MedWorm: Alpha-1 Antitrypsin Deficiency

Effects of alpha 1-antitrypsin on endotoxin-induced lung inflammation in vivo

Inflammation Research — Thu, 18 Mar 2010 15:36:16 +0100

Conclusion Within the short term, AAT enhances the magnitude of LPS-induced specific cytokine/chemokine production, which may play an important role in amplification and resolution of acute-phase inflammatory reactions in vivo. Content Type Journal ArticleCategory Original Research PaperDOI 10.1007/s00011-010-0164-xAuthors Devipriya Subramaniyam, Hannover Medical School Department of Respiratory Medicine Carl-Neuberg Str. 1 30625 Hannover GermanyChad Steele, University of Alabama at Birmingham Department of Medicine, Center of Free Radical Biology, School of Medicine Birmingham AL 35294 USAThomas Köhnlein, Hannover Medical School Department of Respiratory Medicine Carl-Neuberg Str. 1 30625 Hannover GermanyTobias Welte, Hannover Medical School Department of Resp...

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Generation of functional hepatocytes from human embryonic stem cells under chemically defined conditions that recapitulate liver development

Hepatology — Thu, 18 Mar 2010 00:00:00 +0100

Conclusion: We have developed a robust and efficient method to differentiate pluripotent stem cells into hepatic cells, which exhibit characteristics of human hepatocytes. Our approach should facilitate the development of clinical grade hepatocytes for transplantation and for research on drug discovery. (HEPATOLOGY 2010.) (Source: Hepatology)

Omni Bio Pharmaceutical, Inc. Hosts Panel On Alpha-1-Antitrypsin ("AAT") At 8th World Congress On Trauma, Shock, Inflammation And Sepsis

Health News from Medical News Today — Fri, 12 Mar 2010 17:00:00 +0100

Omni Bio Pharmaceutical, Inc. ("Omni Bio") (OTCBB: OMBP) announced that its acting Chief Executive Officer, Dr. Charles A. Dinarello, will moderate a panel at the 8th World Congress on Trauma, Shock, Inflammation and Sepsis ("TSIS") (http://www.tsis2010.org) in Munich, Germany on Friday, March 12, 2010. The panel on Alpha-1 Antitrypsin ("AAT") as a Novel Therapeutic in Inflammatory Diseases will feature the following presentations: "Introduction and Background for AAT Safety in Humans and Experimental Models of AAT Protection," by Dr... (Source: Health News from Medical News Today)

Omni Bio Pharmaceutical, Inc. Hosts Panel On Alpha-1-Antitrypsin ("AAT") At 8th World Congress On Trauma, Shock, Inflammation And Sepsis

Public Health News From Medical News Today — Fri, 12 Mar 2010 17:00:00 +0100

Glycosylation of liver acute-phase proteins in pancreatic cancer and chronic pancreatitis

Proteomics. Clinical Applications — Fri, 05 Mar 2010 00:00:00 +0100

Conclusions and clinical relevance: Changes in APP SLex and branching are probably associated with an inflammatory response because they were detected in both advanced PaC and CP patients and these conditions give rise to inflammation. On the contrary, the increase in APP core fucosylation could be cancer associated and the presence of this glycoform may give an advantage to the tumour. (Source: Proteomics. Clinical Applications)

2010 American Thoracic Society Research Program

ScanGrants feed — Mon, 01 Mar 2010 00:00:00 +0100

The American Thoracic Society and our partners in research are pleased to announce the 2010 ATS Research Program portfolio of grants. The ATS is grateful to its partners and members for the success of the new research program.Potential applicants should submit a letter of intent using the LOI application that is available through the proposalCENTRAL website at https://proposalcentral.altum.com. The letters of intent will be used to narrow the number of applicants for each grant category, in order to avoid having a large number of applicants competing for a limited number of grants. Letters of intent should be submitted via the proposalCENTRAL website by 9:00 am Eastern Time on Monday March 15, 2010. Late submissions will not be accepted. 2010 ATS Research Program Portfolio (funding to beg...

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Knowledge of alpha-1 antitrypsin deficiency among internal medicine house officers and respiratory therapists: results of a survey.

Respiratory Care — Mon, 01 Mar 2010 00:00:00 +0100

CONCLUSIONS: These results indicate a generally low level of knowledge about alpha-1 antitrypsin deficiency among physicians and RTs. Causes of under-recognition of alpha-1 antitrypsin deficiency, including the possibility of poor knowledge as a contributor, warrant further study. PMID: 20196882 [PubMed - in process] (Source: Respiratory Care)

Effect of liver transplant on pulmonary functions in adult patients with alpha 1 antitrypsin deficiency: 7 cases.

Mon, 01 Mar 2010 00:00:00 +0100

Conclusions: It appears from the results of our study that liver transplant probably prevented the progression of pulmonary disease in A1A-deficient patients. Further study and close, postliver, transplant follow-up is warranted to support our initial findings. PMID: 20199364 [PubMed - in process] (Source: Experimental and Clinical Transplantation : official journal of the Middle East Society for Organ Transplantation)

The amounts of alpha 1 antitrypsin protein are reduced in the vascular wall of the acutely dissected human ascending aorta [Original articles]

European Journal of Cardio-Thoracic Surgery — Fri, 26 Feb 2010 22:01:57 +0100

Conclusion: In the vascular wall of ascending aortic dissections, alpha 1 antitrypsin protein amounts are reduced compared with healthy aortas. Local alpha 1 antitrypsin deficiency in the human ascending aorta might lead to proteolytic damage easing aortic dissection. (Source: European Journal of Cardio-Thoracic Surgery)

Identification of a rare p.G320R alpha-1-antitrypsin variant in emphysema and lung cancer patients

Genetics and Molecular Biology — Fri, 26 Feb 2010 16:04:27 +0100

This study reports on the characterization of a p.G320R variant found in two patients, one with emphysema and the other with lung cancer. This variant results from a single base-pair substitution in exon 4 of the A1AT gene, and has been characterized as P by isoelectric focusing. Functional evaluation of the A1AT p.G320R variant was through comparing specific trypsin inhibitory activity in two patients with pulmonary disorders, carriers of the p.G320R variant, and 19 healthy individuals, carriers of normal A1AT M variants. Results showed that specific trypsin inhibitory activity was lower in both emphysema (2.45 mU/g) and lung cancer (2.07 mU/g) patients than in carriers of the normal variants (range 2.51-3.71 mU/g). This rare A1AT variant is associated with reduced functional activity of ...

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

Genetics and Molecular Biology — Fri, 26 Feb 2010 16:04:27 +0100

In this study we tested the hypothesis that common AAT polymorphisms influence the risk of developing COPDs. We investigated PiM1 (Ala213Val), PiM2 (Arg101His), PiM3 (Glu376Asp), PiS (Glu264Val) and PiZ (Glu342Lys) SERPINA1 alleles in 100 COPD patients and 200 healthy controls. No significant differences were observed in allele frequencies between COPD patients and controls, neither did haplotype analysis show significant differences between the two groups. A cross-sectional study revealed no significant relationship between common SERPINA1 polymorphisms (PiM1, PiM2, PiM3) and the emphysematous type of COPD. In addition, FEV1 annual decline, determined during a two-year follow up period, revealed no difference among carriers of the tested polymorphisms. (Source: Genetics and Molecular Biol...

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Prevalence of genetic polymorphisms in the promoter region of the alpha-1 antitrypsin (SERPINA1) gene in chronic liver disease: a case control study

BMC Gastroenterology — Sat, 20 Feb 2010 00:00:00 +0100

Conclusion: In our study, c.-1973T>C polymorphism was not a risk factor for liver disease of various aetiologies. In addition, S allele heterozygosity might contribute to the development of DILI. (Source: BMC Gastroenterology)

Critical role of natural killer cells in the rejection of human hepatocytes after xenotransplantation into immunodeficient mice

Transplant International — Wed, 17 Feb 2010 00:00:00 +0100

The severe combined immunodeficiency/albumin linked-urokinase type plasminogen activator (SCID/Alb-uPA) human liver chimeric mouse model has added a new dimension to studies of liver based human diseases and has important potential for study of human hepatic drug metabolism. However, it remains unclear if natural killer (NK) cell in SCID/Alb-uPA mice has an important negative impact on engraftment and expansion of human hepatocytes after transplantation. Here, we explore the role of mouse NK cells in the rejection of transplanted human hepatocytes in SCID/Alb-uPA mice. We assessed NK cell activity in vivo, using 125I-iodo-2'-deoxyuridine incorporation assay. Low serum human alpha-1 antitrypsin (hAAT, 100 [mu]g/ml) recipients accepted MHC class I knockout marrow, indicating a correlation be...

Kamada Announces Enrollment Of First Patient In Its Pivotal Study For Inhaled AAT In Europe

Health News from Medical News Today — Wed, 10 Feb 2010 05:00:00 +0100

Kamada, a bio-pharmaceutical company engaged in the development, manufacturing and marketing of specialty life-saving therapeutics, announced today that it has enrolled the first patient into its pivotal clinical trial with its new breakthrough compound of inhaled alpha-1 antitrypsin (AAT) delivered by an Investigational eFlow Nebulizer System (PARI Pharma GmbH), in patients with alpha-1 antitrypsin deficiency... (Source: Health News from Medical News Today)

Kamada Announces Enrollment Of First Patient In Its Pivotal Study For Inhaled AAT In Europe

Asthma / Respiratory News From Medical News Today — Wed, 10 Feb 2010 05:00:00 +0100

Kamada, a bio-pharmaceutical company engaged in the development, manufacturing and marketing of specialty life-saving therapeutics, announced today that it has enrolled the first patient into its pivotal clinical trial with its new breakthrough compound of inhaled alpha-1 antitrypsin (AAT) delivered by an Investigational eFlow Nebulizer System (PARI Pharma GmbH), in patients wi... (Source: Asthma / Respiratory News From Medical News Today)

Protein fraction isolated from epididymal fluid re-associates sperm in vitro: Possible role of serpins in rat Rosettes assembly

Molecular Reproduction and Development — Tue, 09 Feb 2010 00:00:00 +0100

In many mammalian species, sperm associate as a consequence of the epididymal transit. From the classic Rouleaux in guinea pig to the most recent work in mouse and echidna, authors have focused mainly on a detailed morphological description of this phenomenon. Some of these articles have also begun to describe the nature of the material present between sperm heads. Here, we try to better understand the factor/s involved in rat sperm association (Rosette). Based on previous work describing the appearance of Rosettes in the distal segments of the rat epididymis, we consider that sperm during their transit must be in contact with factor/s present in the caudal lumen in order to associate with each other. By an in vitro sperm re-associating assay, we try to determine the in vivo phenomenon obs...

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Serum protein biomarkers screening in HCC patients with liver cirrhosis by ICAT-LC-MS/MS

Journal of Cancer Research and Clinical Oncology — Wed, 03 Feb 2010 17:55:59 +0100

Conclusion cICAT combined with LC-MS/MS-based serum proteome analysis can be useful in the screening of serum biomarkers for HCC. Alpha-1-acid glycoprotein combining AFP could aid the diagnosis of HCC. Content Type Journal ArticleCategory Original PaperDOI 10.1007/s00432-010-0762-6Authors Xiaonan Kang, Zhongshan Hospital Liver cancer Institute Shanghai 200032 People’s Republic of ChinaLu Sun, Zhongshan Hospital Liver cancer Institute Shanghai 200032 People’s Republic of ChinaKun Guo, Zhongshan Hospital Liver cancer Institute Shanghai 200032 People’s Republic of ChinaHong Shu, Zhongshan Hospital Liver cancer Institute Shanghai 200032 People’s Republic of ChinaJun Yao, Fudan University Center for Proteomics Research, Institute of Biomedical Sciences Shanghai 2000...

Human XTP3-B binds to {alpha}1-antitrypsin variant nullHong Kong via the C-terminal MRH domain in a glycan-dependent manner

Glycobiology — Tue, 02 Feb 2010 16:04:02 +0100

In this study, the recombinant human XTP3-B fused with IgG-Fc (XTP3-B-Fc), XTP3-B without an N-terminal MRH domain fused with IgG-Fc (XTP3-B1-Fc), or XTP3-B without a C-terminal MRH domain fused with IgG-Fc (XTP3-B2-Fc) were prepared. XTP3-B-Fc and XTP3-B1-Fc bound to Lec1 cells but not to CHO, Lec2, or Lec8 cells, while XTP3-B2-Fc did not bind to any of these cells. The binding of XTP3-B-Fc and XTP3-B1-Fc to Lec1 cells was abrogated by treatment of the cells with endo-β-N-acetylglucosaminidase H, Man1,6Man or Man1,6(Man1,3)Man1,6(Man1,3)Man, or by substitution of Arg428 or Tyr457 in the C-terminal MRH domain with alanine. Arg428 and Tyr457 are homologous to amino acids that mediate glycan binding by the cation-dependent mannose-6-phosphate receptor. An immunoprecipitation experiment ...

