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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
2009-01-01
BACKGROUND: The progression of emphysema is traditionally measured by pulmonary function test, with forced expiratory volume in 1 s (FEV(1)) being the most accepted and used measurement. However, FEV(1) is insensitive in detecting mild/slow progression of emphysema because of low reproducibility as compared to yearly decline. PURPOSE: To investigate the progression of emphysema over a period of 2 years using diffusion-weighted hyperpolarized (HP) (3)He magnetic resonance imaging (MRI) in patients with alpha-1-antitrypsin (A1AT) deficiency. MATERIAL AND METHODS: Nine patients with severe A1AT deficiency were studied over a period of 2 years (baseline, year 1, and year 2) with HP (3)He MRI using apparent diffusion coefficient (ADC), lung function tests (FEV(1) and carbon monoxide lung diffusion capacity [D(L,CO)]), and computed tomography (CT) using densitometric parameters (15th percentile density [CT-PD15] and relative area of emphysema below -910 HU [CT-RA-910]). RESULTS: Seven patients were scanned three times, one patient two times, and one patient only at baseline. The mean increase in ADC values from first to last HP (3)He MR scanning was 3.8% (0.014 cm(2)/s [SD 0.024 cm(2)/s]; not significant). The time trends for FEV(1), D(L,CO), CT-PD15, and CT-RA-910 were all statistically significant. We found a high correlation between ADC and D(L,CO) (P
2009-11-15
Background: The progression of emphysema is traditionally measured by pulmonary function test, with forced expiratory volume in 1 s (FEV1) being the most accepted and used measurement. However, FEV1 is insensitive in detecting mild/slow progression of emphysema because of low reproducibility as compared to yearly decline. Purpose: To investigate the progression of emphysema over a period of 2 years using diffusion-weighted hyperpolarized (HP) 3He magnetic resonance imaging (MRI) in patients with alpha-1-antitrypsin (A1AT) deficiency. Material and Methods: Nine patients with severe A1AT deficiency were studied over a period of 2 years (baseline, year 1, and year 2) with HP 3He MRI using apparent diffusion coefficient (ADC), lung function tests (FEV1 and carbon monoxide lung diffusion capacity [DL,CO]), and computed tomography (CT) using densitometric parameters (15th percentile density [CT-PD15] and relative area of emphysema below -910 HU [CT-RA-910]). Results: Seven patients were scanned three times, one patient two times, and one patient only at baseline. The mean increase in ADC values from first to last HP 3He MR scanning was 3.8% (0.014 cm2/s [SD 0.024 cm2/s]; not significant). The time trends for FEV1, DL,CO, CT-PD15, and CT-RA-910 were all statistically significant. We found a high correlation between ADC and DL,CO (P<0.001). Conclusion: This pilot study indicates the possible use of nonionizing HP 3He MRI for monitoring the progression of emphysema. However, in the future, larger studies are needed to confirm these preliminary results
2009-01-01
Background: The progression of emphysema is traditionally measured by pulmonary function test, with forced expiratory volume in 1 s (FEV1) being the most accepted and used measurement. However, FEV1 is insensitive in detecting mild/slow progression of emphysema because of low reproducibility as compared to yearly decline. Purpose: To investigate the progression of emphysema over a period of 2 years using diffusion-weighted hyperpolarized (HP) 3He magnetic resonance imaging (MRI) in patients with alpha-1-antitrypsin (A1AT) deficiency. Material and Methods: Nine patients with severe A1AT deficiency were studied over a period of 2 years (baseline, year 1, and year 2) with HP 3He MRI using apparent diffusion coefficient (ADC), lung function tests (FEV1 and carbon monoxide lung diffusion capacity [DL,CO]), and computed tomography (CT) using ... >>
Full Text Available.BackgroundAlpha-1 antitrypsin (A1AT) deficiency, caused by the Z allele (p.E342K) and S allele (p.E264V) in the SERPINA1 gene, can induce liver and pulmonary disease. Different mechanisms appear to be responsible for the pathogenesis of these divergent disease expressions. The c.-1973T >C polymorphism located in the SERPINA1 promoter region is found more frequent in A1AT deficiency patients with liver disease compared to patients with pulmonary disease, but data are lacking regarding contribution to the development of liver diseases caused by other aetiologies.AimTo study the prevalence of c.-1973T >C, Z allele and S allele in a cohort of patients with liver disease of various aetiologies compared with healthy controls and to evaluate its effect on disease progression.MethodsA total of 297 patients with liver disease from various aetiologies and 297 age and gender matched healthy controls were included. The c.-1973T >C polymorphism and Z and S alleles of the SERPINA1 gene were analyzed by real-time PCR.Resultsc.-1973T >C was similarly distributed between patients with liver disease of various origins and healthy controls. Furthermore, the distribution of c.-1973T >C was independent from aetiology subgroup. In patients with liver disease mean ages at of onset of liver disease were 44.4, 42.3 and 40.7 years for the c.-1973 T/T, T/C and C/C genotype respectively (NS). S allele heterozygosity was increased in patients with drug induced liver injury (DILI), (OR 4.3; 95%CI 1.1-17.2).ConclusionIn 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.
