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Biomedical subjects

D C Hutchison

Publications and source records attributed to D C Hutchison.

At least 19 recordsLinked to original sources
PubMed1999

A randomized clinical trial of alpha(1)-antitrypsin augmentation therapy.

We have investigated whether restoration of the balance between neutrophil elastase and its inhibitor, alpha(1)-antitrypsin, can prevent the progression of pulmonary emphysema in patients with alpha(1)-antitrypsin deficiency. Twenty-six Danish and 30 Dutch ex-smokers with alpha(1)-antitrypsin deficiency of PI*ZZ phenotype and moderate emphysema (FEV(1) between 30% and 80% of predicted) participated in a double-blind trial of alpha(1)-antitrypsin augmentation therapy. The patients were randomized to either alpha(1)-antitrypsin (250 mg/kg) or albumin (625 mg/kg) infusions at 4-wk intervals for at least 3 yr. Self-administered spirometry performed every morning and evening at home showed no significant difference in decline of FEV(1) between treatment and placebo. Each year, the degree of emphysema was quantified by the 15th percentile point of the lung density histogram derived from computed tomography (CT). The loss of lung tissue measured by CT (mean +/- SEM) was 2.6 +/- 0.41 g/L/yr for placebo as compared with 1.5 +/- 0.41 g/L/yr for alpha(1)-antitrypsin infusion (p = 0.07). Power analysis showed that this protective effect would be significant in a similar trial with 130 patients. This is in contrast to calculations based on annual decline of FEV(1) showing that 550 patients would be needed to show a 50% reduction of annual decline. We conclude that lung density measurements by CT may facilitate future randomized clinical trials of investigational drugs for a disease in which little progress in therapy has been made in the past 30 yr.

Double-Blind Method↗
PubMed1998

Alpha 1-antitrypsin deficiency in Europe: geographical distribution of Pi types S and Z.

alpha 1-Antitrypsin (AT) is the principal serum inhibitor of proteolytic enzymes such as neutrophil elastase. AT can exist as over 90 different genetically determined variants known as the Pi system; the three most important variants are type M (90% of population) and types S and Z, two of the commoner abnormal variants. Homozygotes of type Z have a severe reduction in the serum AT concentration and may develop pulmonary emphysema or hepatic cirrhosis. Heterozygotes of type SZ have a less severe reduction in serum AT concentration and the association with clinical disease is less clear. The S and Z variants are found mainly among those of European stock. The gene frequency for Pi type Z is highest on the north-western seaboard of the continent and the mutation seems likely to have arisen in southern Scandinavia. The distribution of type S is quite different; the gene frequency is highest in the Iberian peninsula and the mutation is likely to have arisen in that region. A population survey for determining the number of type Z homozygotes in a given community is important for planning purposes now that AT replacement therapy is potentially available.

Europe↗
PubMed1997

Molecular basis, clinical consequences and diagnosis of alpha-1 antitrypsin deficiency.

(1) Deficiency of alpha AT is one of the most common hereditary diseases affecting Caucasians in Europe. The alpha 1AT protein is extremely pleomorphic, and around 90 variants due to mutations have been recognized. The prime functions of alpha 1AT is to inhibit neutrophil elastase, and a proportion of individuals who are deficient in alpha 1AT develop emphysema. The most common deficiency variant (Z) is also associated with liver disease. The main site of alpha 1AT synthesis is in the liver. Not all deficient individuals are affected by lung or liver disease, however, so that other factors (genetic and environmental) are clearly important. (2) Investigation of alpha 1AT status is essential in any child or adult presenting with chronic liver disease. The genetic cause cannot be identified clinically or by any other laboratory investigation. The diagnosis carries important prognostic consequences and is important for other family members. Patients with emphysema should have their Pi type determined, especially if they are under the age of 50, have never smoked or there is a suggestive family history. Asymptomatic individuals who are homozygous type Z should be referred to a chest physician for a clinical and radiological assessment together with lung function tests. (3) Several laboratory tests are available to detect alpha 1AT deficiency, and the choice of test(s) will depend on circumstances. Quantitation of the serum protein is simple and cheap. Because alpha 1AT is an acute phase protein, however, quantitation used in isolation may give false negative results which are clearly unacceptable, particularly in association with paediatric liver disease. Phenotyping by isoelectric focusing requires some experience in distinguishing SZ and ZZ phenotypes, and phenotyping should ideally be used in conjunction with quantitation because heterozygous null phenotypes may appear identical to homozygous normal phenotypes. (4) Prenatal diagnosis is usually performed by DNA analysis of CVS samples obtained at 11-13 weeks. Because of the risk that CVS samples might be contaminated by maternal tissue, assays which are less likely to detect minor contaminants are preferable. At present, use of DNA tests is confined to prenatal diagnosis, but the availability of simple tests and the possibility of unequivocal identification of S and Z alleles means that these tests are likely to find greater use in the near future.

Humans↗
PubMed1991

Urinary desmosine, elastolysis, and lung disease.