Polymorphisms in the HPC/ELAC-2 and alpha 1-antitrypsin genes that correlate with human diseases in a North Indian population.

Molecular Biology Reports — Tue, 02 Feb 2010 00:00:00 +0100

Authors: Sobti RC, Thakur H, Gupta L, Janmeja AK, Seth A, Singh SK Two genes HPC/ELAC-2 and AAT were studied in north Indian population. HPC/ELAC-2 was studied in prostate cancer cases and AAT was studied in COPD patients. HPC/ELAC-2 is considered as an important cancer-susceptibility gene in prostate cancer. There are two common polymorphisms of this gene, i.e., Ser217Leu and Ala541Thr. Alpha 1 antitrypsin is a highly polymorphic anti-elastase enzyme, especially active in the protection of alveoli and liver. In the present study, we observed the distribution of two deficient alleles PiZ and Pi S in COPD patients. We extracted the DNA from 157 prostate cancer cases, 200 COPD patients, 170 BPH and 370 healthy controls. The polymorphisms were studied by PCR-RFLP technique. The mutant gen...

Inhibition of heat- and chemical-induced aggregation of various proteins reveals chaperon-like activity of the acute-phase component and serine protease inhibitor human alpha(1)-antitrypsin.

Biochemical and Biophysical Research communications — Thu, 28 Jan 2010 00:00:00 +0100

Authors: Zsila F In vitro chaperone-like activity of the serpin family member and plasma acute-phase component human alpha(1)-antitrypsin (AAT) has been shown for the first time. Results of light scattering experiments demonstrated that AAT efficiently inhibits both heat- and chemical-induced aggregation of various test proteins including alcohol dehydrogenase, aldolase, carbonic anhydrase, catalase, citrate synthase, enolase, glutathione S-transferase, L-lactate dehydrogenase, and beta(L)-crystallin. The results suggest that the unique metastable serpin architecture enables dual function, protease inhibiton as well as chaperone activity and highlights the serpin superfamily as a possible source of additional intra- and extracellular chaperones (e.g. antichymotrypsin). The present find...

Proteomic studies on receptor for advanced glycation end product variants in idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease

Proteomics. Clinical Applications — Fri, 08 Jan 2010 00:00:00 +0100

Conclusions and clinical relevance: This study shows an involvement of the three RAGE variants (FL-RAGE, cRAGE, esRAGE) in IPF. The decline of FL-RAGE and cRAGE, but not esRAGE, in COPD lungs is evidence of involvement of specific RAGE variants also in this disease. (Source: Proteomics. Clinical Applications)

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The Influence of Wall Stress on AAA Growth and Biomarkers.

PubMed: Eur J Vasc Endovasc ... — Thu, 07 Jan 2010 00:00:00 +0100

CONCLUSION: Although lower relative wall stress was associated to a lower AAA growth rate, no relation was found between biomarker concentrations and wall stress. Future research may focus on more and extensive biomarker measurements in relation to AAA wall stress. PMID: 20060752 [PubMed - as supplied by publisher] (Source: PubMed: Eur J Vasc Endovasc ...)

{alpha}1-Antitrypsin deficiency: Forgotten etiology.

Canadian Family Physician Medecin de Famille Canadien — Fri, 01 Jan 2010 00:00:00 +0100

CONCLUSION: alpha(1)-Antitrypsin deficiency is a common genetic condition that can be involved in premature lung and liver disease. Consider the diagnosis to allow earlier institution of AAT augmentation therapy to slow the progression of premature lung disease in affected patients. PMID: 20090075 [PubMed - in process] (Source: Canadian Family Physician Medecin de Famille Canadien)

Proteomic analysis of amniotic fluid in pregnancies with Klinefelter syndrome foetuses.

Journal of Proteomics — Wed, 30 Dec 2009 00:00:00 +0100

Authors: Anagnostopoulos AK, Kolialexi A, Mavrou A, Vougas K, Papantoniou N, Antsaklis A, Kanavakis E, Fountoulakis M, Tsangaris GT Klinefelter syndrome is a sex chromosomal abnormality (47, XXY karyotype), occurring approximately in 1 in 1000 male live births. In the present study proteomic analysis was performed in twelve 2(nd) trimester amniotic fluid samples, eight coming from pregnancies with normal males and four with Klinefelter syndrome foetuses, as shown by routine prenatal cytogenetic analysis. Samples were analysed by 2-DE, coupled with MALDI-TOF-MS analysis . Three proteins (Ceruloplasmin, Alpha-1-antitrypsin and Zinc-alpha-2-glycoprotein) were found to be up-regulated in samples obtained from pregnancies with Klinefelter syndrome foetuses, whereas four proteins (Apolipopro...

Non-Viral-Related Pathologic Findings in Liver Needle Biopsy Specimens From Patients With Chronic Viral Hepatitis.

American Journal of Clinical Pathology — Tue, 22 Dec 2009 20:08:18 +0100

We describe our experience in a 6-year period and discuss the pathologist's role. Liver biopsies of 1,842 patients with hepatitis B or C, for the 2001-2007 period at the University Health Network, Toronto, Canada, were reviewed; 410 other diagnoses were documented in 377 patients (20.5%; mean age, 25.4 years; range, 15-80 years). These diagnoses included 58 hepatocellular carcinomas and 16 dysplastic nodules, which are recognized complications of chronic viral hepatitis. The remaining findings included the following: steatosis/steatohepatitis, 251; hemosiderosis, 62; granulomatous disease, 7; drug-induced hepatitis, 4; primary biliary cirrhosis, 3; Wilson disease, 2; metastases, 2; and cholangiocarcinoma, atypical lymphoid proliferation, alpha(1)-antitrypsin deficiency, cystic fibrosis, an...

Gene Therapy Makes Mice Breath Easier

Health News from Medical News Today — Tue, 22 Dec 2009 10:00:00 +0100

Individuals with single-gene mutations that mean they have abnormally low levels of the protein alpha-1 antitrypsin are highly susceptible to emphysema, a progressive lung disease that causes severe shortness of breath. Previous attempts to correct single-gene defects that cause lung disease by gene transfer have failed to achieve sustained gene expression in the mouse lung... (Source: Health News from Medical News Today)

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Gene Therapy Makes Mice Breath Easier

Asthma / Respiratory News From Medical News Today — Tue, 22 Dec 2009 10:00:00 +0100

Gene Therapy Makes Mice Breath Easier

Asthma / Respiratory News From Medical News Today — Tue, 22 Dec 2009 10:00:00 +0100

Gene therapy makes mice breath easier

EurekAlert! - Medicine and Health — Mon, 21 Dec 2009 05:00:00 +0100

(Journal of Clinical Investigation) Individuals with single-gene mutations that decrease levels of the protein alpha-1 antitrypsin are highly susceptible to emphysema, a progressive lung disease that causes severe shortness of breath. Previous attempts to correct these mutations by gene transfer failed to achieve sustained gene expression in the mouse lung. However, researchers have now developed an approach that enabled them to attain sustained in vivo expression of normal human alpha-1 antitrypsin at levels able to improve emphysema in mice. (Source: EurekAlert! - Medicine and Health)

C-reactive protein and leucocyte activation in psoriasis vulgaris according to severity and therapy

Journal of the European Academy of Dermatology and Venereology — Fri, 11 Dec 2009 00:00:00 +0100

Conclusion We propose CRP as a useful marker of psoriasis severity that could be used to monitor psoriasis and its treatment, and, together with PASI and elastase, could also be used as a global index of severity. (Source: Journal of the European Academy of Dermatology and Venereology)

Alpha-1-antitrypsin phenotypes in adult liver disease patients.

Upsala Journal of Medical Sciences — Wed, 09 Dec 2009 15:44:03 +0100

Authors: Topic A, Alempijevic T, Milutinovic AS, Kovacevic N Abstract Alpha-1-antitrypsin (AAT) is an important serine protease inhibitor in humans. Hereditary alpha-1-antitrypsin deficiency (AATD) affects lungs and liver. Liver disease caused by AATD in paediatric patients has been previously well documented. However, the association of liver disease with alpha-1-antitrypsin gene polymorphisms in adults is less clear. Therefore, we aimed to study AAT polymorphisms in adults with liver disease. We performed a case-control study. AAT polymorphisms were investigated by isoelectric focusing in 61 patients with liver cirrhosis and 9 patients with hepatocellular carcinoma. The control group consisted of 218 healthy blood donors. A significant deviation of observed and expected frequency of ...

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A novel core fractionation process of human plasma by expanded bed adsorption chromatography.

Analytical Biochemistry — Sat, 05 Dec 2009 00:00:00 +0100

Authors: Lihme A, Hansen MB, Andersen IV, Burnouf T Current plasma fractionation technology combines ethanol precipitation with packed bed chromatography. We have developed a novel core fractionation process comprising 5 expanded bed adsorption (EBA) chromatographic steps on high-density modified agarose/tungsten carbide beads. Plasma was first chromatographed on two DEAE-tungsten carbide agarose adsorbents (respective mean particle diameters of d(v)(0.5) = 190 mum and d(v)(0.5) = 37 mum) to isolate at 50-80% recovery a fraction containing 4-7 IU/ml of Factor II (FII), FIX, and FX (specific activity over 1 IU/mg) and another, enriched in FVIII and von Willebrand factor (VWF) (about 1 IU/ml and 0.6 IU/mg), respectively. The flow-through was adsorbed on 4% agarose-10% tungsten carbide be...

Calnexin Phosphorylation Attenuates the Release of Partially Misfolded {alpha}1-Antitrypsin to the Secretory Pathway [Protein Synthesis, Post-Translational Modification, and Degradation]

Journal of Biological Chemistry — Fri, 04 Dec 2009 14:36:50 +0100

Calnexin is a type I integral membrane phosphoprotein resident of the endoplasmic reticulum. Its intraluminal domain has been deduced to function as a lectin chaperone coordinating the timing of folding of newly synthesized N-linked glycoproteins of the secretory pathway. Its C-terminal cytosolic oriented extension has an ERK1 phosphorylation site at Ser563 affecting calnexin association with the translocon. Here we find an additional function for calnexin phosphorylation at Ser563 in endoplasmic reticulum quality control. A low dose of the misfolding agent l-azetidine 2-carboxylic acid slows glycoprotein maturation and diminishes the extent and rate of secretion of newly synthesized secretory 1-antitrypsin. Under these conditions the phosphorylation of calnexin is enhanced at Ser563. Inhi...

Functional life-long maintenance of engineered liver tissue in mice following transplantation under the kidney capsule

Journal of Tissue Engineering and Regenerative Medicine — Fri, 04 Dec 2009 00:00:00 +0100

The ability to engineer biologically active cells and tissue matrices with long-term functional maintenance has been a principal focus for investigators in the field of hepatocyte transplantation and liver tissue engineering. The present study was designed to determine the efficacy and temporal persistence of functional engineered liver tissue following transplantation under the kidney capsule of a normal mouse. Hepatocytes were isolated from human [alpha]-1 antitrypsin (hA1AT) transgenic mouse livers. Hepatocytes were subsequently transplanted under the kidney capsule space in combination with extracellular matrix components (Matrigel) for engineering liver tissues. The primary outcome of interest was to assess the level of engineering liver tissue function over the experimental period, w...

Upper Gastrointestinal Bleeding in a Patient with HIV Infection

Journal of Infection — Tue, 01 Dec 2009 00:00:00 +0100

A 51-year-old male from Brazil presented with three weeks of melaena and abdominal distension and one week of fevers and myalgia. HIV infection was diagnosed 12 years previously. CD4 count was 400 cells/μl and viral load undetectable on emtricitabine/tenofovir/lopinavir/saquinavir in the last 4 years. Previous treatment included zidovudine, stavudine, lamivudine and didanosine. He took no other medications and had no other significant past medical history or family history. He had a male partner and denied alcohol or illicit drug use. He had travelled to Brazil 12 months ago. Physical examination revealed moderate ascites and splenomegaly. Haemaglobin was 5.9g/dL, normal white blood cell and platelet count, albumin 34g/L, liver enzymes unremarkable. Oesophagogastroduodenoscopy confirmed o...

