Augmentation therapy in alpha(1)-antitrypsin deficiency.
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Humans↗
Biomedical subjects
S Brenton
Publications and source records attributed to S Brenton.
Function of a rare variant of alpha-1-antitrypsin, phenotype P(i) EFranklin S, a poor inhibitor of human neutrophil elastase.
A 31-year-old woman with the rare alpha-1-antitrypsin (A1AT) phenotype P(i) EFranklin S presented to this laboratory. Since little is known about the EFranklin protein, a study was established to investigate the biochemical properties of this glycoprotein, notably its inhibitory activity against human neutrophil elastase (HNE), compared with that of the more common A1AT variants M and Z. The serum A1AT level of 1.8 g/l (reference range 0.8-2.2 g/l) and anti-neutrophil elastase capacity (ANEC) value of 28 microM (reference range 15-42 microM) of this variant were normal. However, the association rate constant (AC) of the isolated and purified EFranklin protein 2.7 (0.4) x 10(6) M-1 s-1 at 25 degrees C was significantly lower compared with that in the normal M variant 9.1 (0.9) x 10(6) M-1 s-1. This implies that this form of A1AT is expressed at normal levels in serum but is functionally impaired as an inhibitor of HNE. The in vivo serum inhibition time of HNE was estimated to be 66 ms for the purified EFranklin protein compared with 20 ms for the M protein. While this protein is not an efficient inhibitor of HNE, there are sufficient molecules in the serum to achieve 100% inhibition of HNE and to protect the lung against proteinase attack. In conclusion, individuals who inherit the rare EFranklin variant in conjunction with the M or S A1AT molecules do not appear to have a high risk for the development of emphysema.
Adult↗
The proteinase-antiproteinase theory of emphysema: a speculative analysis of recent advances into the pathogenesis of emphysema.
This review concerns the reasons why only an estimated 10-15% of patients with alpha-1-antitrypsin (A1AT) deficiency develop the destructive lung disease known as emphysema. The arguments presented revolve around the proteinase-antiproteinase balance in the 'microenvironment' of the epithelial space of the lung. Attention is focused on the balance between destructive enzymes such as neutrophil elastase and protective proteins such as A1AT, secretory leucocyte proteinase inhibitor (SLPI), human elastase inhibitor (HEI) and elafin. When neutrophil elastase is already attached to the elastin fibres the smaller molecules SLPI and elafin appear to be better inhibitors of this enzyme than larger inhibitors such as A1AT and HEI. Furthermore, SLPI and elafin may provide the first line of defence against proteinase attack from neutrophil elastase. In trying to explain the variability in the clinical expression of A1AT-deficiency and the development of emphysema, the importance of changes to A1AT, SLPI and elafin molecules induced by smoking and/or oxygen free radicals has been considered. It is possible that emphysema only develops in patients who have SLPI/elafin deficiency as well as A1AT deficiency.
Emphysema↗
Kinetic characterisation of alpha-1-antitrypsin F as an inhibitor of human neutrophil elastase.
Patients homozygous for the Z allele of alpha-1-antitrypsin (alpha 1AT) have very low serum levels and are predisposed to emphysema. There have also been reports of emphysema being associated with the heterozygous phenotype FZ. To investigate whether F alpha 1AT was dysfunctional, the inhibitory activity of F alpha 1AT against human neutrophil elastase (HNE) was compared with that of common alpha 1AT phenotypes. Time-dependent inhibition of HNE by alpha 1AT was used to calculate the association rate constant (k assoc) for M, MZ, FM, FZ, F (partially purified from FZ or FS), Z and S alpha 1AT phenotypes in human sera. The results for k assoc at 25 degrees C were 9.1 (SD 0.9), 9.7 (SD 0.9), 8.0 (SD 0.8), 4.0 (SD 0.4), 4.2 (SD 0.8), 5.1 (SD 0.6) and 8.6 (SD 0.6) x 10(6) M-1s-1 respectively. F was found to have reduced activity much like that of Z, the alpha 1AT most commonly associated with emphysema. MZ (low risk for disease) and FZ heterozygotes had similar intermediate alpha 1AT levels. However the in vivo inhibition time for FZ was almost three times longer than for MZ, indicating greater exposure to proteolytic damage from free elastase for FZ than MZ individuals. In conclusion, F alpha 1AT is expressed in serum at low normal levels but is dysfunctional in its ability to inhibit HNE. Individuals who coinherit the F and a deficiency allele such as Z or Null, are likely to have a high risk for the development of emphysema. The disease risk for F homozygotes remains to be determined.