Full Text Available.Alpha-1 antitrypsin (A1AT or AAT) is a serine protease inhibitor (PI) which, when present at low levels, can cause chronic obstructive pulmonary disease (COPD) and liver disease in both children and adults. Several mutations within the SERPINA1 gene have been found to cause this deficiency. The most common variants are PI*Z and PI*S, each caused by a single nucleotide polymorphism (SNP). We describe a real time polymerase chain reaction (PCR) assay for the rapid genotyping of these polymorphisms. DNA was extracted from fourteen EDTA-anticoagulated whole blood samples using the Qiagen EZ1 blood extraction kit. SNP genotyping was performed using primer/probe sets purchased from Applied Biosystems. These were evaluated for performance and assay conditions on the Applied Biosystems 7500 FAST System. The genotypes of these samples were compared with their phenotype results from isoelectric focusing assays, which were performed by an independent reference laboratory. In addition, twenty samples that were previously genotyped at another laboratory were obtained for accuracy studies. Thirty-four samples were tested; five genotypes were represented and the assay was able to discriminate these successfully. Only one genotype could not be correlated with its phenotype result, as the phenotype was reported as an “unidentified allele”. All other genotyping results were concordant with previously determined genotypes and phenotypes. We describe a rapid real time PCR assay that is suitable for clinical use in genotyping AAT alleles and which can be used as the initial step in A1AT testing algorithms.
Zemaira in Subjects With Emphysema Due to Alpha1-Proteinase Inhibitor (API) Deficiency
Alpha1-proteinase Inhibitor Deficiency; Emphysema
Cancer prevalence estimates based on tumour registry data in the Surveillance, Epidemiology, and End Results (SEER) Program Ray M Merrill,a Riccardo Capocaccia,b Eric J Feuerc and Angela Mariottob Background The Connecticut Tumor Registry (CTR) has collected cancer data for a sufficiently long period of time to capture essentially all prevalent cases of cancer, and to pro-vide unbiased estimates of cancer prevalence.
Thyroid Cancer - Middle East Cancer Consortium (MECC) Cancer Incidence
MECC Monograph 121 Thyroid Cancer
The Use of High Resolution Chest Computed Tomography in Alpha-1 Antitrypsin Deficiency
Alpha-1 Antitrypsin Deficiency
The Urine Proteome as a Biomarker of Radiation Injury
2008-06-18
Terrorist attacks or nuclear accidents could expose large numbers of people to ionizing radiation, and early biomarkers of radiation injury would be critical for triage, treatment and follow-up...Full Text Available
The Urine Proteome as a Biomarker of Radiation Injury
2008-06-18
Full Text Available.Terrorist attacks or nuclear accidents could expose large numbers of people to ionizing radiation, and early biomarkers of radiation injury would be critical for triage, treatment and follow-up of such individuals. However, no such biomarkers have yet been proven to exist. We tested the potential of high throughput proteomics to identify protein biomarkers of radiation injury after total body X-ray irradiation in a rat model. Subtle functional changes in the kidney are suggested by an increased glomerular permeability for macromolecules measured within 24 hours after TBI. Ultrastructural changes in glomerular podocytes include partial loss of the interdigitating organization of foot processes. Analysis of urine by LC-MS/MS and 2D-GE showed significant changes in the urine proteome within 24 hours after TBI. Tissue kallikrein 1-related peptidase, cysteine proteinase inhibitor cystatin C and oxidized histidine were found to be increased while a number of proteinase inhibitors including kallikrein-binding protein and albumin were found to be decreased post-irradiation. Thus, TBI causes immediately detectable changes in renal structure and function and in the urinary protein profile. This suggests that both systemic and renal changes are induced by radiation and it may be possible to identify a set of biomarkers unique to radiation injury.