Increased Arterial Stiffness In Patients With Alpha 1 Antitrypsin Deficiency

Artery Research — Tue, 01 Dec 2009 00:00:00 +0100

Rationale: Alpha 1 Antitrypsin (AAT) deficiency is a familial cause of emphysema, due to reduced antiproteolytic activity within lungs. Systemic manifestations however, remain little explored. We have previously demonstrated increased arterial stiffness (AS) in patients with COPD and hypothesised that AAT deficient patients would present similarly but with lesser smoking exposure. (Source: Artery Research)

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Polymorphism of alpha-1-antitrypsin in hematological malignancies

Genetics and Molecular Biology — Fri, 27 Nov 2009 15:41:51 +0100

Alpha-1-antitrypsin (AAT) or serine protease inhibitor A1 (SERPINA1) is an important serine protease inhibitor in humans. The main physiological role of AAT is to inhibit neutrophil elastase (NE) released from triggered neutrophils, with an additional lesser role in the defense against damage inflicted by other serine proteases, such as cathepsin G and proteinase 3. Although there is a reported association between AAT polymorphism and different types of cancer, this association with hematological malignancies (HM) is, as yet, unknown. We identified AAT phenotypes by isoelectric focusing (in the pH 4.2-4.9 range) in 151 serum samples from patients with HM (Hodgkins lymphomas, non-Hodgkins lymphomas and malignant monoclonal gammopathies). Healthy blood-donors constituted the control group (n...

Liver transplantation and pancreatic resection: A single-center experience and a review of the literature

Liver Transplantation — Tue, 24 Nov 2009 00:00:00 +0100

In conclusion, liver transplantation and pancreatic resection remain uncommon, and a good outcome can be achieved. Recurrence of malignant disease is the main factor limiting survival, and specific morbidity may be related to pancreatic resection and liver transplantation. Liver Transpl 15:1728-1737, 2009. © 2009 AASLD. (Source: Liver Transplantation)

E-Cadherin/{beta}-Catenin and CD10: A Limited Immunohistochemical Panel to Distinguish Pancreatic Endocrine Neoplasm From Solid Pseudopapillary Neoplasm of the Pancreas on Endoscopic Ultrasound-Guided Fine-Needle Aspirates of the Pancreas.

American Journal of Clinical Pathology — Mon, 23 Nov 2009 04:50:55 +0100

Authors: Burford H, Baloch Z, Liu X, Jhala D, Siegal GP, Jhala N Pancreatic endocrine neoplasm (PEN) and solid pseudopapillary neoplasm of the pancreas (SPN) frequently pose diagnostic challenges. We sought to determine which markers could provide the best immunophenotypic characterization of PEN and SPN, allowing separation on limited cytology samples. We retrieved 22 resected PEN (n = 12) and SPN (n = 10) tumors to serve as a training set for the performance of extensive immunohistochemical staining. Based on these results, we selected a subset of antibodies for application to 25 fine-needle aspiration (FNA) samples from PEN (n = 16) and SPN (n = 9). Chromogranin A, synaptophysin, CD56, and progesterone receptor (PR) highlighted PEN cases in the training set; E-cadherin was noted in ...

Complex formation between human prostate-specific antigen and protease inhibitors in mouse plasma

The Prostate — Sat, 21 Nov 2009 00:00:00 +0100

When secreted from the prostate, most of prostate-specific antigen (PSA) is free and enzymatically active. Upon reaching circulation, active PSA is inactivated by complex formation with protease inhibitors. To justify the use of mouse models for evaluation of the function of PSA and for studies on therapeutic modalities based on modulation of PSA activity, it is important to know whether PSA complexation is similar in mouse and man.To characterize the circulating forms of PSA in mouse, we used subcutaneous LNCaP and 22RV1 human prostate cancer cell xenograft tumor models. We also added PSA directly to mouse serum. Free and total PSA were measured by immunoassay, and PSA complexes were extracted by immunopurification followed by SDS-PAGE, in-gel trypsin digestion and identification of signa...

Is Milk Thistle OK for Children?

Dr. Weil Q&A — Tue, 17 Nov 2009 16:28:38 +0100

My son, age three, has been diagnosed with alpha-1 antitrypsin deficiency. His liver enzymes are elevated, but he is in good health. I am very interested in milk thistle for liver support, but his specialist does not agree. Is milk thistle safe for children as a long term supplement? (Source: Dr. Weil Q&A)

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Progression of Emphysema Evaluated by MRI Using Hyperpolarized (3)He (HP (3)He) Measurements in Patients with Alpha-1-Antitrypsin (A1AT) Deficiency Compared with CT and Lung Function Tests.

Acta Radiologica — Sun, 01 Nov 2009 00:00:00 +0100

Conclusion: This pilot study indicates the possible use of nonionizing HP (3)He MRI for monitoring the progression of emphysema. However, in the future, larger studies are needed to confirm these preliminary results. PMID: 19863412 [PubMed - in process] (Source: Acta Radiologica)

CT scan appearance, densitometry, and health status in protease inhibitor SZ alpha1-antitrypsin deficiency.

Chest — Sun, 01 Nov 2009 00:00:00 +0100

CONCLUSIONS: Subjects with PiSZ showed less emphysema on CT scans, more apical predominance, less abnormal respiratory physiology test results, but similar health status impairment compared with matched subjects with PiZZ. PMID: 19892672 [PubMed - in process] (Source: Chest)

Combination of alpha-1 antitrypsin and doxycycline suppresses collagen-induced arthritis

The Journal of Gene Medicine — Wed, 28 Oct 2009 00:00:00 +0100

Rheumatoid arthritis (RA) is a complex disease characterized by autoimmune inflammation and joint destruction. Despite recent advances in RA treatment, current therapies require further improvement to overcome adverse events and ineffectiveness in some cases. By targeting different pathways/molecules using drug combinations, a better treatment can be obtained, whereas adverse events are reduced. In order to develop a new treatment option, the present study employs a gene therapy-based combination therapy using doxycycline and human alpha-1 antitrypsin (hAAT).DBA/1 mice were immunized with type II collagen to induce arthritis. Four weeks before immunization, they received a doxycycline containing diet and a single injection of adeno-associated virus vector expressing hAAT under the control ...

Hepatoid carcinoma of the ovary with sex cord stromal tumor: a previously unrecognized association

Archives of Gynecology and Obstetrics — Sat, 24 Oct 2009 16:57:10 +0100

Conclusion The occurrence of this unreported association of HC with Sertoli-like tumor, the problems of differential diagnosis and therapeutic management of these tumors are the subject of this presentation. A diagnosis of ovarian metastasis from hepatocellular carcinoma is easy in patients with known primary tumor of liver and should be always excluded in these cases as an hepatoid variant of yolk sac tumor. Immunohistochemistry is not useful in these cases. However, a combination of clinical and pathological features is necessary for a correct diagnosis. Content Type Journal ArticleCategory Gynecologic OncologyDOI 10.1007/s00404-009-1259-xAuthors Antonio D’Antonio, A.O. “San Giovanni di Dio e Ruggi d’Aragona” Unit of Pathologic Anatomy and Oncology via S. ...

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

Archives of Disease in Childhood - Fetal and Neonatal Edition — Wed, 21 Oct 2009 17:02:02 +0100

Conclusions: The risk of VKD bleeding in breastfed infants with A1AD was high and did not correlate with serum level of conjugated bilirubin at diagnosis. A similar absolute risk was previously reported in breastfed infants with biliary atresia under the same prophylactic regimen. This confirms that—without adequate prophylaxis—the risk of VKD bleeding is uniformly high in exclusively breastfed infants with cholestatic jaundice, irrespective of underlying aetiology. (Source: Archives of Disease in Childhood - Fetal and Neonatal Edition)

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Neutrophil Elastase Increases Airway Epithelial Nonheme Iron Levels

Clinical and Translational Science — Mon, 05 Oct 2009 23:00:00 +0100

Alpha-1-antitrypsin (A1AT) deficiency is characterized by increased neutrophil elastase (NE) activity and oxidative stress in the lung. We hypothesized that NE exposure generates reactive oxygen species by increasing lung nonheme iron. To test this hypothesis, we measured bronchoalveolar lavage (BAL) iron and ferritin levels, using inductively coupled plasma (ICP) optical emission spectroscopy and an ELISA, respectively, in A1AT-deficient patients and healthy subjects. To confirm the role of NE in regulating lung iron homeostasis, we administered intratracheally NE or control buffer to rats and measured BAL and lung iron and ferritin. Our results demonstrated that A1AT-deficient patients and rats postelastase exposure have elevated levels of iron and ferritin in the BAL. To investigate the...

Development of Predictive Models for Airflow Obstruction in Alpha-1-Antitrypsin Deficiency

American Journal of Epidemiology — Thu, 01 Oct 2009 12:00:44 +0100

Alpha-1-antitrypsin deficiency is a genetic condition associated with severe, early-onset chronic obstructive pulmonary disease (COPD). However, there is significant variability in lung function impairment among persons with the protease inhibitor ZZ genotype. Early identification of persons at highest risk of developing lung disease could be beneficial in guiding monitoring and treatment decisions. Using a multicenter, family-based study sample (2002–2005) of 372 persons with the protease inhibitor ZZ genotype, the authors developed prediction models for forced expiratory volume in 1 second (FEV1) and the presence of severe COPD using demographic, clinical, and genetic variables. Half of the data sample was used for model development, and the other half was used for model validation...

{alpha}1-Antitrypsin deficiency: best clinical practice [Best practice]

Journal of Clinical Pathology — Fri, 25 Sep 2009 17:01:35 +0100

1-Antitrypsin (AAT), a 52 kDa plasma protein, is produced mainly in the liver. It is the most abundant circulating serine proteinase inhibitor (serpin). It has also previously been called protease inhibitor to reflect its function as a general inhibitor of serine proteases. Its main physiological role is to inhibit neutrophil elastase and it contributes to the innate immune system as an anti-inflammatory protein. Severe AAT deficiency is most prevalent in northern Europeans affecting about 1 in 3000 of the population. AAT deficiency predisposes individuals who smoke to developing pulmonary emphysema in the fourth–fifth decade of adult life and to childhood cirrhosis in about 10% of cases, with the initial presentation being prolonged neonatal jaundice. The mean interval from presenta...

[Best practice] {alpha}1-Antitrypsin deficiency: best clinical practice

Journal of Clinical Pathology — Thu, 24 Sep 2009 23:00:00 +0100

Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy [Medical_Sciences]

Proceedings of the National Academy of Sciences — Mon, 21 Sep 2009 23:00:00 +0100

Alpha-1 antitrypsin (AAT) deficiency is well-suited as a target for human gene transfer. We performed a phase 1, open-label, dose-escalation... (Source: Proceedings of the National Academy of Sciences)

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Is lysyl oxidase-like protein-1, alpha-1 antitrypsin, and neutrophil elastase site specific in pelvic organ prolapse?

International Urogynecology Journal — Fri, 18 Sep 2009 06:47:38 +0100

Conclusions ATT, NE, and LOXl-1 expression was variable among different biopsy sites in the vagina. No consistent pattern was present when the subjects were grouped by the most prominent defect. We recommend careful consideration of biopsy sites in future studies on POP to enhance reproducibility of data. Content Type Journal ArticleCategory Original ArticleDOI 10.1007/s00192-009-0905-yAuthors Weng Chi Man, Stanford University School of Medicine Department of Obstetrics and Gynecology 300 Pasteur Drive, HH-333 Stanford CA 94305-5317 USAJason Yen-Ping Ho, Stanford University School of Medicine Department of Obstetrics and Gynecology 300 Pasteur Drive, HH-333 Stanford CA 94305-5317 USAYan Wen, Stanford University School of Medicine Department of Obstetrics and Gynecolog...

