Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Rainey Hospice House, South Carolina's first stand-alone inpatient facility opened in September 1998. During the year 2000, 220 inpatients were served in the house. Patients ranged in age from 23 to 107 years old (average age 73). Cancer was the most common hospice diagnosis, followed by congestive heart failure, cardiovascular disease and cerebrovascular disease, dementia, cirrhosis, renal failure, and COPD. Thirty-three percent of patients were in the program less than ten days. Over 98 percent of deaths under hospice care were described as peaceful. During 2000, our outpatients and our inpatients were similar in age, insurance coverage, diagnoses, and time in the program. Inpatient hospice is highly valued by families and patients alike. It is especially useful for the following patients: those with uncontrolled symptoms, those with exhausted care givers, those with no caregivers, those who require total care, and those very close to death. The symptoms most likely to precipitate inpatient admission include pain, nausea, confusion, and agitation. Given the graying of South Carolina's population and the increase in outpatient hospice care, more areas of the state will need inpatient facilities in the future.
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PMID:Comfort always. The Rainey Hospice House: South Carolina's first inpatient hospice. 1450 98

Alpha-1-antitrypsin (alpha(1)-antitrypsin) is the archetypal member of the serine proteinase inhibitor or serpin superfamily. The most common severe deficiency variant is the Z allele, which results in the accumulation of mutant protein within hepatocytes. This 'protein overload' causes neonatal hepatitis, cirrhosis and hepatocellular carcinoma. The lack of circulating plasma alpha(1)-antitrypsin results in early-onset panlobular emphysema. The mechanism underlying the deficiency of Z alpha(1)-antitrypsin is due to an aberrant conformational transition within the protein and the formation of chains of polymers that tangle within the secretory pathway of hepatocytes. This mechanism also underlies the plasma deficiency of other members of the serpin superfamily to cause a class of diseases called the serpinopathies. Specifically mutant alleles of antithrombin, C1-inhibitor and alpha(1)-antichymotrypsin have been reported that favour the spontaneous formation of polymers and the retention of protein within hepatocytes. The consequent lack of plasma antithrombin, C1-inhibitor and alpha(1)-antichymotrypsin results in thrombosis, angio-oedema and emphysema, respectively. Moreover, the polymerisation of mutants of neuroserpin results in the retention of polymers within neurones to cause the inclusion body dementia, familial encephalopathy with neuroserpin inclusion bodies or FENIB. We review here the genetic and molecular basis and clinical features of alpha(1)-antitrypsin deficiency, and show how this provides a platform to understand the other serpinopathies.
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PMID:Practical genetics: alpha-1-antitrypsin deficiency and the serpinopathies. 1469 55

Members of the serine proteinase inhibitor or serpin superfamily inhibit their target proteinases by a remarkable conformational transition that involves the enzyme being translocated more than 70 A (1 A = 10(-10) m) from the upper to the lower pole of the inhibitor. This elegant mechanism is subverted by point mutations to form ordered polymers that are retained within the endoplasmic reticulum of secretory cells. The accumulation of polymers underlies the retention of mutants of alpha(1)-antitrypsin and neuroserpin within hepatocytes and neurons to cause cirrhosis and dementia respectively. The formation of polymers results in the failure to secrete mutants of other members of the serpin superfamily: antithrombin, C1 inhibitor and alpha1-antichymotrypsin, to cause a plasma deficiency that results in the clinical syndromes of thrombosis, angio-oedema and emphysema respectively. Understanding the common mechanism underlying the retention and deficiency of mutants of the serpins has allowed us to group these conditions as the serpinopathies. We review in this paper the molecular and structural basis of the serpinopathies and show how this has allowed the development of specific agents to block the polymerization that underlies disease.
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PMID:Molecular mousetraps and the serpinopathies. 1578 98

Point mutations in members of the serine proteinase inhibitor or serpin superfamily cause them to change shape, polymerise and be deposited in the tissues. This process is best seen in mutants of alpha1-antitrypsin within hepatocytes to cause periodic acid-Schiff (PAS) positive inclusions and cirrhosis. An identical process underlies the PAS positive inclusions of mutants of neuroserpin within neurones to cause a dementia that we have called familial encephalopathy with neuroserpin inclusion bodies (FENIB). In both cases, there is a direct correlation between the molecular instability, the rate of intracellular polymer formation and the severity of disease. This process of polymerisation also explains the failure to secrete mutants of other members of the serpin superfamily--antithrombin, C1 inhibitor and alpha1-antichymotrypsin--to cause thrombosis, angio-oedema and emphysema, respectively. In view of the common mechanism underlying these conditions, we have grouped them together as the serpinopathies.
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PMID:Molecular mousetraps, alpha1-antitrypsin deficiency and the serpinopathies. 1601 Dec 17

