical News Headlines — Wed, 07 Jul 2010 01:51:59 +0100

Kamada has won U.S. approval for its treatment of alpha-1 antitrypsin deficiency. Reuters Health Information (Source: Medscape Medical News Headlines)

Pricey lung disease drugs have no benefit: study

Reuters: Health — Tue, 06 Jul 2010 23:00:38 +0100

LONDON (Reuters) - Recommendations for expensive treatments made for a genetic disorder called alpha-1 antitrypsin deficiency should be withdrawn because the drugs have no benefit, scientists said on Wednesday. (Source: Reuters: Health)

Horizon scanning: FDA approves alpha-1-antitrypsin (GlassiaT) for alpha 1 deficiency

NeLM - News — Tue, 06 Jul 2010 23:00:00 +0100

Source: BioSpace Area: News The United States Food and Drug Administration (FDA) has approved alpha-1-antitrypsin (GlassiaT), an alpha 1 proteinase inhibitor, for the treatment of alpha 1 deficiency. Glassia is the only ready-to-use liquid alpha- 1-proteinase Inhibitor on the market. (Source: NeLM - News)

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Pricey Lung Disease Drugs Have No Benefit

MedlinePlus Health News — Tue, 06 Jul 2010 22:00:38 +0100

Recommendations for expensive treatments made for a genetic disorder called alpha-1 antitrypsin deficiency should be withdrawn because the drugs have no benefit, scientists said on Wednesday.Source: Reuters Health Related MedlinePlus Pages: Alpha-1 Antitrypsin Deficiency, Medicines (Source: MedlinePlus Health News)

Kamada Wins FDA Approval for Glassia - a New Liquid, Ready-to-Use Treatment for Alpha-1 Antitrypsin Deficiency

Drugs.com - New Drug Approvals — Tue, 06 Jul 2010 19:07:13 +0100

NESS ZIONA, Israel--(BUSINESS WIRE)--Jul 6, 2010 - Kamada today announced that the United States Food and Drug Administration (FDA) has approved Glassia (Alpha 1 Proteinase inhibitor, also known as Alpha-1-Antitrypsin (AAT) for the treatment of... (Source: Drugs.com - New Drug Approvals)

Alpha-1 antitrypsin PI MZ heterozygosity is associated with airflow obstruction in two large cohorts.

Chest — Wed, 30 Jun 2010 23:00:00 +0100

CONCLUSIONS: Compared to PI MM individuals, PI MZ heterozygotes had lower FEV(1)/(F)VC ratio in two independent studies. Our results suggest that PI MZ individuals may be slightly more susceptible to development of airflow obstruction than PI MM individuals. PMID: 20595457 [PubMed - as supplied by publisher] (Source: Chest)

Effects of major human antiprotease alpha-1-antitrypsin on the motility and proliferation of stromal cells from human exfoliated deciduous teeth.

Regenerative Medicine — Wed, 30 Jun 2010 23:00:00 +0100

Conclusion: AAT at physiologic and inflammatory concentrations positively modulates the proliferation and motility of SHEDs in vitro. These results suggest the importance of AAT in the maintenance and regulation of tissue progenitor cells in vivo. PMID: 20632864 [PubMed - in process] (Source: Regenerative Medicine)

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

Transplantation Proceedings — Wed, 30 Jun 2010 23:00:00 +0100

Conclusion: Culture of impure human islet fractions in the presence of A1AT prevented insulin cleavage and improved islet recovery. A1AT supplementation of islet culture media, therefore, may increase the proportion of human islet products that meet release criteria for transplantation. (Source: Transplantation Proceedings)

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Trial Approved For Type 1 Diabetes Treatment By Ben-Gurion U. And U. Colorado

Health News from Medical News Today — Wed, 30 Jun 2010 12:00:00 +0100

The U.S. Food & Drug Administration (FDA) has granted Investigational New Drug (IND) regulatory clearance to initiate a Phase I/II clinical trial evaluating Alpha-1 Antitrypsin (AAT) in type 1 diabetics, based on research by Dr. Eli Lewis of Israel's Ben-Gurion University of the Negev. This is the first time AAT will be evaluated in humans with type 1 diabetes. AAT is an FDA-approved off-patent drug currently used to treat pulmonary emphysema among youngsters and adults with an AAT genetic deficiency... (Source: Health News from Medical News Today)

Proteomic analysis of pubocervical fascia in women with and without pelvic organ prolapse and urodynamic stress incontinence