Kamada Presents Data On Inhaled Alpha-1 Antitrypsin In Cystic Fibrosis Patients At The European Respiratory Society Meeting 2009, Vienna

Health News from Medical News Today — Wed, 16 Sep 2009 07:00:00 +0100

Kamada, a bio-pharmaceutical company engaged in the development, manufacturing and marketing of specialty life-saving therapeutics, announced that data on its next-generation alpha-1 antitrypsin (Inhaled-AAT) in cystic fibrosis patients was presented, at the Annual Congress of the European Respiratory Society (ERS) 2009, Vienna. (Source: Health News from Medical News Today)

Kamada Presents Data on Inhaled Alpha-1 Antitrypsin in Cystic Fibrosis Patients at the European Respiratory Society Meeting 2009, Vienna

Drugs.com - Clinical Trials — Tue, 15 Sep 2009 16:16:12 +0100

NESS ZIONA, Israel--(BUSINESS WIRE)--Sep 14, 2009 - Kamada, a bio-pharmaceutical company engaged in the development, manufacturing and marketing of specialty life-saving therapeutics, announced that data on its next-generation alpha-1... (Source: Drugs.com - Clinical Trials)

High burden of acute exacerbation found in COPD with AATD

MedWire News - Respiratory — Thu, 10 Sep 2009 00:00:00 +0100

The vast majority of patients with chronic obstructive pulmonary disease and concurrent alpha-1 antitrypsin deficiency will experience at least one exacerbation per year, despite augmentation therapy, study findings show. (Source: MedWire News - Respiratory)

Z and Mmalton-1-antitrypsin deficiency-associated hepatocellular carcinoma: a genetic study

Liver International — Wed, 09 Sep 2009 23:00:00 +0100

The histological hallmark of [alpha]-1-antitrypsin deficiency (AATD) is the presence of periodic acid-Schiff diastase (PASD)-resistant positive globules in hepatocytes, with a heterogeneous distribution. It is noteworthy that hepatocellular carcinoma (HCC) arises specifically from the AAT-negative areas but the reason for this remains unclear. To determine whether the different distribution of AAT globules within neoplastic and non-neoplastic hepatocytes is the result of a self-induced correction of the genetic defect. Two HCV-positive patients with AATD-associated HCC were studied. One patient harboured a compound heterozygous PiSZ genotype whereas the other showed the rarer PiMMmalton in heterozygosity. In both cases, neoplastic hepatocytes appeared globule devoid, while non-neoplastic h...

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Gene variant heightens risk of severe liver disease

Medicineworld.org: New Article Alert — Wed, 09 Sep 2009 12:43:32 +0100

Scientists at the University of North Carolina at Chapel Hill have discovered a genetic risk factor for severe liver disease in people with cystic fibrosis. Those who carry a particular variant of the SERPINA1 gene (also known as alpha-1-antitrypsin or alpha-1-antiprotease) are five times more likely to develop cirrhosis and other liver complications than patients who carry the normal version of the gene........ (Source: Medicineworld.org: New Article Alert)

Development of Predictive Models for Airflow Obstruction in Alpha-1-Antitrypsin Deficiency.

Am J Epidemiol — Tue, 01 Sep 2009 23:00:00 +0100

Authors: Castaldi PJ, Demeo DL, Kent DM, Campbell EJ, Barker AF, Brantly ML, Eden E, McElvaney NG, Rennard SI, Stocks JM, Stoller JK, Strange C, Turino G, Sandhaus RA, Griffith JL, Silverman EK Alpha-1-antitrypsin deficiency is a genetic condition associated with severe, early-onset chronic obstructive pulmonary disease (COPD). However, there is significant variability in lung function impairment among persons with the protease inhibitor ZZ genotype. Early identification of persons at highest risk of developing lung disease could be beneficial in guiding monitoring and treatment decisions. Using a multicenter, family-based study sample (2002-2005) of 372 persons with the protease inhibitor ZZ genotype, the authors developed prediction models for forced expiratory volume in 1 second (FE...

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

Respiratory Research — Wed, 12 Aug 2009 23:00:00 +0100

Conclusions: PD15 is the most sensitive index of emphysema progression and of treatment modification. Targeted sampling may be more sensitive than whole lung analysis.Trial registration: Registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887. (Source: Respiratory Research)

Gene therapy hope for people with alpha-1 antitrypsin deficiency

MedWire News - Respiratory — Wed, 12 Aug 2009 11:21:17 +0100

Patients with a genetic deficiency that increases the risk for emphysema could soon benefit from therapy to “replace” the defective gene, say researchers. (Source: MedWire News - Respiratory)

Gene Therapy Trial Succeeds In Boosting Protective Protein In Patients With Hereditary Lung Disease

ScienceDaily Headlines — Tue, 11 Aug 2009 11:53:02 +0100

Gene therapy researchers have safely given new, functional genes to patients with a hereditary defect that can lead to fatal lung and liver diseases, according to clinical trial findings. Three patients, apparently for the first time in their lives, produced trace amounts of the protective form of a protein called alpha-1 antitrypsin for up to one year, a potential step toward a gene therapy for about 100,000 Americans with alpha-1 antitrypsin deficiency. (Source: ScienceDaily Headlines)

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New genes at work in patients with hereditary lung disease

EurekAlert! - Medicine and Health — Mon, 10 Aug 2009 04:00:00 +0100

(University of Massachusetts Medical School) Researchers at the University of Massachusetts Medical School and the University of Florida in Gainesville have safely given new, functional genes to patients with alpha-1 antitrypsin deficiency, a hereditary defect that can lead to fatal lung and liver diseases. (Source: EurekAlert! - Medicine and Health)

New genes at work in patients with hereditary lung disease

EurekAlert! - Medicine and Health — Mon, 10 Aug 2009 04:00:00 +0100

(University of Florida) Gene therapy researchers have safely given new, functional genes to patients with a hereditary defect that can lead to fatal lung and liver diseases, according to clinical trial findings. Three patients, apparently for the first time in their lives, produced trace amounts of the protective form of a protein called alpha-1 antitrypsin for up to one year, a potential step toward a gene therapy for about 100,000 Americans with alpha-1 antitrypsin deficiency. (Source: EurekAlert! - Medicine and Health)

Angiostatic factors normally restrict islet endothelial cell proliferation and migration: implications for islet transplantation

Transplant International — Thu, 06 Aug 2009 23:00:00 +0100

In conclusion, VEGF may attract recipient blood vessels towards intrahepatically transplanted islets, but intra-islet vascular expansion is hampered by angiostatic factors present within the islets and the islet endothelium. Inhibition of angiostatic factors early after transplantation may provide a strategy to restore the islet vascular network and improve islet graft function. (Source: Transplant International)

Alpha-1 Foundation Research Opportunities

ScanGrants feed — Tue, 04 Aug 2009 23:00:00 +0100

The objective of this grant is to provide support for excellent Alpha-1 Antitrypsin (AAT) Deficiency-related research projects that have been submitted to and approved by the National Institutes of Health (NIH), but cannot be supported by the available NIH funds. Thus, this award complements the granting mechanism of the NIH for projects of potential interest to individuals served by the Alpha-1 Foundation. Funds provided by the Alpha-1 Foundation through this program are intended to lead to the development of sufficient preliminary data to make AAT-related applications highly competitive in the NIH review process. Information derived from Alpha-1 Foundation supported research studies is intended to lead to solicitation of additional, subsequent funds from other agencies such as the NIH. E...

Kamada's Biologics License Application for IV-AAT to Treat Alpha-1 Antitrypsin Deficiency is Accepted for Review by the US Food and Drug Administration

Drugs.com - New Drug Applications — Tue, 04 Aug 2009 16:28:11 +0100

NESS ZIONA, Israel--(BUSINESS WIRE)--Aug 4, 2009 - Kamada, a bio-pharmaceutical company engaged in the development, manufacturing and marketing of specialty life-saving therapeutics, announced today that the United States Food and... (Source: Drugs.com - New Drug Applications)

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Chlorhexidine prevents hypochlorous acid-induced inactivation of alpha-1-antitrypsin (alpha-1-AT).

Clinical and Experimental Pharmacology and Physiology — Mon, 03 Aug 2009 23:00:00 +0100

Authors: Montecucco F, Bertolotto M, Ottonello L, Pende A, Dapino P, Quercioli A, Mach F, Dallegri F 1. Chlorhexidine digluconate has been used as a topical antiseptic in the treatment of acne vulgaris and periodontitis. The acute phase of these diseases involves neutrophilic infiltration. Neutrophil activation and recruitment to inflammatory sites are crucial in both protection against bacterial infections and induction of hystotoxic damage. Activated neutrophils release several enzymes (elastase and myeloperoxidase [MPO]), which contribute to tissue injury through the direct toxic activity, the generation of oxidants and the inactivation of protective factors, such as alpha-1-antitrypsin (alpha-1-AT). In the present study, we investigated if chlorhexidine might modulate neutrophil-me...

Impact of rituximab-associated B-cell defects on West Nile virus meningoencephalitis in solid organ transplant recipients

Clinical Transplantation — Thu, 30 Jul 2009 23:00:00 +0100

We describe a case of a patient with alpha-1-antitrypsin deficiency who underwent single lung transplantation in 2005 and was maintained on tacrolimus, cytoxan and prednisone. More recently, she had received two courses of rituximab for recurrent A2[ndash]A3 grade rejection with concomitant capillaritis and presented six months later with rapid, fulminant WNV meningoencephalitis. Her diagnosis was made by cerebrospinal fluid (CSF) PCR but serum and CSF WNV IgM and IgG remained negative. She received WNV-specific hyperimmune globulin (Omr-Ig-Am®) through a compassionate protocol. She experienced a rapidly progressive and devastating neurological course despite treatment and died three wk after onset of her symptoms. Autopsy revealed extensive meningoencephalomyelitis. (Source: Clinical Tra...

Oxidized {alpha}1-antitrypsin stimulates the release of monocyte chemotactic protein-1 from lung epithelial cells: potential role in emphysema

AJP: Lung Cellular and Molecular Physiology — Wed, 22 Jul 2009 23:00:00 +0100

1-Antitrypsin (AT) is a major elastase inhibitor within the lung. Oxidation of critical methionine residues in AT generates oxidized AT (Ox-AT), which has a greatly diminished ability to inhibit neutrophil elastase. This process may contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD) by creating a functional deficiency of AT permitting lung destruction. We show here that Ox-AT promotes release of human monocyte chemoattractant protein-1 (MCP-1) and IL-8 from human lung type epithelial cells (A549) and normal human bronchial epithelial (NHBE) cells. Native, cleaved, polymeric AT and secretory leukoproteinase inhibitor (SLPI) and oxidized conformations of cleaved, polymeric AT and SLPI did not have any significant effect on MCP-1 and IL-8 secretion. These findings ...

Activity-based mass spectrometric characterization of proteases and inhibitors in human saliva

Proteomics. Clinical Applications — Wed, 08 Jul 2009 23:00:00 +0100

Proteases present in oral fluid effectively modulate the structure and function of some salivary proteins and have been implicated in tissue destruction in oral disease. To identify the proteases operating in the oral environment, proteins in pooled whole saliva supernatant were separated by anion-exchange chromatography and individual fractions were analyzed for proteolytic activity by zymography using salivary histatins as the enzyme substrates. Protein bands displaying proteolytic activity were particularly prominent in the 50-75 kDa region. Individual bands were excised, in-gel trypsinized and subjected to LC/ESI-MS/MS. The data obtained were searched against human, oral microbial and protease databases. A total of 13 proteases were identified all of which were of mammalian origin. Pro...

Proteomic analysis of circulating immune complexes in juvenile idiopathic arthritis reveals disease-associated proteins

Proteomics. Clinical Applications — Wed, 08 Jul 2009 23:00:00 +0100

In this study, the circulating immune complex proteome was examined to elucidate disease-associated proteins that are overexpressed in patients with an aggressive, and at times destructive, disease phenotype. To solve this proteome, circulating immune complexes were isolated from the sera of patients with chronic, erosive or early-onset, aggressive disease and from patients in medical remission or healthy controls subsequent to protein separation by 2-DE. Thirty-seven protein spots were overexpressed in the circulating immune complexes of the aggressive disease groups as compared to controls, 28 of which have been confidently identified to date. Proteolytic fragments of glyceraldehyde-3-phosphate dehydrogenase, serotransferrin, and [alpha]-1-antitrypsin have been identified among others. I...

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Serum trypsin inhibitory capacity in hemodialysis patients.