Adult↗
Antiproteinase deficiency, emphysema and replacement therapy.
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Humans↗
Alpha-1-antitrypsin PLowell: a normally functioning variant present in low concentration.
BACKGROUND: Alpha-1-antitrypsin deficiency is associated with a high risk for the development of emphysema, particularly for phenotype Pi ZZ, which is both deficient and an abnormal inhibitor of the powerful proteolytic enzyme, human neutrophil elastase. The rare variant PLowell is also expressed at abnormally low levels, but its anti-elastase activity has not been described. AIM: To study the anti-elastase activity of alpha-1-antitrypsin PLowell and compare it to the common M, S and Z proteins. METHOD: Alpha-1-antitrypsin from a female patient aged 75 years with the rare genotype PLowell NullBellingham was studied for its ability to inhibit human neutrophil elastase in a time dependent manner. RESULTS: PLowell has near normal function as an inhibitor of human neutrophil elastase with an association rate constant of 7.4 x 10(6) M-1 S-1 at 25 degrees C, similar to that of M and S. CONCLUSION: Alpha-1-antitrypsin PLowell is associated with a severe deficiency of alpha-1-antitrypsin similar to Z, but unlike that protein it has near normal function as an anti-elastase.
Aged↗
Absence of alpha-1-antitrypsin (Pi Null Bellingham) and the early onset of emphysema.
BACKGROUND: Alpha-1-antitrypsin is the body's major inhibitor of human neutrophil elastase, a powerful proteolytic enzyme capable of degrading the common tissue components. There are over 70 genetic variants of alpha-1-antitrypsin, with the Z allele being of greatest clinical relevance. Individuals homozygous for this allele (approximately one in 2500 in Caucasians) have low serum alpha-1-antitrypsin levels (10-20% of normal) and are predisposed to emphysema, especially if they smoke. Much rarer are mutations which result in the complete or almost complete absence of alpha-1-antitrypsin in the serum. AIM: To determine the cause of complete absence of alpha-1-antitrypsin in a patient who at age 27 years had both emphysema and idiopathic cardiomyopathy. METHODS: Molecular biology techniques were used to sequence the alpha-1-antitrypsin gene. Allele specific amplification was used to show the presence of the mutations in other family members. RESULTS: Investigation showed that the proband was homozygous for the Pi Null Bellingham variant of alpha-1-antitrypsin due to the mutation Lys 217 (AAG) to Stop (TAG). His grandmother was heterozygous for Pi Null Bellingham and the additional rare variant P Lowell, Asp 256 (GAT) to Val (GTT), a variant that also results in alpha-1-antitrypsin deficiency. CONCLUSION: Patients with complete absence of alpha-1-antitrypsin develop premature emphysema not having smoked or after only minimal exposure, and much earlier than the more common Pi Z individuals who have the usual form of alpha-1-antitrypsin deficiency.
Adult↗
Making numbers talk--promoting home care legislators.
The home care industry stands to gain a lot in the coming health care reform. To argue effectively for home care's inclusion in new health care legislation, the industry must present hard facts and figures.
Aged↗
Standards--if we don't set them who will?
Anticipating the coverage of home IV therapy, the Arizona Association for Home Care set out to prepare the "Home IV Infusion Standards." In doing so, they had to consider the widespread variation in agency needs and operations. The standards were adopted in 1989, although the committee's work continues.
Arizona↗
RSV specimen collection methods: nasal vs. nasopharyngeal.
PURPOSE: To compare two types of specimen collection methods for RSV (respiratory syncytial virus): nasal wash and nasopharyngeal wash. METHODOLOGY: An exploratory descriptive research design was used to examine nasopharyngeal wash and nasal wash methods of collecting specimens for RSV to determine if one method gives more consistently accurate results. Sample size was 66. FINDINGS: Using chi square analysis on a contingency table, there was no significant difference between the two collection methods. Only 2 of the 66 samples showed a difference in the two collection methods by giving a positive result with the nasopharyngeal method. CONCLUSIONS: There is no significant difference between using nasal wash and nasopharyngeal wash methods for collecting specimen for RSV testing. Nasal wash is a safe and accurate method for obtaining specimen for RSV.
Humans↗