Serum and Urine Electrophoresis for Detection and Identification of Monoclonal Proteins
2009-08-01
Full Text Available.Electrophoresis may be defined as the separation of charged particles in a uniform electric field. For a particular system of electrophoresis, the voltage is held constant as are the pH and ionic strength of the suspending medium.Tiselius, using a moving boundary liquid system, separated serum proteins by electrophoresis into four components in 1937.1 Paper electrophoresis, popular in the 1950s, provided the rst solid electrophoresis support. The fragility of paper as a support medium saw the introduction of the more robust cellulose acetate a decade later. An improvement in resolution was subsequently gained by using agarose gel, which, in serum samples, gave 5 bands of separation.2,3 In the late 1980s, high resolution agarose gels were introduced which produced at least 6 bands, and depending on the system, as many as 17 bands in serum.4,5Fully automated serum electrophoresis commenced in the 1990s with the introduction of capillary electrophoresis (CE), a reintroduction of a liquid medium but with exquisite resolution compared to Tiselius’ procedure. Using CE instrumentation it is possible to program a sequence of samples and leave them overnight to be processed.Amalgamation of laboratories with an increasing number of patient samples was probably the reason for the semi-automation of gel electrophoresis. The introduction of the Helena SPIFE and Sebia Hydrasys gel systems provided ways of electrophoresing over a hundred serum samples per day. There is certainly a role for such instrumentation in electrophoresis laboratories today.
Serum and Urine Electrophoresis for Detection and Identification of Monoclonal Proteins
2009-08-01
Electrophoresis may be defined as the separation of charged particles in a uniform electric field. For a particular system of electrophoresis, the voltage is held constant as are the pH and ionic strength...Full Text Available
2009-01-01
Full Text Available.Alpha-1-antitrypsin deficiency (AATD), also known as alpha1-proteinase inhibitor deficiency, is an autosomal co-dominant condition. The genotypes associated with AATD include null, deficient, and dysfunctional alpha-1-antitrypsin (A1AT) variants, which result in low levels of circulating functional A1AT, unbalanced protease activity, and an increased risk of developing lung emphysema, the leading cause of morbidity in these patients. Furthermore, the most common abnormal genotype, Pi*ZZ may also cause trapping of abnormally folded protein polymers in hepatocytes causing liver dysfunction. A major focus of therapy for patients with lung disease due to AATD is to correct the A1AT deficiency state by augmenting serum levels with intravenous infusions of human plasma-derived A1AT. This strategy has been associated with effective elevations of A1AT levels and function in serum and lung epithelial fluid and observational studies suggest that it may lead to attenuation in lung function decline, particularly in patients with moderate impairment of lung function. In addition, an observational study suggests that augmentation therapy is associated with a reduction of mortality in subjects with AATD and moderate to severe lung impairment. More recent randomized placebo-controlled studies utilizing computer scan densitometry suggest that this therapy attenuates lung tissue loss. Augmentation therapy has a relative paucity of side effects, but it is highly expensive. Therefore, this therapy is recommended for patients with AATD who have a high-risk A1AT genotype with plasma A1AT below protective levels (11 μM) and evidence of obstructive lung disease. In this article, we review the published evidence of A1AT augmentation therapy efficacy, side effects, and safety profile.
2009-01-01
Alpha-1-antitrypsin deficiency (AATD), also known as alpha1-proteinase inhibitor deficiency, is an autosomal co-dominant condition. The genotypes associated with AATD include null, deficient, and dysfunctional...Full Text Available
Role of Lung Maintenance Program in the Heterogeneity of Lung Destruction in Emphysema
2006-11-01
Full Text Available.Centrilobular emphysema caused by chronic cigarette smoking is a heterogeneous disease with a predominance of upper lobe involvement. It is presumed that this heterogeneity indicates a particular susceptibility to cigarette smoke or the fact that the inhaled smoke distributes preferentially to upper lung zones. The less involved areas might therefore retain the capacity for lung regeneration and gain of pulmonary function in terminally ill patients. We propose that the interplay between molecular and cellular switches involved in the lung response to environmental injuries determines the heterogeneous pattern of emphysema due to cigarette smoke. Regional activation of alveolar destruction by apoptosis and oxidative stress coupled with regional failure of defense mechanisms may account for the irregular pattern of lung destruction in cigarette smoke–induced emphysema. Protection afforded by the key antioxidant transcription factor Nrf-2 and the antiproteolytic and antiapoptotic actions of α1-antitrypsin is central to maintain lung homeostasis and lung structure. As the lung is injured by environmental pollutants, including cigarette smoke, molecular sensors of cellular stress, such as the mTOR/protein translation regulator RTP-801, may engage both inflammation and alveolar cell apoptosis. As injury prevails during the course of this chronic disease, it leads to a more homogeneous pattern of lung disease.