Saudi Journal of Kidney Diseases and Transplantation — Tue, 30 Jun 2009 23:00:00 +0100

Authors: Hashemi M, Mehrabifar H, Homayooni F, Naderi M, Montazerifar F, Ghavami S It has been established that overproduction of reactive oxygen species (ROS) occurs during hemodialysis causing oxidation of proteins. Alpha-1-antitrypsin is the major circulating anti-protease which contains methionine in the active site. The aim of the present study was to measure the level of serum trypsin inhibitory capacity (sTIC) in hemodialysis patients. This case-control study was performed in 52 hemodialysis patients and 49 healthy controls. sTIC was measured by enzymatic assay. The sTIC was significantly (P< 0.001) lower in hemodialysis patients (1.87 +/- 0.67 micromol/min/mL) than healthy controls (2.83 +/- 0.44 micromol/min/L). Reduction of sTIC may be due to the oxidation of methionine re...

[Biochemical and molecular diagnosis of alpha 1 antitrypsin deficiency in a Tunisian family.]

Annales de Biologie Clinique — Tue, 30 Jun 2009 23:00:00 +0100

Authors: Denden S, Braham W, Amri F, Lakhdar R, Lefranc G, Knani J, Chibani JB, Khelil AH Our study investigated alpha 1 antitrypsin deficiency (AATD) diagnosis in a family originated from central Tunisia and showing a familial history of asthma. Biochemical and genetic diagnosis for AATD was performed according to current diagnostic standards. AAT level quantification in affected individuals showed plasma AAT levels consistent with intermediate AATD (ranged from 0.91 to 1.04 g/L). The molecular analysis was assessed using the genotyping of the most prevalent PI*S and PI*Z SERPINA1 mutations and the sequencing of AAT coding exons for rare AATD variants detection. No PI*S or PI*Z deficient variants were seen in this family. Sequencing results showed the inheritance of the deficient rare...

High intestinal IgA associates with reduced risk of IgE-associated allergic diseases

Pediatric Allergy and Immunology — Sun, 28 Jun 2009 23:00:00 +0100

Kukkonen K, Kuitunen M, Haahtela T, Korpela R, Poussa T, Savilahti E. High intestinal IgA associates with reduced risk of IgE-associated allergic diseases.Pediatr Allergy Immunol 2009.© 2009 John Wiley & Sons A/S Development of oral tolerance and its stimulation by probiotics are still incomprehensible. Microbial stimulation of the gut may induce a subtle inflammation and induce secretion of mucosal IgA, which participates in antigen elimination. In a cohort of allergy-prone infants receiving probiotics and prebiotics or placebo we studied intestinal IgA and inflammation in the development of eczema, food allergy, asthma, and rhinitis (allergic diseases). We performed a nested unmatched case[ndash]control study of 237 infants participating in a randomized double-blind placebo-controlled a...

Protein profiling of low-density lipoprotein from obese subjects

Proteomics. Clinical Applications — Tue, 23 Jun 2009 23:00:00 +0100

Although obesity and high levels of low-density lipoprotein (LDL) are well-known risk factors for cardiovascular disease, the precise role(s) of different LDL constituents in obesity has not been explored. In the present study, we compared the LDL proteome of healthy control adults (body mass index30). LDL was isolated by density-gradient ultracentrifugation and proteins were separated with 2-D PAGE, quantified, and identified by peptide mass fingerprinting using MALDI-TOF MS. A new LDL-associated protein was identified as transthyretin and found to be significantly more abundant in LDL from the obese subjects. In addition, LDL from the obese subjects contained relatively more [alpha]1-antitrypsin, apo J, apo C-II, than LDL from controls, and also more of an acidic isoform (pI/Mr; 5.2/23 1...

[Mechanisms Of Signal Transduction] Selenoprotein S/SEPS1 Modifies Endoplasmic Reticulum Stress in Z Variant {alpha}1-Antitrypsin Deficiency

Journal of Biological Chemistry — Thu, 11 Jun 2009 23:00:00 +0100

Z 1-antitrypsin (ZAAT) deficiency is a disease associated with emphysematous lung disease and also with liver disease. The liver disease of AAT deficiency is associated with endoplasmic reticulum (ER) stress. SEPS1 is a selenoprotein that, through a chaperone activity, decreases ER stress. To determine the effect of SEPS1 on ER stress in ZAAT deficiency, we measured activity of the grp78 promoter and levels of active ATF6 as markers of the unfolded protein response in HepG2 cells transfected with the mutant form of AAT, a ZAAT transgene. We evaluated levels of NFB activity as a marker of the ER overload response. To determine the effect of selenium supplementation on the function of SEPS1, we investigated glutathione peroxidase activity, grp78 promoter activity, and NFB activity in the pre...

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Oxidized alpha-1 antitrypsin stimulates the release of monocyte chemotactic protein-1 from lung epithelial cells: potential role in emphysema.

American Journal of Physiology. Lung Cellular and Molecular Physiology — Thu, 11 Jun 2009 23:00:00 +0100

Authors: Li Z, Alam S, Wang J, Sandstrom CS, Janciauskiene S, Mahadeva R Alpha-1 antitrypsin (AT) is a major elastase inhibitor within the lung. Oxidation of critical methionine residues in AT generates Oxidized AT (Ox-AT) which has a greatly diminished ability to inhibit neutrophil elastase. This process may contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD) by creating a functional deficiency of AT permitting lung destruction. We show here that Ox-AT promotes release of human monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) from human lung type epithelial cells (A549) and normal human bronchial epithelial (NHBE) cells. Unoxidized and oxidized cleaved, native and polymeric conformations and oxidized secretory leukoproteinase inhibitor did...

Kamada Reports Positive Proof-of-Concept Data for Inhaled Alpha-1 Antitrypsin in Bronchiectasis

Drugs.com - Clinical Trials — Tue, 09 Jun 2009 15:30:45 +0100

NESS ZIONA, Israel--(BUSINESS WIRE)--Jun 9, 2009 - Kamada (TASE:KMDA), a bio-pharmaceutical company engaged in the development, manufacturing and marketing of specialty life-saving therapeutics, announced today positive proof of concept data from a... (Source: Drugs.com - Clinical Trials)

Expression of liver-specific markers in naïve adipose-derived mesenchymal stem cells

Liver International — Tue, 09 Jun 2009 04:00:00 +0100

Increasing evidence suggests that adipose tissue contains mesenchymal stem cells (MSC) that possess the ability to transdifferentiate into other cell types including hepatocytes, similar to bone marrow-derived stem cells. The existence of precommitted cells in the MSC population may explain transdifferentiation. Our aim was to identify a population of putative hepatocyte-like precursor cells in human adipose tissue. We analysed the 'basal' hepatic potential of undifferentiated, naïve human adipose-derived mesenchymal stem cells (hADMSC). hADMSC were isolated from human adipose tissue and characterized for cell surface markers and for liver-specific gene expression. The isolated undifferentiated naïve hADMSCs expressed MSC surface markers. They also expressed [alpha]-fetoprotein, CK18, CK...

Cluster headache and alpha 1-antitrypsin deficiency

Cephalalgia — Mon, 08 Jun 2009 04:00:00 +0100

Summ O, Gregor N, Marziniak M, Gralow I, Husstedt IW & Evers S. Cluster headache and alpha 1-antitrypsin deficiency. Cephalalgia 2009. London. ISSN 0333-1024 Little is known about the pathophysiology of cluster headache (CH), one of the most debilitating primary headaches. Interestingly, associations of lung affecting diseases or lifestyle habits such as smoking and sleep apnoea syndrome and CH have been described. Certain genotypes for alpha 1-antitrypsin ([alpha]1-AT) are considered risk factors for emphysema. Our aim was to investigate possible associations between common genotypes of the SERPINA1 gene and CH. Our study included 55 CH patients and 55 controls. [alpha]1-AT levels in serum and the genotype were analysed. Patients CH characteristics were documented. We could not detect any...

Interactions of alpha(1)-proteinase inhibitor with small ligands of therapeutic potential: binding with retinoic acid.

Amino Acids — Tue, 02 Jun 2009 23:00:00 +0100

The objective of this study was to evaluate the potential of alpha(1)-PI to bind small non-peptide ligands of pharmaceutical interest that may attain additional properties to currently available alpha(1)-PI therapeutic preparations. Among putative ligands of bio-medical interest examined in this study, all-trans retinoic acid (RA) was selected due to its recently proposed roles in the lungs, and as an efficient optical probe. The results of this study, including absorption spectroscopy data, fluorescence quenching and the protein-induced chirality of the visible circular dichroism strongly suggest that alpha(1)-PI does bind RA in vitro to non-covalent complexes of up to two moles of RA per one mole of the protein. To our knowledge, this is the first report that provides experimental eviden...

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Kamada Submits U.S. Biologics License Application for the First Liquid, Ready to Use AAT for the Treatment of Alpha-1 Antitrypsin Deficiency

Drugs.com - New Drug Applications — Tue, 02 Jun 2009 15:37:16 +0100

NESS ZIONA, Israel--(BUSINESS WIRE)--Jun 2, 2009 - Kamada (TASE:KMDA) – a bio-pharmaceutical company engaged in the development, manufacturing and marketing of specialty life-saving therapeutics, announced that it has submitted a Biologics License... (Source: Drugs.com - New Drug Applications)

Exacerbations in subjects with alpha-1 antitrypsin deficiency receiving augmentation therapy

Respiratory Medicine — Sun, 24 May 2009 23:00:00 +0100

Conclusion: COPD exacerbations occur frequently and are associated with significant disease burden in subjects with AATD receiving augmentation therapy. (Source: Respiratory Medicine)

Kamada Presents New Data on its Alpha-1 Antitrypsin at the American Thoracic Society Annual Meeting

Drugs.com - Clinical Trials — Tue, 19 May 2009 20:49:41 +0100

<p><dateline></dateline>NESS ZIONA, Israel--(BUSINESS WIRE)--May 19, 2009 - Kamada, a bio-pharmaceutical company engaged in the development, manufacturing and marketing of specialty life-saving therapeutics, today announced that... (Source: Drugs.com - Clinical Trials)

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

Respiratory Medicine — Sun, 17 May 2009 23:00:00 +0100

Summary: Alpha-1-antitrypsin (AAT) deficiency is a common genetic disease which affects both lung and liver. Early diagnosis can help asymptomatic patients to adjust their lifestyle choices in order to reduce the risk of Chronic Obstructive Pulmonary Disease (COPD). The determination of this genetic deficiency prevalence in Madeira Island (Portugal) population is important to clarify susceptibility and define the relevance of performing genetic tests for AAT on individuals at risk for COPD.Two hundred samples of unrelated individuals from Madeira Island were genotyped for the two most common AAT deficiency alleles, PI*S and PI*Z, using Polymerase Chain Reaction-Mediated Site-Directed Mutagenesis.Our results show one of the highest frequencies for both mutations when compared to any already...

Morbid Obesity and Inflammation: A Prospective Study After Adjustable Gastric Banding Surgery

Obesity Surgery — Thu, 14 May 2009 06:53:17 +0100

Conclusions Our results indicate that amelioration of inflammatory markers after LAGB does not seem to negatively impact nutritional status following weight reduction surgery. However, careful attention should be driven to serum IgA. Adequacy of nutritional intake and complete serial laboratory measurements should be always included in the required life-long follow-up of patients surgically treated for morbid obesity. Content Type Journal ArticleCategory Clinical ResearchDOI 10.1007/s11695-009-9848-0Authors Renata Ramalho, University of Porto Immunology, Faculty of Medicine Alameda Prof. Hernâni Monteiro 4202 Porto PortugalCristina Guimarães, University of Porto Immunology, Faculty of Medicine Alameda Prof. Hernâni Monteiro 4202 Porto PortugalCidália Gil, Hospita...

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Mortality in alpha-1-antitrypsin deficiency in the United Kingdom

Respiratory Medicine — Wed, 13 May 2009 23:00:00 +0100

Summary: Background: Four hundred and eighty-eight PiZ alpha-1-antitrypsin deficient patients, who had joined the UK registry over a 9-year period, were followed in an observational study to determine mortality. None had received A1AT augmentation therapy.Methods: Cause of death was confirmed from death certification and medical records. Patients were censored according to length of time on the program or until they withdrew from the program.Results: There were 56 deaths of which 30 were attributed to respiratory causes. Of the remaining 26 deaths, 4 were due to complications from lung transplant, 6 due to liver disease (including 2 post-liver transplant) and the other 16 due to a variety of causes. Kaplan–Meier plots indicated a cumulative hazard for mortality of 18.1% in 9 years, corre...