Desmosine is an amino acid specific to elastin. Animal studies suggest that urinary desmosine (UD) represents endogenous elastin degradation. Therefore, UD has previously been used to investigate endogenous elastolysis, but was not elevated in subjects with chronic obstructive airways disease (COAD), although accelerated pulmonary elastolysis is thought to contribute to COAD. We have investigated whether this reflects large day-to-day and between-subject variation in UD and whether, in man, dietary desmosine contributes significantly to that in urine. Mean 24-hour UD output (over 5 consecutive days) from 10 asymptomatic subjects (5 males) was higher in males than females (77.4 +/- 9.6 and 40.2 +/- 5.0 nmol/24 hours, respectively; mean +/- SD, P less than .001), but not significantly different when expressed in terms of creatinine (micrograms desmosine/100 mg creatinine: males, 2.5 +/- 0.4; females, 3.1 +/- 0.8; mean +/- SD). The lowest between-subject variation was observed when the mean of 5 days' 24-hour UD values was analyzed on the basis of gender (coefficient of variation [CV], 12.5%); when gender was not considered, the least between-subject variation was found for the mean of 5 days' desmosine/creatinine analysis (CV, 24.5%). Approximately 1% of dietary desmosine (ingested as [3H]elastin and [3H] desmosine) was excreted in the urine within 24 hours, contributing approximately 15% of UD while on a normal diet. Although ingestion of a low elastin diet (less than 1/10 desmosine/24 hours than a normal diet) resulted in lower within-subject variation in 24-hour UD excretion (mean CV decreased from 31.5% to 20.2%), the between-subject CV and UD levels did not alter.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

The epidemiology of alpha 1-antitrypsin deficiency.

Alpha 1-protease inhibitor can exist as over 70 different biochemical variants (the Pi system) which are inherited as autosomal-codominant alleles. The majority of these variants are of no clinical significance. Epidemiologically, the most abundant are Pi types M, S, and Z. Homozygotes of type Z have only 10%-20% of the normal serum concentration of the inhibitor and have an increased risk of developing pulmonary emphysema. Cigarette smoking is the most important risk factor. A minority of Pi Z homozygotes (10%-20%) develop a form of neonatal hepatitis and a proportion of these suffer from liver cirrhosis in adult life. Heterozygotes of Pi type SZ have about one third of the normal serum alpha 1-protease inhibitor concentration but this phenotype does not in itself appear to be a significant emphysema risk factor. Heterozygotes of Pi type MZ are thought to have a moderately increased risk of developing emphysema but only if they smoke; there is also evidence for an increased risk of cirrhosis among subjects of type MZ. No excessive risk appears to be attached to the MS phenotype. Cumulative survival curves have suggested that type Z homozygotes have a poor prognosis but such estimates are based on clinic or hospital patients who already have respiratory symptoms. Calculations based on population frequencies however, suggest that about 90% of the total number of type Z subjects are not accounted for in such surveys. Their whereabouts remains unclear at present; some will undoubtedly have died of liver or lung disease but it is possible that the majority escape and live undetected among the general population.

Asthma↗
PubMed1990

Epidemiology of alpha 1-protease inhibitor deficiency.

Alpha 1-protease inhibitor can exist as over seventy different biochemical variants (the Pi system) which are inherited as autosomal codominant alleles. The majority of these variants are of no clinical significance. Epidemiologically, the most abundant are Pi types M, S and Z. Homozygotes of type Z have only 10 to 20% of the normal serum concentration of the inhibitor and have an increased risk of developing pulmonary emphysema. Cigarette smoking is the most important risk factor. A minority of Pi Z homozygotes (10 to 20%) develop a form of neonatal hepatitis and a proportion of these suffer from cirrhosis in adult life. Heterozygotes of Pi type SZ have about one third of the normal serum alpha 1-protease inhibitor concentration but this phenotype does not in itself appear to be a significant emphysema risk factor. Heterozygotes of Pi type MZ are thought to have a moderately increased risk of developing emphysema but only if they smoke; there is also evidence for an increased risk of cirrhosis among subjects of type MZ. No excessive risk appears to be attached to the MS phenotype. Cumulative survival curves have suggested that type Z homozygotes have a poor prognosis but such estimates are based on clinic or hospital patients who already have respiratory symptoms. Calculations based on population frequencies however, suggest that about 90% of the total number of type Z subjects are not accounted for in such surveys. Their whereabouts remains unclear at present; some will undoubtedly have died of liver or lung disease but it is possible that the majority escape and live undetected among the general population.

Arthritis, Rheumatoid↗
PubMed1988

Natural history of alpha-1-protease inhibitor deficiency.