Role of Lung Maintenance Program in the Heterogeneity of Lung Destruction in Emphysema
2006-11-01
Centrilobular emphysema caused by chronic cigarette smoking is a heterogeneous disease with a predominance of upper lobe involvement. It is presumed that this heterogeneity indicates a particular susceptibility...Full Text Available
Recent developments in the understanding of the combined deficiency of FV and FVIII
2009-04-01
SummaryCombined deficiency of factor V (FV) and factor VIII (FVIII) (F5F8D) is a genetic disorder characterized by mild-to-moderate bleeding and coordinate reduction in plasma...Full Text Available
Recent developments in the understanding of the combined deficiency of FV and FVIII
2009-04-01
Full Text Available.SummaryCombined deficiency of factor V (FV) and factor VIII (FVIII) (F5F8D) is a genetic disorder characterized by mild-to-moderate bleeding and coordinate reduction in plasma FV and FVIII levels, as well as platelet FV level. Recent studies identified mutations in two genes (LMAN1 and MCFD2) as the cause of F5F8D. Though clinically indistinguishable, MCFD2 mutations generally exhibit lower levels of FV and FVIII than LMAN1 mutations. LMAN1 is a mannose-specific lectin that cycles between the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment. MCFD2 is an EF-hand domain protein that forms a calcium-dependent heteromeric complex with LMAN1 in cells. Missense mutations in the EF-hand domains of MCFD2 abolish the interaction with LMAN1. The LMAN1-MCFD2 complex may serve as a cargo receptor for the ER-to-Golgi transport of FV and FVIII, and perhaps a number of other glycoproteins. The B domain of FVIII may be important in mediating its interaction with the LMAN1-MCFD2 complex.
Alpha-1 antitrypsin (A1AT or AAT) is a serine protease inhibitor (PI) which, when present at low levels, can cause chronic obstructive pulmonary disease (COPD) and liver disease in both children and...Full Text Available
2008-01-01
Full Text Available.Cystic fibrosis is the most common, inherited fatal disease in Caucasians. The major cause of morbidity and mortality is chronic lung disease due to infection and inflammation in the airways leading to bronchiectasis and respiratory failure. The signature pathologic features of CF lung disease including abnormal mucus obstructing airways, chronic infection with S. aureus, P. aeruginosa and other gram negative bacteria, and a robust neutrophil-dominant airway inflammation, are exacerbated by unopposed proteases present at high concentrations in the ASL. There is strong evidence that proteases, particularly neutrophil elastase, contribute to the pathology of CF by impairing mucociliary clearance, interfering with innate immune functions, and perpetuating neutrophilic inflammation. The mechanisms employed by proteases to impact airway function in CF will be reviewed.
2008-01-01
Cystic fibrosis is the most common, inherited fatal disease in Caucasians. The major cause of morbidity and mortality is chronic lung disease due to infection and inflammation in the airways...Full Text Available
BackgroundAlpha-1 antitrypsin (A1AT) deficiency, caused by the Z allele (p.E342K) and S allele (p.E264V) in the SERPINA1 gene,...Full Text Available
Patterns of hepatocellular carcinoma incidence in Egypt from a population-based cancer registry Elizabeth M. Lehman,1 Amr S. Soliman,1 Kadry Ismail,2 Ahmed Hablas,2 Ibrahim A. Seifeldin,2 Mohamed Ramadan,2 Hesham El-Hamzawy,2 Christiana S. Shoushtari1 and Mark L.
No Excess Mortality Risk Found in Counties with Nuclear Facilities
A fact sheet about an NCI survey that showed no general increased risk of death from cancer for people living in 107 U.S. counties containing or closely adjacent to 62 nuclear facilities.