Lung Volume Reduction Surgery for Patients with Alpha-1 Antitrypsin Deficiency Emphysema

Thoracic Surgery Clinics — Thu, 30 Apr 2009 23:00:00 +0100

Alpha-1 antitrypsin deficiency (A1AD) is a rare genetic disorder characterized by early-onset emphysema and, rarely, liver disease and vasculitis. In the lungs, unopposed and enhanced elastase activity results in accelerated parenchymal destruction leading to emphysematous changes predominantly in the lower lung fields. Medical treatment includes standard therapies for emphysema and so-called “augmentation therapy” using purified pooled plasma alpha-1 antitrypsin. Surgical options include lung transplantation and lung volume reduction surgery. The option of lung volume reduction surgery potentially provides palliation of dyspnea and a bridge to lung transplantation. (Source: Thoracic Surgery Clinics)

Public Workshop: Improving Endpoints, Improving Care

What's New at CBER — Tue, 28 Apr 2009 12:12:00 +0100

Alpha-1 Antitrypsin Augmentation Therapy and Clinical Trials (Source: What's New at CBER)

Tiny change in checkpoint protein hastens onset of liver failure in genetic disease

Baylor College of Medicine News — Tue, 28 Apr 2009 05:00:00 +0100

In this study, Dr. Richard Sifers , associate professor of pathology at BCM, and his colleagues, identify a particular mutation in the gene for a checkpoint enzyme called ER mannosidase I. This … (Source: Baylor College of Medicine News)

Pancreatic-type acinar cell carcinoma of the stomach beneath a focus of pancreatic metaplasia of the gastric mucosa

Human Pathology — Tue, 21 Apr 2009 21:11:59 +0100

Summary: Acinar cell carcinoma is an uncommon type of carcinoma of the pancreas that can exceptionally arise in ectopic pancreatic tissue. Herein, we report a case of a 52-year-old man with pancreatic-type acinar cell carcinoma of the stomach and concomitant pancreatic metaplasia of the adjacent nonneoplastic gastric mucosa. There was neither clinical nor radiographic evidence of a tumor in the pancreas itself. A subtotal gastrectomy was performed. Macroscopically, an ulcerated tumor, measuring 4 × 1.7 cm, was found in the distal antrum. Microscopically, the biopsy and the surgical specimen revealed a neoplasm with a predominantly trabecular architecture composed of moderately atypical cells with finely dispersed chromatin and indistinct nucleoli. The neoplastic cells and those of the adj...

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Serum proteomic profiling and haptoglobin polymorphisms in patients with GVHD after allogeneic hematopoietic cell transplantation

Journal of Hematology and Oncology — Mon, 20 Apr 2009 04:00:00 +0100

In this study, quantitative serum Hp levels were shown to be related to cGVHD development. Further, the data suggest the possibility that specific Hp polymorphisms may be associated with cGVHD development and warrant further investigation. (Source: Journal of Hematology and Oncology)

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

Orphanet Journal of Rare Diseases — Wed, 15 Apr 2009 04:00:00 +0100

Conclusion: this pilot study demonstrated that alleles related to deficiency of AAT are not absent in the Tunisian population, and that rare AATD variants prevailed over commonest PI*Z variant. These results would support a larger scale screening for AATD in Tunisia. (Source: Orphanet Journal of Rare Diseases)

Serum trypsin inhibitory capacity in normal pregnancy and gestational diabetes mellitus.

Diabetes Research and Clinical Practice — Wed, 01 Apr 2009 04:00:00 +0100

CONCLUSION: In gestational diabetes mellitus reduction of serum trypsin inhibitory capacity may be due to non-enzymatic glycosylation of alpha-1-antitrypsin or oxidation of methionin in the active site of alpha-1-antitrypsin which remains to be cleared. PMID: 19344972 [PubMed - as supplied by publisher] (Source: Diabetes Research and Clinical Practice)

Med Sci Monit 2009; 15(4):CR177-184 "Kinetics and prognostic value of inflammatory-sensitive protein, IL-6, and white blood cell levels in patients undergoing coronary stent implantation"

Medical Science Monitor — Mon, 30 Mar 2009 19:21:00 +0100

Conclusions: FIB, CRP, IL-6, CER, HPT, A1AT, A1GP, and WBC levels increase significantly after stenting, but they are not related to prognosis. (Source: Medical Science Monitor)

Alpha-1 Foundation and The CHEST Foundation Clinical Research Award in COPD and Alpha-1 Antitrypsin (AAT) Deficiency

ScanGrants feed — Fri, 27 Mar 2009 04:00:00 +0100

Alpha-1 Foundation and The CHEST Foundation Clinical ResearchAward in COPD and Alpha-1 Antitrypsin (AAT) DeficiencyApplication Deadline: April 30, 2009BackgroundThe year 2009 marks the fifth year of the successful partnership between The CHEST Foundation and Alpha-1 Foundation in sponsoring a one-year clinical research award in COPD and Alpha-1 Antitrypsin (AAT) Deficiency. The CHEST Foundation, the philanthropic arm of the American College of Chest Physicians, was founded in 1996 and focuses its programs and initiatives on four key areas: critical care and end-of-life care, tobacco prevention, humanitarian service, and clinical research. Its mission is to provide resources to advance the prevention and treatment of diseases of the chest.The Alpha-1 Foundation is dedicated to providing the...

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Peter Smith Scholarship--Alpha-1 Antitrypsin Deficiency

ScanGrants feed — Wed, 25 Mar 2009 04:00:00 +0100

The Peter Smith Scholarship Fund is available for post high-school education to individuals with Alpha-1 Antitrypsin deficiency, their spouses, and their children. This scholarship honors the memory of Peter Smith, who believed that knowledge is power. He demonstrated this by writing, editing and publishing Alpha-1 News from 1989 until 1992. By October of that year, he had spread the word to over 1200 households. His efforts encouraged, enlightened and inspired those with Alpha-1 to reach out to one another and to learn. The intent of the Peter Smith Scholarship is to continue the tradition of inspiring and assisting by helping those with Alpha-1 and their families learn and achieve. The program is currently administered by the Alpha-1 Association, located in Miami, Florida. Eligibility C...

COMMENTARY: Myths and Misconceptions About {alpha}1-Antitrypsin Deficiency

Archives of Internal Medicine — Mon, 23 Mar 2009 04:00:00 +0100

(Source: Archives of Internal Medicine)

Kamada Completes Last Patient Visit In Phase II Bronchiectasis Study With Its Inhaled AAT

Health News from Medical News Today — Thu, 19 Mar 2009 09:00:00 +0100

Kamada , a bio-pharmaceutical company engaged in the development, manufacturing and marketing of specialty life-saving therapeutics, announced today that it has completed the last patient visit in a Phase II bronchiectasis study with its Inhaled Alpha-1 Antitrypsin (AAT), delivered via an optimized Investigational eFlow Nebulizer System (PARI Pharma GmbH). (Source: Health News from Medical News Today)

Alpha-1-Antitrypsin Deficiency

About.com Lung Cancer — Sat, 07 Mar 2009 05:00:00 +0100

Definition of alpha-1-antitrypsin deficiency, a genetic disorder. (Source: About.com Lung Cancer)

α1-antitrypsin prevents polymorphonuclear leucocyte-elastase effects on spermatozoa quality

International Journal of Andrology — Thu, 05 Mar 2009 05:00:00 +0100

Elevated levels of polymorphonuclear leucocyte (PMN)-derived elastase, which is suggested as marker for inflammations in the male genital tract, correlate well with spermatozoa deterioration. PMN elastase caused a time- and concentration-dependent (up to a elastase concentration of 0.5 [mu]g/mL) externalization of phosphatidylserine and intercalation of propidium iodide on human spermatozoa. There are apparently a limited number of target sites for elastase on spermatozoa surface, because the further enhancement of elastase amount did not fasten alterations in spermatozoa parameters. Analysis of flow cytometry data revealed that most spermatozoa were in a necrotic state after an exposure with elastase for 22 h. Some apoptotic cells were only detected at shorter incubation periods. Seminal ...

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alpha-antitrypsin prevents polymorphonuclear leucocyte-elastase effects on spermatozoa quality.

International Journal of Andrology — Thu, 05 Mar 2009 05:00:00 +0100

Authors: Leßig J, Arnhold J, Glander HJ Elevated levels of polymorphonuclear leucocyte (PMN)-derived elastase, which is suggested as marker for inflammations in the male genital tract, correlate well with spermatozoa deterioration. PMN elastase caused a time- and concentration-dependent (up to a elastase concentration of 0.5 mug/mL) externalization of phosphatidylserine and intercalation of propidium iodide on human spermatozoa. There are apparently a limited number of target sites for elastase on spermatozoa surface, because the further enhancement of elastase amount did not fasten alterations in spermatozoa parameters. Analysis of flow cytometry data revealed that most spermatozoa were in a necrotic state after an exposure with elastase for 22 h. Some apoptotic cells were only d...

[Construction of a eukaryotic expression vector for alpha-1-antitrypsin and the localization of the expression product in NIH 3T3 cells.]

Journal of Southern Medical University — Sun, 01 Mar 2009 05:00:00 +0100

CONCLUSION: The expression vector for AAT-HA fusion protein has been successfully constructed and effectively expressed in mammalian cells to allow future functional study of AAT in mammalian cells. PMID: 19304512 [PubMed - in process] (Source: Journal of Southern Medical University)

Search for serum biomarkers associated with abdominal aortic aneurysm growth--a pilot study.

PubMed: Eur J Vasc Endovasc ... — Sun, 01 Mar 2009 05:00:00 +0100

CONCLUSIONS: Alpha 1-antitrypsin may be a promising biomarker of AAA growth. PMID: 19111482 [PubMed - indexed for MEDLINE] (Source: PubMed: Eur J Vasc Endovasc ...)

Shed Syndecan-1 Restricts Neutrophil Elastase from {alpha}1-Antitrypsin in Neutrophilic Airway Inflammation.

Am J Respir Cell Mol... — Fri, 27 Feb 2009 05:00:00 +0100

Authors: Chan SC, Leung VO, Ip MS, Shum DK Persistent proteolytic imbalance in chronic inflammatory diseases has been ascribed to neutrophil elastase (NE)/antielastase imbalance in wound fluids. In sputum sols of patients with bronchiectasis, we found unopposed NE activity despite overwhelming excess of the physiological antielastase, alpha-1-antitrypsin. Western blot analysis found NE in a supramolecular complex with shed ectodomains of syndecan-1 in sputum sol samples and as such, inhibition of NE activity was incomplete even with addition of exogenous alpha-1-antitrypsin. To confirm that NE binding to heparan sulfate components of syndecan-1 limits the antielastase effect, recombinant human syndecan-1 was recovered from stable syndecan-1 transfectants of a human B-lymphoid cell line...

Conformational Pathology of the Serpins: Themes, Variations, and Therapeutic Strategies.

Annual Review of Biochemistry — Thu, 26 Feb 2009 05:00:00 +0100

Authors: Gooptu B, Lomas DA Point mutations cause members of the serine protease inhibitor (serpin) superfamily to undergo a novel conformational transition, forming ordered polymers. These polymers characterize a group of diseases termed the serpinopathies. The formation of polymers underlies the retention of alpha(1)-antitrypsin within hepatocytes and of neuroserpin within neurons to cause cirrhosis and dementia, respectively. Point mutations of antithrombin, C1 inhibitor, alpha(1)-antichymotrypsin, and heparin cofactor II cause a similar conformational transition, resulting in a plasma deficiency that is associated with thrombosis, angioedema, and emphysema. Polymers of serpins can also form in extracellular tissues where they activate inflammatory cascades. This is best described f...

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[Automation and Analytical Techniques] Automated Determination of Serum {alpha}1-Antitrypsin by Antitryptic Activity Measurement

Clinical Chemistry — Wed, 25 Feb 2009 05:00:00 +0100

Conclusion: This assay is stable, reliable, and easily automated by use of open-system analyzers, allowing for the rapid evaluation of patients. After further validation on a larger randomized cohort, this new approach should function as a useful method to explore A1AT deficiency, especially in large-scale studies. (Source: Clinical Chemistry)

{alpha}-1-Antitrypsin is an endogenous inhibitor of proinflammatory cytokine production in whole blood.