International Urogynecology Journal — Wed, 23 Jun 2010 08:48:19 +0100

Clinical practice

European Journal of Pediatrics — Tue, 22 Jun 2010 18:33:25 +0100

Abstract Protein-losing enteropathy (PLE) is a rare complication of a variety of intestinal disorders characterized by an excessive loss of proteins into the gastrointestinal tract due to impaired integrity of the mucosa. The clinical presentation of patients with PLE is highly variable, depending upon the underlying cause, but mainly consists of edema due to hypoproteinemia. While considering PLE, other causes of hypoproteinemia such as malnutrition, impaired synthesis, or protein loss through other organs like the kidney, liver, or skin, have to be excluded. The disorders causing PLE can be divided into those due to protein loss from intestinal lymphatics, like primary intestinal lymphangiectasia or congenital heart disease and those with protein loss due to an inflamed ...

Self-Assembled Nucleic Acid Nanoparticles Capable of Controlled Disassembly in Response to a Single Nucleotide Mismatch.

Biomacromolecules — Mon, 07 Jun 2010 23:00:00 +0100

Authors: Kim J, Im CA, Jung Y, Qazi A, Shin JS We have demonstrated the self-assembled DNA nanoparticles capable of controlled disassembly in response to a single nucleotide change (SNC) in a target nucleic acid. The DNA nanoparticles (avg diameter = 51 +/- 22 nm) were constructed by joining two types of streptavidin-DNA conjugates with 2 molar equiv of a linker strand that carries complementary sequences to both conjugates. Nanoparticle disassembly triggered by a target strand (i.e., a perfect complement to the linker) selectively over mismatched targets was achieved by kinetically controlled nucleation occurring at a 6-nt overhang in the linker. The disassembly process was shown to be dramatically slowed down when using mismatch targets in which the SNC was positioned at the fourth n...

Successful endovascular treatment of multiple mesenteric arterial aneurysms associated with alpha-1-antitrypsin deficiency

Journal of Vascular Surgery — Sun, 06 Jun 2010 23:00:00 +0100

We present a rare case of a patient who presented with acute abdominal pain with a previous history of alpha-1-antitrypsin deficiency (α1-antitrypsin deficiency). Further clinical deterioration necessitated computed tomography (CT) imaging, which demonstrated a hemoperitoneum. Angiography confirmed the rupture of multiple aneurysms originating from the mesenteric arterial arcade, which were treated successfully with endovascular embolization. The association between mesenteric arterial aneurysm rupture and α-1-antitrypsin deficiency is explored. (Source: Journal of Vascular Surgery)

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Alpha-1-antitrypsin Phenotypes and Neutrophil Elastase Gene Promoter Polymorphisms in Lung Cancer.

Pathology Oncology Research — Wed, 02 Jun 2010 23:00:00 +0100

In conclusion, we found that PiM1 homozygosity could be associated with the lung cancer, probably due to increased synthesis of this antiapoptotic protein. Non-MM variants of AAT and ELA2 genotypes with predicted intermediate or high activity could also represent a risk factor for aggressive form of lung cancer associated with extrathoracic metastases. PMID: 20521180 [PubMed - as supplied by publisher] (Source: Pathology Oncology Research)

Alpha-1 Antitrypsin Deficiency: Whom to Test, Whom to Treat?

Seminars in Respiratory and Critical Care Medicine — Sat, 22 May 2010 14:15:32 +0100

This article reviews the current recommendations for testing and treatment of AATD. Some of these recommendations are expected to change as legislation to prevent genetic discrimination is refined and new therapies for this relatively common genetic predisposition are developed. Additional genetic modifiers of COPD will be found, and the path set by AATD will facilitate their incorporation into our future management of COPD.[...]© Thieme Medical PublishersGet connected:Table of contents | Abstract | Full text (Source: Seminars in Respiratory and Critical Care Medicine)

Association of plastic bronchitis to protein-losing enteropathy after fontan operation

Arquivos Brasileiros de Cardiologia — Fri, 21 May 2010 12:54:03 +0100

We report an unusual case of association of plastic bronchitis (PB) to protein-losing enteropathy (PLE) in a girl of 4 years and 9 months of age with double inlet single left ventricle and ventriculoarterial concordance. submitted to total cavopulmonary surgery. with an intracardiac lateral tunnel at the age of three. The elimination of the 10 cm fibrin bronchial mold (PB) and the alpha-1-antitrypsin elevation of 52 mg/g in feces had both become outstanding. Using sildenafil. the thoracic duct ligature and the cardiac transplant were programmed in case of continuity of the process (Source: Arquivos Brasileiros de Cardiologia)