Alpha-1-protease inhibitor (A1PI) exists in over 30 biochemical variants (the Pi system), inherited as autosomal codominant alleles. Homozygotes of Pi type Z have only 10 to 20 percent of the normal serum A1PI concentration and have a high risk of developing pulmonary emphysema. A1PI is an inactivator of polymorph lysosomal elastase, the unopposed action of which may damage the lung. Cigarette smoking is an important additional risk factor. Neonatal hepatitis occurs in 10 to 20 percent of Pi type Z persons, and cirrhosis develops in a number of them in later childhood or in adult life. In heterozygotes of Pi type MZ, pulmonary or hepatic disease may also develop, though they are at lesser risk than type Z homozygotes. Specific A1PI replacement therapy derived from human plasma is now available and has been administered to Pi type Z patients by weekly intravenous infusion without adverse effects. A controlled clinical trial would be desirable, though this would be attended by organizational and economic problems.

Arthritis, Rheumatoid↗
PubMed1987

Biologically-significant scavenging of the myeloperoxidase-derived oxidant hypochlorous acid by some anti-inflammatory drugs.

Neutrophils contain the enzyme myeloperoxidase, which oxidizes Cl- ions into the powerful oxidant hypochlorous acid (HOCl). HOCl inactivates alpha 1-antiprotease, permitting uncontrolled protease activities. Most anti-inflammatory drugs tested are capable of reacting with HOCl, but the reactions seem insufficiently rapid under physiological conditions to protect alpha 1-antiprotease against inactivation by HOCl. However, rapid scavenging of HOCl might contribute to the anti-inflammatory effects of penicillamine, gold sodium thiomalate, phenylbutazone and primaquine.

Animals↗
PubMed1987

The specificity of thiourea, dimethylthiourea and dimethyl sulphoxide as scavengers of hydroxyl radicals. Their protection of alpha 1-antiproteinase against inactivation by hypochlorous acid.

Thiourea and dimethylthiourea are powerful scavengers of hydroxyl radicals (.OH), and dimethylthiourea has been used to test the involvement of .OH in several animal models of human disease. It is shown that both thiourea and dimethylthiourea are scavengers of HOCl, a powerful oxidant produced by neutrophil myeloperoxidase. Hence the ability of dimethylthiourea to protect against neutrophil-mediated tissue damage cannot be used as evidence for a role of .OH in causing such damage. Dimethyl sulphoxide also reacts with HOCl, but at a rate that is probably too low to be biologically significant at dimethyl sulphoxide concentrations up to 10 mM. Neither mannitol nor desferrioxamine, at the concentrations normally used in radical-generating systems, appears to react with HOCl.

Deferoxamine↗
PubMed1987

The antioxidant action of human extracellular fluids. Effect of human serum and its protein components on the inactivation of alpha 1-antiproteinase by hypochlorous acid and by hydrogen peroxide.

The elastase-inhibitory capacity of purified human alpha 1-antiproteinase is inactivated by low concentrations of the myeloperoxidase-derived oxidant hypochlorous acid, but much higher concentrations are required to inhibit the elastase-inhibitory capacity of serum samples. The protective effect of serum appears to be largely due to albumin. High concentrations of H2O2 also inactivate the elastase-inhibitory capacity of alpha 1-antiproteinase, by a mechanism not involving formation of hydroxyl radicals. Serum offers protection against H2O2 inactivation of alpha 1-antiproteinase. The relevance of these results to the tissue damage produced by activated phagocytes is discussed.

Blood↗
PubMed1987

Transcutaneous oxygen tension during exercise in patients with pulmonary emphysema.

Transcutaneous PO2 (tcPO2) and arterial PO2 (PaO2) were compared during exercise in six patients with pulmonary emphysema. For calibration purposes, the tcPO2 electrode was first attached to the skin and after stabilisation its reading was adjusted to correspond to the PO2 of an initial arterial blood sample. It was shown that tcPO2 measurement could follow accurately the rapid changes in PaO2 occurring during exercise. Sixty-eight paired comparisons of PaO2 and tcPO2 were available and the regression equation was given by: tcPO2 (mmHg) = 0.98 PaO2 + 0.7 (correlation coefficient, 0.985; 95% confidence limits, 5.7 mmHg).

Aged↗
PubMed1987

In vivo calibration of a transcutaneous oxygen electrode in adult patients.

Transcutaneous oxygen tension (tcPO2) has been compared with arterial oxygen tension (PaO2 in 14 haemodynamically stable patients in an intensive care unit. Two calibration methods have been compared: (1) "In vitro" calibration, a two point calibration procedure carried out before attachment to the skin. (2) "In vivo" calibration, calibration using a single arterial sample, to recalibrate the upper point after attachment of the electrode to the skin and stabilisation of the electrical output. After "in vitro" calibration the regression equation was given by tcPO2 (mmHg) = 0.58 PaO2 + 13.4 (95% confidence limits +/- 19.6). After "in vivo" calibration, the regression equation for 55 comparisons over the range 50 to 120 mmHg was given by: tcPO2 (mmHg) = 0.98 PaO2 + 1.6 (95% confidence limits +/- 6.6). The "in vivo" calibration method therefore allows a close estimate of PaO2 to be made from tcPO2 values in adult patients providing strict operating criteria observed.

Adult↗