Journal of Leukocyte Biology — Thu, 05 Feb 2009 05:00:00 +0100

Authors: Pott GB, Chan ED, Dinarello CA, Shapiro L Several observations suggest endogenous suppressors of inflammatory mediators are present in human blood. alpha-1-Antitrypsin (AAT) is the most abundant serine protease inhibitor in blood, and AAT possesses anti-inflammatory activity in vitro and in vivo. Here, we show that in vitro stimulation of whole blood from persons with a genetic AAT deficiency resulted in enhanced cytokine production compared with blood from healthy subjects. Using whole blood from healthy subjects, dilution of blood with RPMI tissue-culture medium, followed by incubation for 18 h, increased spontaneous production of IL-8, TNF-alpha, IL-1beta, and IL-1R antagonist (IL-1Ra) significantly, compared with undiluted blood. Dilution-induced cytokine production sugges...

Improving Endpoints, Improving Care: Alpha-1 Antitrypsin Augmentation Therapy and Clinical Trials

What's New at CBER — Tue, 03 Feb 2009 14:07:00 +0100

Public Workshop (Source: What's New at CBER)

Alpha 1 antitrypsin activity is decreased in human amnion in premature rupture of the fetal membranes

Molecular Human Reproduction — Mon, 02 Feb 2009 05:00:00 +0100

In this study, we assessed the expression and localization of AAT in human amnion, as well as its biological activity in cases with PROM. Human amniotic epithelial (hAE) cells expressed AAT. After stimulation with oncostatin M (OSM), interleukin-6 (IL-6) or tumor necrotic factor alpha (TNF ), hAE cells increased the expression of AAT, while the expression of MMP9 was reduced by OSM and induced by TNF . Oxidized AAT (inactivated form) was detected in the amnion with PPROM and TPROM, but not in specimens without PROM. Moreover, AAT activity was decreased in amnions from cases with PROM, regardless of gestational age. Thus, the results showed that AAT in the amnion may function as a protective shield at inflammatory sites, and not as it loses it inhibitory activity in cases with PROM, possibl...

A unique plasma proteomic profiling with imbalanced fibrinogen cascade in patients with Kawasaki disease

Pediatric Allergy and Immunology — Mon, 19 Jan 2009 04:31:21 +0100

In this study, we sought to elucidate potential plasma proteomic markers in KD patients in comparison to that in febrile controls. Plasma samples from KD patients and febrile controls were subjected to two-dimensional polyacrylamide gel electrophoresis analysis. Differential protein displays between KD patients and febrile controls were determined. Fibrinogen beta and gamma chains, alpha-1-antitrypsin (A1AT), CD5 antigen-like precursor (CD5L), and clusterin were increased in KD patients, whereas immunoglobulin free light chains were decreased, as compared with controls. The differential protein displays were validated with enzyme-linked immunosorbent assay tests. We found higher fibrinogen-related proteins (fibrinogen, A1AT, clusterin, and CD5L), along with a lower level of the immunoglobu...

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Regulatory T cells and their prognostic value for patients with squamous cell carcinoma of the head and neck

Journal of Cellular and Molecular Medicine — Wed, 14 Jan 2009 00:00:00 +0100

Regulatory T cells (Treg) are important regulators of anti-cancer immune responses, and an increase in Treg frequency was observed in the blood of cancer patients. Blood samples from 112 patients with head and neck squamous cell carcinoma antigen (HNSCC) were obtained at the time of tumour diagnosis, and lymphocyte subpopulations (CD3+; CD3[minus]CD16+CD56+; CD4+; CD8+; CD19+; CD4+CD45RA+) with emphasis on Treg counts (CD3+CD4+CD25+), complete blood count and tumour markers (squamous cell carcinoma [SCC]; CEA; [alpha]-1-antitrypsin [AAT]; Cyfra 21[ndash]1; C-reactive protein [CRP]) were analysed. The data were grouped according to TNM classification, and their significance for the course of the disease at an interval of 1 year after the end of the therapy was determined. The percentage of ...

Functional unfolding of alpha 1-antitrypsin probed by hydrogen-deuterium exchange coupled with mass spectrometry.

Molecular and Cellular Proteomics : MCP — Sun, 11 Jan 2009 05:00:00 +0100

Authors: Baek JH, Yang WS, Lee C, Yu MH The native state of a1-antitrypsin (alpha(1)AT), a member of the serpin (serine protease inhibitor) family, is considered a kinetically trapped folding intermediate that converts to a more stable form upon complex formation with a target protease. While previous structural and mutational studies of alpha(1)AT revealed the structural basis of the native strain and the kinetic trap, the mechanism of how the native molecule overcomes the kinetic barrier to reach the final stable conformation during complex formation remains unknown. We hypothesized that during complex formation, a substantial portion of the molecule undergoes unfolding, which we dubbed functional unfolding. Hydrogen-deuterium exchange (H/D-EX) coupled with electro-spray ionization m...

Assessment of Myeloperoxidase and Oxidative {alpha}1-Antitrypsin in Patients on Hemodialysis.

Clinical Journal of the American Society of Nephrology : CJASN — Wed, 07 Jan 2009 05:00:00 +0100

CONCLUSIONS: High MPO with high oxAT and high MPO with PEW seem to contribute to plaque formation in patients on HD, whereas elevated MPO or oxAT alone might not predict increasing CIMT. In contrast, a high oxAT value seems to be an independent predictor of PEW in patients on HD. PMID: 19129321 [PubMed - as supplied by publisher] (Source: Clinical Journal of the American Society of Nephrology : CJASN)

Oxidative Damage to Nucleic Acids in Severe Emphysema.

Chest — Wed, 31 Dec 2008 05:00:00 +0100

Conclusion We demonstrate for the first time that nucleic acids, and especially RNA are oxidized in human emphysematous lungs. The correlation between the levels of oxidative damage to nucleic acids in alveolar wall cells and the severity of emphysema suggests a potential role in the pathogenesis of emphysema. PMID: 19118262 [PubMed - as supplied by publisher] (Source: Chest)

King Of Pop's Reported Diagnosis Sheds Light On Relatively Unknown Disease

Health News from Medical News Today — Sat, 27 Dec 2008 09:00:00 +0100

In light of reports that Michael Jackson is suffering from a rare respiratory condition caused by Alpha 1-Antitrypsin Deficiency, Jeffrey Teckman, M.D., associate professor of pediatrics, biochemistry and molecular biology at Saint Louis University School of Medicine, is available to talk about the diagnosis, causes and treatment of the disease. (Source: Health News from Medical News Today)

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Search for Serum Biomarkers Associated with Abdominal Aortic Aneurysm Growth - A Pilot Study.

European Journal of Vascular and Endovascular Surgery — Wed, 24 Dec 2008 05:00:00 +0100

CONCLUSIONS: Alpha 1-antitrypsin may be a promising biomarker of AAA growth. PMID: 19111482 [PubMed - as supplied by publisher] (Source: European Journal of Vascular and Endovascular Surgery)

Michael Jackson's Reported Lung Disease: Alpha-1 Antitrypsin Deficiency

WebMD Health — Mon, 22 Dec 2008 05:00:00 +0100

Pop superstar Michael Jackson may need a lung transplant due to a genetic condition called alpha-1 antitrypsin deficiency, according to media reports. (Source: WebMD Health)

Patients with Alpha-1 Antitrypsin Deficiency: Disease Management Considerations.

Disease Management and Health Outcomes — Thu, 18 Dec 2008 08:51:33 +0100

Page: 345DOI: 10.2165/0115677-200816050-00011Authors: Carter, Rick 1; Tiep, Brian L 2 3 4 (Source: Disease Management and Health Outcomes)

Patients with Alpha-1 Antitrypsin Deficiency: Disease Management Considerations

Disease Management — Thu, 18 Dec 2008 04:02:56 +0100

(Source: Disease Management)

Small-molecule peptides inhibit Z alpha(1)-antitrypsin polymerization.

J Cell Mol Med — Tue, 16 Dec 2008 05:00:00 +0100

Authors: Chang YP, Mahadeva R, Chang WS, Lin SC, Chu YH Abstract The Z variant of alpha(1)-antitrypsin polymerizes within the liver and gives rise to liver cirrhosis and the associated plasma deficiency leads to emphysema. In this work, a combinatorial approach based on the inhibitory mechanism of alpha(1)-antitrypsin was developed to arrest its pathogenic polymerization. One peptide, Ac-TTAI-NH(2), emerged as the most tight-binding ligand for Z alpha(1)-antitrypsin. Characterization of this tetrapeptide by gel electrophoresis and biosensor analysis revealed its markedly improved binding specificity and affinity compared with all previously reported peptide inhibitors. In addition, the peptide is not cytotoxic to lung cell lines. A model of the peptide-protein complex suggests that the...

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Barriers to Genetic Testing Among Persons at Risk for Alpha-1 Antitrypsin Deficiency

Genetic Testing — Mon, 15 Dec 2008 13:03:15 +0100

Genetic Testing Dec 2008, Vol. 12, No. 4: 501-505. The alpha coded testing (ACT) study offers free and confidential testing for alpha-1 antitrypsin deficiency (AATD) and includes surveys to provide data to study the psychosocial correlates of genetic testing. The purpose of the current study is to better ... (Source: Genetic Testing)

Analysis of the Alpha-1-Antitrypsin Deficient Alleles M3S, MZ, and ZZ by Biochemical and Molecular Methods: A Family Study.

Biochemical Genetics — Sat, 13 Dec 2008 05:00:00 +0100

This study attempted to determine the degree of association between serum alpha(1)-AT levels and phenotypes and to provide a strategy for reliable laboratory evaluation of deficiencies. The study group consisted of a 38-year-old male proband with clinical features of emphysema, his first-degree relatives, and healthy controls. Family history revealed a four-generation pedigree. Genomic DNA was isolated from peripheral blood leukocytes. Alpha-1-AT levels were determined from human serum by immunonephelometry. Phenotypes were determined by isoelectric focusing of blood samples. DNA sequences of coding exons were analyzed by the amplification DNA technique and direct sequencing. Inheritance and plasma levels of the ZZ, MM, M3S, and MZ phenotypes were confirmed by the family study. In the fami...

[Original articles] Incidence, management and clinical outcomes of patients with airway complications following lung transplantation

European Journal of Cardio-Thoracic Surgery — Tue, 02 Dec 2008 05:00:00 +0100

Conclusions: The incidence of AC after LT is 12.6% with a related mortality of 1%, irrespective of the technique of bronchial anastomosis performed. DLT, airway colonizations, and prolonged intubation post-transplant are associated with AC. Either endoscopic procedures or surgical therapy resolve these complications in most cases. (Source: European Journal of Cardio-Thoracic Surgery)

[Molecular diagnostics of alpha-1-antitrypsin deficiency in clinical practice]

Pneumonologia i Alergologia Polska — Mon, 01 Dec 2008 15:53:14 +0100

Authors: Struniawski R, Szpechciński A, Chorostowska-Wynimko J The deficiency of serine protease inhibitor, alpha-1-antitrypsin (AATD), is genetically determined defect that increases the risk of lung and liver disease development. The results of recent epidemiological studies indicate the overwhelming majority of individuals with alpha-1-antitrypsin deficiency still remain undiagnosed. The complete laboratory diagnosis of AATD is based on combination of quantitative and qualitative methods. The measurement of plasma/serum AAT concentration is always the initial test performed in clinically suspected individuals. Nevertheless, only the AAT phenotype or genotype identification allows the full medical verification of the diagnosis. Among the various techniques of either AAT variant...

Protein-losing gastroenteropathy associated with primary Sjögren’s syndrome: a characteristic oriental variant

Rheumatology International — Sun, 30 Nov 2008 07:07:29 +0100

We report a case of a 41-year-old Japanese man, who is the first male patient, with PLGE associated with primary SS. Although serum anti-SSA and SSB antibodies were detected, he had no subjective sicca symptoms. He had multiple annular erythema: a characteristic skin manifestation of Asian SS patients. A diagnosis of PLGE was made from results of 99mTc-labelled albumin scintigraphy and a faecal alpha-1-antitrypsin clearance test. Intravenous administration of high-dose glucocorticoid was not effective, but pulse methylprednisolone therapy alleviated disease manifestations. As all cases of PLGE associated with primary SS have been reported from East Asia, this complication could be essentially limited to Asian patients. Content Type Journal ArticleCategory Case ReportDOI 10.1007/s0...