A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with [alpha]1-antitrypsin deficiency

Hepatology — Thu, 13 May 2010 23:00:00 +0100

Conclusion: Z and shutter domain mutants of [alpha]1-antitrypsin form polymers with a shared epitope and so are likely to have a similar structure. HEPATOLOGY 2010 (Source: Hepatology)

Role of the Lectin VIP36 in Post-ER Quality Control of Human α1-Antitrypsin

Traffic — Thu, 06 May 2010 23:00:00 +0100

The leguminous-type (L-type) lectin VIP36 localizes to the Golgi apparatus and cycles early in the secretory pathway. In vitro, VIP36 binds high-mannose glycans with a pH optimum of 6.5, a value similar to the luminal pH of the Golgi apparatus. Although the sugar-binding properties of VIP36 in vitro have been characterized in detail, the function of VIP36 in the intact cell remains unclear as no convincing glycoprotein cargo has been identified. Here, we used yellow fluorescent protein (YFP) fragment complementation to identify luminal interaction partners of VIP36. By screening a human liver cDNA library, we identified the glycoprotein [alpha]1-antitrypsin ([alpha]1-AT) as a cargo of VIP36. The VIP36/[alpha]1-AT complex localized to Golgi and endoplasmic reticulum (ER). In the living cell...

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Establishment of lentiviral-vector-mediated model of human alpha-1 antitrypsin delivery into hepatocyte-like cells differentiated from mesenchymal stem cells.

Tissue and Cell — Wed, 28 Apr 2010 23:00:00 +0100

Authors: Ghaedi M, Lotfi AS, Soleimani M Alpha-1 antitrypsin (AAT) deficiency is a lethal hereditary disorder characterized by a severe diminution in plasma levels of AAT leading to progressive liver dysfunction. Since mesenchymal stem cells can differentiate into hepatocyte-like cells they offer a potential unlimited source in autologous transplant procedures. The transfer of genetically modified hepatocyte cells derived from hMSCs into the body constitutes a novel paradigm of coupling cell therapy with gene therapy for this disease. hMSCs were isolated by density gradient centrifugation and plastic adherence. Hepatic differentiation was induced by exposing hMSC to induction medium for up to 21 days. The mRNA levels and protein expression of several important hepatic genes were determ...

Survival in severe alpha-1-antitrypsin deficiency (PiZZ)

Respiratory Research — Sun, 25 Apr 2010 23:00:00 +0100

Conclusion: Smokers with severe AAT deficiency, irrespective of mode of identification, have a significantly higher mortality risk than the general Swedish population. (Source: Respiratory Research)

TRAM1 is involved in disposal of ER membrane degradation substrates.

Experimental Cell Research — Sun, 25 Apr 2010 23:00:00 +0100

Authors: Ng CL, Oresic K, Tortorella D ER quality control consists of monitoring protein folding and targeting misfolded proteins for proteasomal degradation. ER stress results in an unfolded protein response (UPR) that selectively upregulates proteins involved in protein degradation, ER expansion, and protein folding. Given the efficiency in which misfolded proteins are degraded, there likely exist cellular factors that enhance the export of proteins across the ER membrane. We have reported that translocating chain-associated membrane protein 1 (TRAM1), an ER-resident membrane protein, participates in HCMV US2- and US11-mediated dislocation of MHC class I heavy chains (Oresic, K., Ng, C.L., and Tortorella, D. 2009). Consistent with the hypothesis that TRAM1 is involved in the disposal...

Alpha 1 antitrypsin deficiency alleles are associated with joint dislocation and scoliosis in Williams syndrome

American Journal of Medical Genetics Part C: Seminars in Medical Genetics — Wed, 21 Apr 2010 23:00:00 +0100

We examined a cohort of 205 individuals with WS for mutations in SERPINA1, the gene that encodes alpha-1-antitrypsin (AAT), the inhibitor of elastase. Individuals with classic WS deletions and SERPINA1 genotypes PiMS or PiMZ were more likely than those with a SERPINA1 PiMM genotype to have joint dislocation or scoliosis. However, carrier status for AAT deficiency was not correlated with presence of inguinal hernia or with presence or severity of SVAS. These findings suggest that genes important in elastin metabolism are candidates for variability in the connective tissue abnormalities in WS. © 2010 Wiley-Liss, Inc. (Source: American Journal of Medical Genetics Part C: Seminars in Medical Genetics)