Nephrogenic Systemic Fibrosis in Liver Disease: A Systematic Review
2009-12-01
Nephrogenic systemic fibrosis may develop in patients with liver disease, a fact highlighted by recent FDA announcements cautioning against the use of gadolinium-based contrast agents (GBCAs)...Full Text Available
Nephrogenic Systemic Fibrosis in Liver Disease: A Systematic Review
2009-12-01
Full Text Available.Nephrogenic systemic fibrosis may develop in patients with liver disease, a fact highlighted by recent FDA announcements cautioning against the use of gadolinium-based contrast agents (GBCAs) in select liver disease patients. The purpose of this systematic literature review is to characterize the risk of NSF in patients with liver disease. All published articles on NSF from September 2000, through August 2008, were identified via Pubmed searches and examination of articles’ reference lists. Two reviewers independently read each article and identified unique patients with biopsy-proven or suspected NSF. Data on demographics, liver status, renal status, and GBCA exposure were collected. A total of 324 articles were reviewed, with 108 articles containing case descriptions on 335 unique NSF patients. After excluding the 95/335 (28%) patients in whom the presence or absence of liver disease was uncertain, liver disease was confirmed present in 41/239 (17%) patients. Renal insufficiency could be assessed in 35 of the liver disease patients; severe renal insufficiency, defined as a glomerular filtration rate (GFR) or estimated GFR (eGFR) < 30 mL/min/1.73m2 or dialysis requirement, was present in 34/35 (97%) patients. The lone patient who developed NSF with mild-moderate renal insufficiency was atypical and received a total gadodiamide load of 0.76 mmol/kg over a 10-week period peri-liver transplantation. The published medical literature demonstrates that patients with liver disease who develop NSF also have severe renal insufficiency, suggesting that liver disease does not confer a risk for NSF beyond that of the underlying renal insufficiency.
Mortality in alpha-1-antitrypsin deficiency in the United Kingdom
2009-01-01
SummaryBackground 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, correcting...
Morphometric examination of native lungs in human lung allograft recipients:
2006-01-01
Wiebe BM, Burton CM, Milman N, Iversen M, Andersen CB. Morphometric examination of native lungs in human lung allograft recipients. APMIS 2006;114:795-804. The aim of the study was to estimate the degree of lung damage in patients with a1-antitrypsin (a1AT) deficiency, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) at the time of lung transplantation. Using unbiased stereological methods, lung-, bronchial- and vessel-volume, capillary length, and alveolar surface area and densities were estimated in recipient lungs from 21 consecutive patients with pre-transplant diagnoses including COPD (n=7), a1AT deficiency (n=6) and CF (n=8). Six unused adult donor lungs served as controls. Information relating to patient demography and pre-transplant lung function was obtained ...
Montreal Axion - Wikipedia, the free encyclopedia
The Montreal Axion are a National Women's Hockey League team located in Montreal, Quebec, Canada. v ? d ? e · Sports teams based in the province of Quebec, ...
Middle East Cancer Consortium (MECC) - Cancer Incidence in MECC vs. US SEER
Micha Barchana (Israel) Brenda K. Edwards (USA) Sultan Eser (USA) Amal Samy Ibrahim (Egypt) Charitini Komodiki (Cyprus) Khamis Najjar (Palestinian Authority) Elaine Ron (USA) Abdel Razzaq Salhab (Palestinian Authority) John L.
Micha Barchana (Israel) Brenda K. Edwards (USA) Sultan Eser (USA) Amal Samy Ibrahim (Egypt) Charitini Komodiki (Cyprus) Khamis Najjar (Palestinian Authority) Elaine Ron (USA) Abdel Razzaq Salhab (Palestinian Authority) John L.
Gene targeted therapeutics for liver disease in alpha-1 antitrypsin deficiency
2009-01-01
Full Text Available.Alpha-1 antitrypsin (A1AT) is a 52 kDa serine protease inhibitor that is synthesized in and secreted from the liver. Although it is present in all tissues in the body the present consensus is that its main role is to inhibit neutrophil elastase in the lung. A1AT deficiency occurs due to mutations of the A1AT gene that reduce serum A1AT levels to <35% of normal. The most clinically significant form of A1AT deficiency is caused by the Z mutation (Glu342Lys). ZA1AT polymerizes in the endoplasmic reticulum of liver cells and the resulting accumulation of the mutant protein can lead to liver disease, while the reduction in circulating A1AT can result in lung disease including early onset emphysema. There is currently no available treatment for the liver disease other than transplantation and therapies for the lung manifestations of the disease remain limited. Gene therapy is an evolving field which may be of use as a treatment for A1AT deficiency. As the liver disease associated with A1AT deficiency may represent a gain of function possible gene therapies for this condition include the use of ribozymes, peptide nucleic acids (PNAs) and RNA interference (RNAi), which by decreasing the amount of aberrant protein in cells may impact on the pathogenesis of the condition.