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A1ATVar: a relational database of human SERPINA1 gene variants leading to [alpha]1-antitrypsin deficiency and application of the VariVis software

Human Mutation — Thu, 20 Nov 2008 05:00:00 +0100

We have developed a relational database of human SERPINA1 gene mutations, leading to [alpha]1-antitrypsin (AAT) deficiency, called A1ATVar, which can be accessed over the World Wide Web at . Extensive information has been extracted from the literature and converted into a searchable database, including genotype information, clinical phenotype, allelic frequencies for the commonest AAT variant alleles, methods of detection, and references. Mutation summaries are automatically displayed and user-generated queries can be formulated based on fields in the database. A separate module, linked to the FINDbase database for frequencies of inherited disorders allows the user to access allele frequency information for the three most frequent AAT alleles, namely PiM, PiS, and PiZ. The available experi...

[Alpha-1-antitrypsin deficiency] Clinical course and prognosis of never-smokers with severe alpha-1-antitrypsin deficiency (PiZZ)

Thorax — Wed, 19 Nov 2008 05:00:00 +0100

Conclusion: Non-smoking PiZZ individuals identified by screening do not have an increased mortality risk compared with the Swedish general population. (Source: Thorax)

Clinical Characteristics of Symptomatic Subjects With {alpha}1-Antitrypsin Deficiency Older Than 60 Years.

Chest — Tue, 18 Nov 2008 05:00:00 +0100

Conclusions Subjects with AATD-associated COPD that reach an older age exhibit a more indolent clinical course than younger affected individuals, possibly related in part to differences in tobacco exposure. This findings support current guidelines that recommend screening all patients with COPD for AATD regardless of their age and prior smoking history. PMID: 19017884 [PubMed - as supplied by publisher] (Source: Chest)

Syringotropic hypersensitivity reaction associated with infliximab and leflunomide combination therapy in a child with psoriatic arthritis

Journal of Cutaneous Pathology — Sun, 09 Nov 2008 00:00:00 +0100

A 17-year-old boy with refractory psoriatic arthritis and alpha-1 antitrypsin deficiency who developed a syringotropic hypersensitivity reaction after 9 months of therapy with infliximab and leflunomide is described. Clinically, our patient showed a vasculitic-like skin rash involving both palms and soles, and histopathological examination revealed a syringotropic lymphocytic infiltrate directed toward the intra-epidermal portion of the eccrine ducts. These features have not been previously associated with infliximab or leflunomide therapy and represent a unique cutaneous hypersensitivity reaction that does not fit any known description of an immune-mediated hypersensitivity reaction. Vesel T, Luzar B, Calonje E, Avčin T. Syringotropic hypersensitivity reaction associated with infli...

[Miscellanea] Alpha-1-antitrypsin deficiency and increased lung cancer risk

Thorax — Tue, 04 Nov 2008 05:00:00 +0100

(Source: Thorax)

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Well Known Drug Might Overcome Obstacles To Pancreatic Islet Transplantation

Immune System / Vaccines News From Medical News Today — Fri, 31 Oct 2008 12:00:00 +0100

Researchers from Ben-Gurion University of the Negev (BGU) in Beer-Sheva, Israel have demonstrated that treating diabetic animals with alpha-1-antitrypsin (AAT) following an islet transplantation procedure eliminates the inflammation that causes islet transplants to fail. (PNAS Article #08-07627: "Alpha-1-Antitrypsin Monotherapy Induces Immune Tolerance during Islet Allograft Transplantation in Mice") ( (Source: Immune System / Vaccines News From Medical News Today)

The US FDA Has Approved Clinical Trials Which Could Eliminate The Need For Long-term Immunosuppression Following Transplantation

Immune System / Vaccines News From Medical News Today — Fri, 31 Oct 2008 08:00:00 +0100

Well-known Drug (AAT) Could Overcome Obstacles To Islet Transplantation, Study Suggests

ScienceDaily Headlines — Fri, 31 Oct 2008 00:00:00 +0100

Researchers have demonstrated that treating diabetic animals with alpha-1-antitrypsin following an islet transplantation procedure eliminates the inflammation that causes islet transplants to fail. (Source: ScienceDaily Headlines)

Alpha-1-antitrypsin could overcome obstacles to islet transplantation

Huliq Health News — Thu, 30 Oct 2008 20:05:43 +0100

The US FDA has approved clinical trials which could eliminate the need for long-term immunosuppression following transplantation according to Ben-Gurion University of the Negev Dr. Eli Lewis (Source: Huliq Health News)

Exhaled nitric oxide levels in alpha-1-antitrypsin PiMZ subjects

Journal of Internal Medicine — Wed, 29 Oct 2008 04:00:00 +0100

Conclusions. Not only did PiMZ subjects show increased FeNO levels compared with COPD patients and controls; FeNO levels proved to be related to the reduced concentration of plasma AAT. Such findings seem to suggest the importance of FeNO measurements on PiMZ subjects for monitoring a possible progression of airway inflammation to obstructive lung disease as observed in some of these patients. (Source: Journal of Internal Medicine)

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Liver Disease Associated with ZZ [alpha]1-Antitrypsin Deficiency and Ursodeoxycholic Acid Therapy in Children.

Journal of Pediatric Gastroenterology and Nutrition — Tue, 28 Oct 2008 10:38:47 +0100

Page: 623DOI: 10.1097/MPG.0b013e31817b6dfbAuthors: Lykavieris, Panayotis *; Ducot, Beatrice +; Lachaux, Alain ++; Dabadie, Alain [S]; Broue, Pierre [P]; Sarles, Jacques ||; Bernard, Olivier *; Jacquemin, Emmanuel * (Source: Journal of Pediatric Gastroenterology and Nutrition)

Kamada: Pivotal Phase III Data Confirms Efficacy And Safety Of Intravenous Alpha-1 Antitrypsin

Endocrinology News From Medical News Today — Tue, 28 Oct 2008 08:00:00 +0100

Kamada, a biopharmaceutical company engaged in the development, manufacturing and marketing of specialty life-saving therapeutics, announced today that it has completed the final analysis of its US Phase III trial with intravenous Alpha-1 Antitrypsin (AAT), for hereditary AAT deficiency. In keeping with headline results announced in April, the study met its primary endpoint. (Source: Endocrinology News From Medical News Today)

Alpha-1 Antitrypsin Deficiency

MedicineNet Skin General — Tue, 28 Oct 2008 07:00:00 +0100

Title: Alpha-1 Antitrypsin DeficiencyCategory: Diseases and ConditionsCreated: 12/31/1997Last Editorial Review: 10/28/2008 (Source: MedicineNet Skin General)

What Is The Differential Diagnosis of Hepatomegaly?

PediatricEducation.org — Tue, 21 Oct 2008 12:16:35 +0100

Discussion Liver masses in children include primary liver cancer, metastatic cancer from other sites, cysts and inflammatory masses. Primary liver cancer only constitutes 1-2% of all pediatric malignancies. Primary liver malignancies in infants and young children usually are caused by hepatoblastoma. In older children hepatocellular carcinoma is the most common. For intermediate ages both are common along with transitional cell tumors and primary sarcomas. Other malignant liver tumors include angiosarcoma, biliary rhabdomyosarcoma, undifferentiated sarcomas and rhabdoid tumor. Benign liver tumors include adenoma, focal nodular hyperplasia, infantile hemangioma, mesenchymal hamartoma and teratoma. Primary hepatic sarcoma is rare with the outcome depending on tumor resection, sensitivity ...

Kamada has announced positive phase II data showing that inhaled alpha 1-antitrypsin (AAT)

Inpharma — Tue, 21 Oct 2008 07:02:31 +0100

(Source: Inpharma)

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[Immunology] {alpha}1-Antitrypsin monotherapy induces immune tolerance during islet allograft transplantation in mice

Proceedings of the National Academy of Sciences — Tue, 21 Oct 2008 04:00:00 +0100

Human pancreatic islet transplantation offers diabetic patients tight glucose control but has low graft survival rates. The immunosuppressive drugs that... (Source: Proceedings of the National Academy of Sciences)

[Immunology] Curative and {beta} cell regenerative effects of {alpha}1-antitrypsin treatment in autoimmune diabetic NOD mice

Proceedings of the National Academy of Sciences — Tue, 21 Oct 2008 04:00:00 +0100

Invasive insulitis is a destructive T cell-dependent autoimmune process directed against insulin-producing β cells that is central to the pathogenesis... (Source: Proceedings of the National Academy of Sciences)

Kamada has announced positive phase II data showing that inhaled alpha 1-antitrypsin (AAT).

Inpharma Weekly — Sat, 18 Oct 2008 10:25:24 +0100

Page: 9 (Source: Inpharma Weekly)

Heritability of Lung Function in Severe Alpha-1 Antitrypsin Deficiency

Human Heredity — Thu, 16 Oct 2008 15:10:52 +0100

Hum Hered 2009;67:38-45 (DOI:10.1159/000164397) (Source: Human Heredity)

Kamada Reports Positive Phase II Data With Inhaled AAT In Cystic Fibrosis

Health News from Medical News Today — Mon, 13 Oct 2008 16:00:00 +0100

Kamada (TASE:KMDA), a biopharmaceutical company engaged in the development, manufacturing and marketing of specialty life-saving therapeutics, announced today positive data from its Phase II study evaluating inhaled Alpha-1 Antitrypsin (AAT) delivered via an Investigational eFlow® Nebulizer System (PARI Pharma GmbH), in the treatment of cystic fibrosis. (Source: Health News from Medical News Today)

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AAT Protein Restores Blood Glucose in Type 1 Diabetes Model

Diabetes News from dLife.com — Mon, 13 Oct 2008 04:00:00 +0100

OCtober 13, 2008 (Press Release) - A protein made by the liver in response to inflammation and used to treat patients suffering from a genetic form of emphysema has been shown to restore blood glucose levels in a mouse model of Type 1 diabetes mellitus, according to a new study led by researchers at Beth Israel Deaconess Medical Center (BIDMC). The findings, which appear in the Online Early Edition of the Proceedings of the National Academy of Sciences (PNAS) this week, provide further proof that inflammation plays a key role in the development of Type 1 diabetes and suggest that the protein – known as AAT --might be an option for clinical testing in humans. Formerly known as juvenile-onset or insulin-dependent diabetes, Type 1 diabetes is an autoimmune disease that develops when th...

Kamada reports positive data with inhaled Alpha-1 Antitrypsin in cystic fibrosis

News-Medical News Feed — Sun, 12 Oct 2008 22:47:20 +0100

Kamada has announced today positive data from its Phase II study evaluating inhaled Alpha-1 Antitrypsin (AAT) delivered via an Investigational eFlow Nebulizer System (PARI Pharma GmbH), in the treatment of cystic fibrosis. The results demonstrate the product has an excellent safety profile and shows promising signs of efficacy, as indicated by a reduction in lung inflammation. (Source: News-Medical News Feed)

{alpha}1-Antitrypsin Augmentation Therapy for PI*MZ Heterozygotes: A Cautionary Note.

Chest — Wed, 01 Oct 2008 04:00:00 +0100

Authors: Sandhaus RA, Turino G, Stocks J, Strange C, Trapnell BC, Silverman EK, Everett SE, Stoller JK, The use of IV augmentation therapy with plasma-derived alpha(1)-antitrypsin (AAT) has become the standard of care for the treatment of pulmonary disease associated with the severe genetic deficiency of AAT. The Medical and Scientific Advisory Committee of the Alpha-1 Foundation has become aware that physicians are prescribing this expensive blood product for the treatment of individuals with a single abnormal AAT gene, primarily the PI*MZ genotype. We are aware of no evidence that such therapy is effective in this patient population. The most important therapeutic interventions in such patients remain smoking cessation and elimination of other risk factors for lung disease. This com...

Proteomics of plasma and urine in primary nephrotic syndrome in children.

Contributions to Nephrology — Wed, 24 Sep 2008 01:14:55 +0100

Authors: Candiano G, Musante L, Petretto A, Bruschi M, Santucci L, Urbani A, Scolari F, Gusmano R, Carraro M, Zennaro C, Vincenti F, Ghiggeri GM Primary nephrotic syndrome in children, especially the variant with segmental glomerulosclerosis, remains an unsolved clinical problem. In spite of some progress, its pathogenesis is still unknown and the therapy options are confined to gross immune modulation. Indirect evidence based on posttransplant recurrence of the disease suggested an implication of plasma factors, whose characterization remains in course. Besides historical candidates, research is now considering glyco- and lipoderivatives. Structural analysis of plasma and urinary proteins based on proteomics has recently shown an increased proteolysis of major components such as album...