Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of the National Exposure Registry is to assess the long-term health consequences to a general population from long-term, low-level exposures to specific substances in the environment. This study investigates the health outcomes of 1,143 persons (1,127 living, 16 deceased) living in south central Texas who had documented environmental exposure to benzene (up to 66ppb) in tap water. As with all subregistries, face-to-face interviews were used to collect self-reported information for 25 general health status questions. Using computer-assisted telephone interviewing, the same health questions were asked 1 year (Followup 1, F1) and 2 years later (Followup 2, F2). The health outcome rates for Baseline and Followup 1 and 2 data collections for the Benzene Subregistry were compared with national norms, that is, the National Health Interview Survey (NHIS) rates. For at least one of the three reporting periods, specific age and sex groups of the Benzene Subregistry population reported more adverse health outcomes when compared with the NHIS population, including anemia and other blood disorders, ulcers, gall bladder trouble, and stomach or intestinal problems, stroke, urinary tract disorders, skin rashes, diabetes, kidney disease, and respiratory allergies. Statistically significant deficits for the Benzene Subregistry population overall were found for asthma, emphysema, or chronic bronchitis; arthritis, rheumatism, or other joint disorders; hearing impairment; and speech impairment. No statistically significant differences between the two populations were seen for the outcomes hypertension; liver disease; mental retardation; or cancer. These results do not identify a causal relationship between benzene exposure and adverse health effects; however, they do reinforce the need for continued followup of registrants.
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PMID:The National Exposure Registry: analyses of health outcomes from the benzene subregistry. 956 45

alpha 1-Antitrypsin (alpha 1AT) provides the major protection in the lung against neutrophil elastase-mediated proteolysis. Inheritance of alpha 1AT deficiency alleles is associated with an increased risk of emphysema and liver disease. alpha 1AT null alleles cause the total absence of serum alpha 1AT and represent the ultimate in a continuum of alleles associated with alpha 1AT deficiency. The molecular mechanisms responsible for absence of serum alpha 1AT include splicing abnormalities, deletion of alpha 1AT coding exons, and premature stop codons. We identified an Italian individual with asthma, emphysema, and a very low level of serum alpha 1AT. DNA sequencing demonstrated the Mprocida deficiency allele and a novel null allele, QOtrastevere (c654 G-->A, W194Z), a nonsense mutation near the intron 2 (IVS2) splice acceptor site. To determine the molecular basis of QOtrastevere and specifically to evaluate whether this nonsense mutation interfered with mRNA processing by altered splicing, we used a Chinese hamster ovary cell line permanently transfected with QOtrastevere or normal M alpha 1AT with and without IVS2. Northern blot analysis demonstrated that the normal M construct, with or without IVS2, expressed alpha 1AT mRNA of a similar size. The nonsense mutation was associated with moderately reduced alpha 1AT mRNA regardless of the presence or absence of IVS2. Reduction in alpha 1AT mRNA regardless of the opportunity for splicing supports a translational-translocation model as the cause of reduced alpha 1AT mRNA rather than the nuclear scanning model. Pulse-chase studies followed by immunoprecipitation demonstrated an endoplasmic reticulum-retained 31 kDa QOtrastevere alpha 1AT, which was rapidly degraded. Although mRNA content was moderately reduced, retention and rapid intracellular degradation of the truncated form are the major mechanisms for the absence of secreted alpha 1AT.
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PMID:Alpha 1-antitrypsin nonsense mutation associated with a retained truncated protein and reduced mRNA. 963 95

