Pulmonary oxidative stress response in young children with cystic fibrosis

BACKGROUND: It has been suggested that oxidative stress contributes to lung injury in cystic fibrosis. There is, however, no direct evidence of increased pulmonary oxidative stress in cystic fibrosis nor of the effects of inflammation on the major pulmonary antioxidant, glutathione. A study was undertaken to measure these parameters in infants and young children in the presence or absence of pulmonary inflammation. METHODS: Thirty two infants and young children with cystic fibrosis of mean (SD) age 21.4 (15.3) months (range 2-54) and seven non-cystic fibrosis control subjects of mean (SD) age 21.0 (21.2) months (range 2-54) were studied using bronchoalveolar lavage (BAL). On the basis of the BAL findings the cystic fibrosis group was divided into those with (CF-I) and those without pulmonary inflammation (CF- NI). Levels of lipid hydroperoxide, total glutathione, and gamma- glutamyl transpeptidase (gamma-GT) were then measured in the BAL fluid. RESULTS: The concentrations of lipid hydroperoxide and gamma-GT in the epithelial lining fluid were significantly increased in the CF-I group compared with the control and CF-NI groups, each of which had similar values for these parameters (ratio of geometric means for CF-I group versus control for lipid hydroperoxide 5.4 (95% confidence interval (CI) 1.8 to 15.8) and for gamma-GT 5.2 (95% CI 1.4 to 19.4)). The glutathione concentration tended to be lower in the CF-I subjects but the difference did not reach statistical significance. CONCLUSIONS: These results demonstrate that the airways in patients with cystic fibrosis are exposed to increased oxidative stress which appears to be a consequence of pulmonary inflammation rather than part of the primary cystic fibrosis defect. The increase in gamma-GT in the CF-I group suggests a mechanism by which extracellular glutathione could be utilised by airway epithelial cells.


     

Education modifies the effect of apolipoprotein epsilon 4 on cognitive decline

OBJECTIVES: To assess the influence of education on the association between apolipoprotein E and cognitive change. DESIGN: Prospective cohort. PARTICIPANTS: HMO-based sample of 2168 non-demented community-dwelling elderly followed over 6 years. MEASUREMENTS: Generalized estimating equations were used with the difference between baseline and follow-up cognitive abilities screening instrument (CASI) as the outcome variable. RESULTS: At follow-up, 6% of the sample had a decline of 1.5 S.D. or greater on the CASI. Compared to individuals without an APOE4 allele, individuals with a single APOE4 allele did not have greater CASI decline. By contrast, individuals with two APOE4 alleles experienced greater decline in cognitive performance and the magnitude of that decline decreased as years of educational attainment increased. These relationships held after adjusting for age, gender, ethnicity, depression, diabetes, and history of vascular disease. CONCLUSION: Lower education was associated with steep 4-year cognitive decline for APOE4 homozygotes but not for APOE4 heterozygotes. Potentially modifiable host factors such as education could influence the association of high-risk genotypes and cognitive decline.     

Projection neurons in the rat dorsolateral septal nucleus possess recurrent axon collaterals

Projection neurons in the rat dorsolateral septal nucleus (DLSN) were labeled intracellularly with horseradish peroxidase (HRP) in an in vitro slice preparation. The labeled neurons exhibited widespread 'isodendritic' type dendritic fields. Each of the neurons was identified as a projection neuron by the tracing of its main axon out of DLSN. The axons of these neurons gave rise to intrinsic collaterals which branched to form an extensive axon plexus which was confined to DLSN. These axon collaterals exhibited numerous en passant swellings suggestive of boutons. It is proposed that the recurrent axon collaterals of DLSN projection neurons may form an anatomical substrate for local inhibition within DLSN.     

Some observations on the measurement of haemoglobin A2 and S percentages by high performance liquid chromatography in the presence and absence of alpha thalassaemia

AIMS: To assess the accuracy and precision of measuring haemoglobin A(2) by high performance liquid chromatography (HPLC) in the presence and absence of sickle cell trait, with or without alpha thalassaemia trait. METHODS: The haemoglobin A(2) percentage and the haemoglobin A(2) plus S percentages were determined by HPLC on 82 normal controls and 78 patients with sickle cell trait, respectively; the alpha thalassaemia status of each patient was determined by polymerase chain reaction. Red cell indices and haemoglobin A(2) and S percentages were compared in patients with two, three, or four alpha genes. RESULTS: Of the 78 patients with sickle cell trait, 17 were heterozygous for alpha(+) thalassaemia (-alpha(3.7)/alphaalpha) and 13 were homozygous (-alpha(3.7)/-alpha(3.7)). Microcolumn chromatography showed that the haemoglobin A(2) percentage was slightly, but significantly, higher than normal in sickle cell trait. HPLC determinations of haemoglobin A(2) percentage in patients with sickle cell trait are precise but inaccurate, the percentage being appreciably overestimated. The measured haemoglobin A(2) percentage is stable for one week, but inaccuracy increases by two weeks in most samples. Despite this inaccuracy, there are significant differences in the HPLC "haemoglobin A(2) percentage" between groups of individuals with two, three, and four alpha genes. CONCLUSIONS: Haemoglobin A(2) determinations by HPLC are precise but inaccurate. Nevertheless, there are significant differences in the haemoglobin A(2) percentage in subjects with two, three, and four alpha genes. Although there is some overlap between groups, this can be useful, together with the red cell indices, in predicting the likelihood of coexisting alpha thalassaemia.     

AOP2 (antioxidant protein 2): structure and function of a unique thiol-specific antioxidant

The accumulation of reactive oxygen species (ROS) in response to extracellular signals or intracellular biochemical processes can be regulated by the coordinate action of many antioxidant proteins. Because moderate levels of ROS can act as intracellular messengers in many of these processes, this modulation is critical for the transduction of specific signals. The thiol-specific antioxidant (TSA) family is a highly conserved group of enzymes that can reduce hydroperoxides in the presence of a thiol-containing electron donor. AOP2 (antioxidant protein 2) is a newly described member that shows significant evolutionary conservation between many different organisms. The protein contains three motifs that are highly conserved within the TSA family, including a cysteine residue that is the active site of oxidation for this class of proteins. Although AOP2 possesses TSA activity, it has several unique characteristics, including the absence of a second cysteine residue that is conserved in all other TSA proteins, the presence of a unique carboxy-terminal domain, and a demonstrated phospholipase activity. Furthermore, AOP2 shows conservation of several amino acids important in dimer formation and active site configuration that are not found in the other family members. Together, these data strongly suggest that AOP2 is a novel thiol-dependent antioxidant that functions to scavenge particular hydroperoxides in the cell and mediate specific signals. There is also evidence supporting a role for AOP2 in certain disease processes including atherosclerosis. Further evaluation of this protein and its substrate specificity will likely shed light on its precise role in cellular oxidant defense, signal transduction and pathogenesis.     

Physiological and psychosocial contributors to malnutrition in children with cystic fibrosis: review

Malnutrition was once thought to be an inevitable consequence of cystic fibrosis (CF). It is now considered preventable but still contributes considerable morbidity in children. Malnutrition is linked to poorer pulmonary function, reduced survival and quality of life. As the anticipated lifespan of children with CF continues to lengthen, the prevention of malnutrition attains greater importance. This review explores the complex organic and psychosocial factors implicated in the aetiology of malnutrition associated with CF.