Gene targeted therapeutics for liver disease in alpha-1 antitrypsin deficiency
2009-01-01
Alpha-1 antitrypsin (A1AT) is a 52 kDa serine protease inhibitor that is synthesized in and secreted from the liver. Although it is present in all tissues in the body the present consensus is that its...Full Text Available
Future therapeutic treatment of COPD: Struggle between oxidants and cytokines
2007-09-01
Full Text Available.Chronic obstructive pulmonary disease (COPD) is a global health problem. Being a progressive disease characterized by inflammation and predominantly caused by tobacco smoking, it deteriorates pulmonary and skeletal muscle functioning, and reduces physical behavior, societal participation and quality of life. During the last two decades studies were focused on the airway and systemic inflammation, oxidative stress, and airway and/or parenchymal remodeling. Macrophages, neutrophils and T cells are thought to be important key players, as well as structural cells like fibroblasts, epithelial, endothelial and smooth muscle cells. Mediators and proteins including cytokines, chemokines, growth factors, proteinases, and oxidants seem to be involved differentially in its pathogenesis. Current pharmacological treatments are directed to reducing airway inflammation, boosting the endogenous levels of anti-oxidants and relieving airway contraction and sputum production. Most agents were primarily used for treating asthma. But in contrast to asthma, these treatments are not very effective in COPD. As a result, novel more specifically acting interventional drugs with less side effects are being developed to treat chronic inflammatory diseases, including COPD. This review highlights studies on novel or potential drug antioxidants such as dietary antioxidants supplementation, N-acetyl-L-cysteine, N-acystelyn, endosteine, antioxidant enzyme mimetics, and anti-inflammatory agents like antagonists of cytokines, such as tumor necrosis factor (TNF)-α, CXCL8, and CCL2, and inhibitors of signal transduction proteins including phosphodiesterase 4, MAPK p38, Pl-3k, and NFκB.
Future therapeutic treatment of COPD: Struggle between oxidants and cytokines
2007-09-01
Chronic obstructive pulmonary disease (COPD) is a global health problem. Being a progressive disease characterized by inflammation and predominantly caused by tobacco smoking, it deteriorates pulmonary...Full Text Available
Full Text Available.BackgroundHereditary Hemochromatosis (HH) is a genetic disease associated with iron overload, in which individuals homozygous for the mutant C282Y HFE associated allele are at risk for the development of a range of disorders particularly liver disease. Conformational diseases are a class of disorders associated with the expression of misfolded protein. HFE C282Y is a mutant protein that does not fold correctly and consequently is retained in the Endoplasmic Reticulum (ER). In this context, we sought to identify ER stress signals associated with mutant C282Y HFE protein expression, which may have a role in the molecular pathogenesis of HH.ResultsVector constructs of Wild type HFE and Mutant C282Y HFE were made and transfected into HEK293 cell lines. We have shown that expression of C282Y HFE protein triggers both an unfolded protein response (UPR), as revealed by the increased GRP78, ATF6 and CHOP expression, and an ER overload response (EOR), as indicated by NF-κB activation. Furthermore, C282Y HFE protein induced apoptotic responses associated with activation of ER stress. Inhibition studies demonstrated that tauroursodeoxycholic acid, an endogenous bile acid, downregulates these events. Finally, we found that the co-existence of both C282Y HFE and Z alpha 1-antitrypsin protein (the protein associated with the liver disease of Z alpha 1-antitrypsin deficiency) expression on ER stress responses acted as potential disease modifiers with respect to each other.ConclusionOur novel observations suggest that both the ER overload response (EOR) and the unfolded protein response (UPR) are activated by mutant C282Y HFE protein.