The intimate relation between amino acids and protein and nitrogen requirements is well recognized. Nutrition research has focused on the capacity of food to meet the need for nitrogen and indispensable amino acids (IAA) and led to the conclusion that the quality, not just the quantity, of protein is critical. This is especially relevant in regard to the sulfur amino acids (SAA) methionine and cysteine because of the increased understanding of their relation to chronic diseases (e.g., cardiovascular disease, dementia, cirrhosis), immunomodulation, DNA transcription, and RNA translation. Considerable effort has been expended to determine whether and to what extent cysteine can spare the requirement for the IAA methionine. In vivo studies in humans generally concur that the dietary requirement of the SAA ranges between 13 and 16 mg.kg(-1).d(-1), but how much can be met by cysteine relative to methionine remains controversial. This review examines the current status of in vivo estimates of methionine and cysteine requirements in human adults and considers needs beyond what is necessary for protein synthesis. Factors influencing the utilization of methionine and cysteine, especially those conditions that lead to toxicity on the one hand or beneficial effects on the other, are discussed. Data on alternative dietary sources of methyl groups (e.g., betaine, choline, phosphatidylcholine, S-adenosylmethionine, S-methylmethionine) or sulfur (e.g., N-acetylcysteine or L-2-oxothiazolidine-4-carboxylic acid) support a role for the SAA "beyond protein." Other pathways may influence the specific requirement for methionine and/or cysteine, especially when the person is challenged by disease, inadequate availability of food, or environmental stress.
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PMID:Sparing of methionine requirements: evaluation of human data takes sulfur amino acids beyond protein. 1670 39

Mutations in neuroserpin and alpha1-antitrypsin cause these proteins to form ordered polymers that are retained within the endoplasmic reticulum of neurones and hepatocytes, respectively. The resulting inclusions underlie the dementia familial encephalopathy with neuroserpin inclusion bodies (FENIB) and Z alpha1-antitrypsin-associated cirrhosis. Polymers form by a sequential linkage between the reactive centre loop of one molecule and beta-sheet A of another, and strategies that block polymer formation are likely to be successful in treating the associated disease. We show here that glycerol, the sugar alcohol erythritol, the disaccharide trehalose and its breakdown product glucose reduce the rate of polymerization of wild-type neuroserpin and the Ser49Pro mutant that causes dementia. They also attenuate the polymerization of the Z variant of alpha1-antitrypsin. The effect on polymerization was apparent even when these agents had been removed from the buffer. None of these agents had any detectable effect on the structure or inhibitory activity of neuroserpin or alpha1-antitrypsin. These data demonstrate that sugar and alcohol molecules can reduce the polymerization of serpin mutants that cause disease, possibly by binding to and stabilizing beta-sheet A.
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PMID:Sugar and alcohol molecules provide a therapeutic strategy for the serpinopathies that cause dementia and cirrhosis. 1670 19

The archetypal status of alpha(1)-antitrypsin in biology and medicine grew from the finding, thirty years ago, by Carl-Bertil Laurell, of the association of its deficiency with emphysema. In biology, alpha(1)-antitrypsin now provides the model for both the structure and the remarkable mechanism of the serpin protease inhibitors that control the key proteolytic pathways of the body. In medicine, the plasma deficiency of alpha(1)-antitrypsin has drawn attention to protease-antiprotease imbalance as a contributory cause of chronic obstructive pulmonary disease. But even more significantly, the finding that the common genetic deficiency of alpha(1)-antitrypsin was also associated with the development of liver cirrhosis introduced the new entity of the conformational diseases. The proposal that the same general mechanism was responsible for the best known of the conformational diseases, the common late-onset dementias, was controversial. It was vindicated however by the recent finding that a mutation, which results in the liver aggregation of alpha(1)-antitrypsin, also results in a typical late-onset dementia when it occurs in a brain-specific homologue of alpha(1)-antitrypsin. The extensive development of such diverse fields of studies, each based on alpha(1)-antitrypsin, is a measure of the encouragement Laurell gave to younger colleagues in the field. It also reflects the great advantage of linked contributions from clinical as well as basic sciences. Time after time, scientific controversies and deadlocks have been solved by landmark clinical cases, which have revealed unexpected findings and insights, within and beyond the fields of study.
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PMID:What we owe to alpha(1)-antitrypsin and to Carl-Bertil Laurell. 1699 40