The mutant Z form of alpha1-antitrypsin (alpha1AT) is responsible for > 95% of all individuals with alpha1AT deficiency, an important inherited cause of emphysema and liver disease. Since secreted Z alpha1AT is a functional antiprotease, we hypothesized that interrupting catabolism of retained Z alpha1AT might increase its transport out of cells, causing an increase in extracellular protease protection. Both the protein translation inhibitor cycloheximide and the specific inhibitor of proteasome function, lactacystin, prevented intracellular degradation of Z alpha1AT. Moreover, this inhibition of degradation was associated with partial restoration of Z alpha1AT vesicular transport. This effect was observed in a model system of transfected CHO cells as well as in human alveolar macrophages synthesizing Z alpha1AT. This study supports the hypothesis that altering the intracellular fate of a mutant protein may be an option in the treatment of diseases associated with misfolded but potentially functional proteins.
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PMID:Inhibition of intracellular degradation increases secretion of a mutant form of alpha1-antitrypsin associated with profound deficiency. 963 3

Alpha 1-Antitrypsin (alpha 1AT) deficiency is the most common genetic cause of liver disease in children and emphysema in adults. Therapy for pulmonary disease attributable to alpha 1AT deficiency includes alpha 1AT augmentation therapy along with supportive measures. The alpha 1AT preparation that is currently used for therapy is derived from fractionated plasma. The results of clinical trials suggest that augmentation therapy with alpha 1AT slows the progression of emphysema and causes few adverse events. Patients with plasma levels of alpha 1AT that are < 11 mumol/L and who have airway obstruction should be considered for augmentation therapy. Novel approaches include the administration of aerosolised alpha 1AT, recombinant alpha 1AT, gene therapy and synthetic elastase inhibitors.
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PMID:Alpha 1-antitrypsin. Hope on the horizon for emphysema sufferers? 963 92

The alpha1-protease inhibitor proteins of laboratory mice are homologous in sequence and function to human alpha1-antitrypsin and are encoded by a highly conserved multigene family comprised of five members. In humans, the inhibitor is expressed in liver and in macrophages and decreased expression or inhibitory activity is associated with a deficiency syndrome which can result in emphysema and liver disease in affected individuals. It has been proposed that macrophage expression may be an important component of the function of human alpha1-antitrypsin. Clearly, it is desirable to develop a mouse model of this deficiency syndrome, however, efforts to do this have been largely unsuccessful. In this paper, we report that aside from the issues of potentially redundant gene function, the mouse may not be a suitable animal for such studies, because there is no significant expression of murine alpha1-protease inhibitor in the macrophages of mice. This difference between the species appears to result from an absence of a functional macrophage-specific promoter in mice.
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PMID:Divergent expression of alpha1-protease inhibitor genes in mouse and human. 968 98

Alpha1-Antitrypsin (alpha1AT) deficiency is characterized by a high risk of developing pulmonary emphysema and liver disease. Arteriopathy may be associated with alpha1AT deficiency. We present a patient with only one kidney and alpha1AT deficiency, but only mild pulmonary symptoms and no signs of liver disease, and atraumatic loss of the remaining kidney. Histological examination of the renal artery showed desposits of a mucoid ground substance in the arterial media, as has been demonstrated in other patients with alpha1AT deficiency. After dialysis treatment for 15 months, the patient underwent an uneventful kidney transplantation. The case draws attention to the awareness of complications of alpha1AT deficiency even in cases with only mild pulmonary manifestations of the disorder. To our knowledge, atraumatic loss of a kidney in a patient with alpha1AT deficiency has not previously been reported.
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PMID:Atraumatic loss of a kidney in a patient with alpha1-antitrypsin deficiency. 973 Jul 8

Homozygous PIZZ alpha 1-antitrypsin deficiency, which has an incident of 1 in 1600 to 1 in 2000 live births, is the most common genetic cause of liver disease in children. It is also associated with chronic liver disease and hepatocellular carcinoma in adults. It is a well-known cause of pulmonary emphysema. Although emphysema is due to uninhibited proteolytic destruction of the connective tissue backbone of the lung, liver disease is thought to result from the toxic effects of the mutant alpha 1AT molecule retained within the endoplasmic reticulum of liver cells. Screening studies done by Sveger in Sweden have shown that only 10 to 15% of the PIZZ population develop clinically significant liver disease over the first 20 years of life. Recent studies have suggested that a subgroup of PIZZ individuals are predisposed to liver injury because of an inefficient degradation of mutant alpha 1ATZ within the endoplasmic reticulum. Altered migration of the abnormal alpha 1ATZ molecule in isoelectric focussing gels is the basis of the diagnosis of alpha 1AT deficiency. Treatment of alpha 1AT deficiency-associated liver disease is mostly supportive. Liver replacement therapy has been used successfully for severe liver injury. An increasing number of patients with severe emphysema have undergone lung transplantation.
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PMID:Alpha-1-antitrypsin deficiency. 977 22