BackgroundHereditary Hemochromatosis (HH) is a genetic disease associated with iron overload, in which individuals homozygous for the mutant C282Y HFE associated...Full Text Available
Experimental Gene Transfer Procedure to Treat Alpha 1-Antitrypsin Deficiency
Alpha 1-Antitrypsin Deficiency
2007-03-13
Immature and nonnative proteins are retained in the endoplasmic reticulum (ER) by the quality control machinery. Folding-incompetent glycoproteins are eventually targeted for ER-associated protein degradation...Full Text Available
2007-03-13
Full Text Available.Immature and nonnative proteins are retained in the endoplasmic reticulum (ER) by the quality control machinery. Folding-incompetent glycoproteins are eventually targeted for ER-associated protein degradation (ERAD). EDEM1 (ER degradation-enhancing α-mannosidase-like protein 1), a putative mannose-binding protein, targets misfolded glycoproteins for ERAD. We report that endogenous EDEM1 exists mainly as a soluble glycoprotein. By high-resolution immunolabeling and serial section analysis, we find that endogenous EDEM1 is sequestered in buds that form along cisternae of the rough ER at regions outside of the transitional ER. They give rise to ≈150-nm vesicles scattered throughout the cytoplasm that are lacking a recognizable COPII coat. About 87% of the immunogold labeling was over the vesicles and ≈11% over the ER lumen. Some of the EDEM1 vesicles also contain Derlin-2 and the misfolded Hong Kong variant of α-1-antitrypsin, a substrate for EDEM1 and ERAD. Our results demonstrate the existence of a vesicle budding transport pathway out of the rough ER that does not involve the canonical transitional ER exit sites and therefore represents a previously unrecognized passageway to remove potentially harmful misfolded luminal glycoproteins from the ER.
Consensus Recommendations for the Use of 18F-FDG PET as an Indicator of Therapeutic Response in Patients in National Cancer Institute Trials Lalitha K. Shankar1, John M. Hoffman2, Steve Bacharach3, Michael M. Graham4, Joel Karp5, Adriaan A. Lammertsma6, Steven Larson7, David A. Mankoff8, Barry A.
Definitions used to define adolescent and adult smokers differ. Adolescent-based surveys define smokers as respondents who have smoked at least one cigarette in the last 30 days; the definitions are intended to be sensitive enough to capture respondents who are experimenting with ciga-rettes and are in the early stages of beginning smoking. Adult-based surveys define smokers as respondents who have smoked at least 100 cigarettes and currently smoke every day or some days.
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Axion Project Incubation Status - Apache Incubator
For general project status, see the Axion project website. ... The axion project never moved to the ASF from tigris.org. 2003-12-19: The Apache Incubator ...
Axion - Wikipedia, the free encyclopedia
The axion is a hypothetical elementary particle postulated by Peccei-Quinn theory in 1977 to resolve the strong-CP problem in quantum chromodynamics (QCD). ...
Autotaxin/Lysopholipase D and Lysophosphatidic Acid Regulate Murine Hemostasis and Thrombosis*S⃞
2009-03-13
The lipid mediator lysophosphatidic acid (LPA) is a potent regulator of vascular cell function in vitro, but its physiologic role in the cardiovasculature is largely unexplored. To...Full Text Available
Autotaxin/Lysopholipase D and Lysophosphatidic Acid Regulate Murine Hemostasis and Thrombosis*S⃞
2009-03-13
Full Text Available.The lipid mediator lysophosphatidic acid (LPA) is a potent regulator of vascular cell function in vitro, but its physiologic role in the cardiovasculature is largely unexplored. To address the role of LPA in regulating platelet function and thrombosis, we investigated the effects of LPA on isolated murine platelets. Although LPA activates platelets from the majority of human donors, we found that treatment of isolated murine platelets with physiologic concentrations of LPA attenuated agonist-induced aggregation. Transgenic overexpression of autotaxin/lysophospholipase D (Enpp2), the enzyme necessary for production of the bulk of biologically active LPA in plasma, elevated circulating LPA levels and induced a bleeding diathesis and attenuation of thrombosis in mice. Intravascular administration of exogenous LPA recapitulated the prolonged bleeding time observed in Enpp2-Tg mice. Enpp2+/- mice, which have ∼50% normal plasma LPA levels, were more prone to thrombosis. Plasma autotaxin associated with platelets during aggregation and concentrated in arterial thrombus, and activated but not resting platelets bound recombinant autotaxin/lysoPLD in an integrin-dependent manner. These results identify a novel pathway in which LPA production by autotaxin/lysoPLD regulates murine hemostasis and thrombosis and suggest that binding of autotaxin/lysoPLD to activated platelets may provide a mechanism to localize LPA production.
2009-01-01
Full Text Available.Emphysema is mainly caused by cigarette smoking and is characterized by the loss of alveolar integrity and an enlargement of the alveolar space. However, mechanisms involved in its development are not fully understood. Alveolar cell apoptosis has been previously investigated in the lung of emphysematous subjects as a potential contributor to the loss of alveolar cell and has been found abnormally elevated. Though, mechanisms involved in the increased alveolar apoptosis that occurs in emphysema have now become a prolific field of research. Those mechanisms are reviewed here with special focus on how they affect cell viability and how they may be implicated in emphysema. Moreover, we suggest a model that integrates all those mechanisms to explain the increased alveolar apoptosis observed in emphysema. This review also includes some reflections and suggestions on the research to come.