Nowadays Palliative Medicine (PM) is changing from a specific point of view towards patients with advanced cancer, to another more generic that also keep in mind patients with advanced non malignant disease. Likewise it is more and more deeply rooted customs that the end-of-life care has become a fundamental right of our Society. But as a matter of fact, these patients with non-cancer diseases unusually go into a Palliative Care (PC) programme. It is known the difficulty to diagnosis the end of life clinical condition (EOLCC) in them. In this article we comment the justification and restriction of PC in patients with non-malignant cancer diseases, as well as the paradoxical situation to come out, in spite of the increasing programes of PC gradually. But above all we propose in a practical way resolve when a patient with non malignant organ advanced disease (NMOAD) could be subsidiary of PC. For that purpose we have to know the diagnosis and the prognostic factors in connection with the EOLCC of the NMOAD more common (advanced chronical pulmonary disease, advanced chronical heart failure, advanced cirrhosis hepatic, advanced chronical renal failure and very evolved dementia), to set up an appropriate make decisions keeping in mind the preferences and wishes of the patient and family, to document and record in the clinical history all those parameters and offerer to the patient the treatment more suitable with the intention to get a worthy death bearing in mind clinical, cultural and ethical standards. It is pointed out the necessity to carry out prospective studies to help setting up some inclusion criterions in PC programmes for patients with NMOAD.
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PMID:[Approximation to palliative care in the advanced non-malignant diseases]. 1860 37

Repeating intermolecular protein association by means of beta-sheet expansion is the mechanism underlying a multitude of diseases including Alzheimer's, Huntington's and Parkinson's and the prion encephalopathies. A family of proteins, known as the serpins, also forms large stable multimers by ordered beta-sheet linkages leading to intracellular accretion and disease. These 'serpinopathies' include early-onset dementia caused by mutations in neuroserpin, liver cirrhosis and emphysema caused by mutations in alpha(1)-antitrypsin (alpha(1)AT), and thrombosis caused by mutations in antithrombin. Serpin structure and function are quite well understood, and the family has therefore become a model system for understanding the beta-sheet expansion disorders collectively known as the conformational diseases. To develop strategies to prevent and reverse these disorders, it is necessary to determine the structural basis of the intermolecular linkage and of the pathogenic monomeric state. Here we report the crystallographic structure of a stable serpin dimer which reveals a domain swap of more than 50 residues, including two long antiparallel beta-strands inserting in the centre of the principal beta-sheet of the neighbouring monomer. This structure explains the extreme stability of serpin polymers, the molecular basis of their rapid propagation, and provides critical new insights into the structural changes which initiate irreversible beta-sheet expansion.
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PMID:Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization. 1897 12

The serpins are the largest superfamily of protease inhibitors. They are found in almost all branches of life including viruses, prokaryotes and eukaryotes. They inhibit their target protease by a unique mechanism that involves a large conformational transition and the translocation of the enzyme from the upper to the lower pole of the protein. This complex mechanism, and the involvement of serpins in important biological regulatory processes, makes them prone to mutation-related diseases. For example the polymerization of mutant alpha(1)-antitrypsin leads to the accumulation of ordered polymers within the endoplasmic reticulum of hepatocytes in association with cirrhosis. An identical process in the neuron specific serpin, neuroserpin, results in the accumulation of polymers in neurons and the dementia FENIB. In both cases there is a clear correlation between the molecular instability, the rate of polymer formation and the severity of disease. A similar process underlies the hepatic retention and plasma deficiency of antithrombin, C1 inhibitor, alpha(1)-antichymotrypsin and heparin co-factor II. The common mechanism of polymerization has allowed us to group these conditions together as a novel class of disease, the serpinopathies.
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PMID:Protein misfolding and the serpinopathies. 1916 89


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