Protein misfolding plays a role in the pathogenesis of many diseases. alpha1-Antitrypsin misfolding leads to the accumulation of long chain polymers within the hepatocyte, reducing its plasma concentration and predisposing the patient to emphysema and liver disease. In order to understand the misfolding process, it is necessary to examine the folding of alpha1-antitrypsin through the different structures involved in this process. In this study we have used a novel technique in which unique cysteine residues were introduced at various positions into alpha1-antitrypsin and fluorescently labeled with N, N'-dimethyl-N-(iodoacetyl)-N'-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl)ethylenediamine. The fluorescence properties of each protein were studied in the native state and as a function of guanidine hydrochloride-mediated unfolding. The studies found that alpha1-antitrypsin unfolded through a series of intermediate structures. From the position of the fluorescence probes, the fluorescence quenching data, and the molecular modeling, we show that unfolding of alpha1-antitrypsin occurs via disruption of the A and C beta-sheets followed by the B beta-sheet. The implications of these data on both alpha1-antitrypsin function and polymerization are discussed.
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PMID:Probing the unfolding pathway of alpha1-antitrypsin. 1009 31

alpha 1-Antitrypsin (alpha 1-AT) deficiency, one of the most common hereditary disorders that mainly affects the lung and liver in Caucasian people, is caused by mutations of alpha 1-AT gene. Decrease of serum alpha 1-AT concentration is directly responsible for lung emphysema, replacement of plasma-derived alpha 1-AT concentrate is administered to patients of alpha 1-AT deficiency with lung emphysema, and lung transplantation is employed for end-stage lung emphysema. Augmentation therapy is not adequate for alpha 1-AT deficiency with liver disease, because liver injury is caused by accumulation of mutated alpha 1-AT protein in hepatocytes. Currently liver transplantation is the only treatment for severe liver cirrhosis. To correct the genetic defects of alpha 1-AT gene, several approaches for gene therapy are under investigation in vitro and in vivo animal models.
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PMID:[Recent progress of pathogenesis and treatment in alpha 1-antitrypsin deficiency]. 1049 21

A 16-year-old girl presented painful, red, nodular lesions on the abdomen. A cutaneous biopsy showed inflammatory cell infiltrate and fibrosis in the dermis and in the septa with isolated adipocyte lobules. alpha1-antitrypsin level was found to be normal but M1S phenotype of alpha1-antitrypsin was determined by isoelectric focusing in polyacrylamide gel. alpha1-antitrypsin level was normal for her family but M2S phenotype was found in her father. Alpha 1-antitrypsin (alpha1 AT) deficiency is a common hereditary disorder of Caucasians. The locus is pleiomorphic and 75 alleles have been identified. Numerous pathological mutations can be classified by the mechanisms which cause the deficiency. The major clinical importance of this deficiency is emphysema and liver disease. Panniculitis is rarely reported and seems to occur principally for the ZZ or MZ phenotype and for low levels of alpha1 AT. MS phenotype has been more rarely reported and triggering agents such as trauma and infections must be present. However, normal levels of alpha1 AT in the serum have previously been reported as in our case, and we suggest the study of alpha1 AT phenotype even if the plasma level is normal.
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PMID:Panniculitis revealing qualitative alpha 1 antitrypsine deficiency (MS variant). 1052 39


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