2009-01-01
Emphysema is mainly caused by cigarette smoking and is characterized by the loss of alveolar integrity and an enlargement of the alveolar space. However, mechanisms involved in its development are not...Full Text Available
A Novel Antiapoptotic Role for α1-Antitrypsin in the Prevention of Pulmonary Emphysema
2006-06-01
Rationale: There is growing evidence that alveolar cell apoptosis plays an important role in emphysema pathogenesis, a chronic inflammatory lung disease characterized by alveolar destruction....Full Text Available
A Novel Antiapoptotic Role for α1-Antitrypsin in the Prevention of Pulmonary Emphysema
2006-06-01
Full Text Available.Rationale: There is growing evidence that alveolar cell apoptosis plays an important role in emphysema pathogenesis, a chronic inflammatory lung disease characterized by alveolar destruction. The association of α1-antitrypsin deficiency with the development of emphysema has supported the concept that protease/antiprotease imbalance mediates cigarette smoke–induced emphysema.Objectives: We propose that, in addition to its antielastolytic effects, α1-antitrypsin may have broader biological effects in the lung, preventing emphysema through inhibition of alveolar cells apoptosis.Methods, Measurements, and Main Results: Transduction of human α1-antitrypsin via replication-deficient adeno-associated virus attenuated airspace enlargement and emphysema caused by inhibition of vascular endothelial growth factor (VEGF) receptors with SU5416 in mice, a model of apoptosis-dependent emphysema lacking neutrophilic inflammation. The overexpressed human serine protease inhibitor accumulated in lung cells and suppressed caspase-3 activation and oxidative stress in lungs treated with the VEGF blocker or with VEGF receptor-1 and -2 antibodies. Similar results were obtained in SU5416-treated rats given human α1-antitrypsin intravenously.Conclusions: Our findings suggest that inhibition of structural alveolar cell apoptosis by α1-antitrypsin represents a novel protective mechanism of the serpin against emphysema. Further elucidation of this mechanism may extend the therapeutic options for emphysema caused by reduced level or loss of function of α1-antitrypsin.
10434_2007_9800_15_4-web 1048..1055
Annals of Surgical Oncology 15(4):1048?1055 DOI: 10.1245/s10434-007-9800-2 The Possible Association between IVF and Breast Cancer Incidence I. Pappo, MD,1,2 L. Lerner-Geva, MD PhD,3 A. Halevy, MD,2 L. Olmer, MSc,4 S. Friedler, MD,5 A. Raziel, MD,5
α-1 Antitrypsin Inhibits Caspase-3 Activity, Preventing Lung Endothelial Cell Apoptosis
2006-10-01
Full Text Available.α-1 Antitrypsin (A1AT) is an abundant circulating serpin with a postulated function in the lung of potently inhibiting neutrophil-derived proteases. Emphysema attributable to A1AT deficiency led to the concept that a protease/anti-protease imbalance mediates cigarette smoke-induced emphysema. We hypothesized that A1AT has other pathobiological relevant functions in addition to elastase inhibition. We demonstrate a direct prosurvival effect of A1AT through inhibition of lung alveolar endothelial cell apoptosis. Primary pulmonary endothelial cells internalized human A1AT, which co-localized with and inhibited staurosporine-induced caspase-3 activation. In cell-free studies, native A1AT, but not conformers lacking an intact reactive center loop, inhibited the interaction of recombinant active caspase-3 with its specific substrate. Furthermore, overexpression of human A1AT via replication-deficient adeno-associated virus markedly attenuated alveolar wall destruction and oxidative stress caused by caspase-3 instillation in a mouse model of apoptosis-dependent emphysema. Our findings suggest that direct inhibition of active caspase-3 by A1AT may represent a novel anti-apoptotic mechanism relevant to disease processes characterized by excessive structural cell apoptosis, oxidative stress, and inflammation, such as pulmonary emphysema.
α-1 Antitrypsin Inhibits Caspase-3 Activity, Preventing Lung Endothelial Cell Apoptosis
2006-10-01
α-1 Antitrypsin (A1AT) is an abundant circulating serpin with a postulated function in the lung of potently inhibiting neutrophil-derived proteases. Emphysema attributable to A1AT deficiency...Full Text Available
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