John L. Skosey

Elevated breath pentane in heart failure reduced by free radical scavenger

UNLABELLED Pentane, a product of lipid peroxidation, has been detected in situations involving ischemic injury. Such injury may be limited if lipid peroxidation can be controlled by antioxidants. The role of lipid peroxidation in chronic heart failure (CHF) was assessed by measuring breath pentane in patients with CHF vs. age matched controls. The effect of a free radical scavenger on pentane released during CHF was also measured. Pentane levels were correlated with the daily dose of captopril, a sulfhydril-containing drug used to treat CHF, which is an angiotensin converting enzyme inhibitor. To separate the scavenging effects of captopril from the pharmacologic effects of converting enzyme inhibitors, a crossover study using a nonsulfhydril inhibitor was used. Patients with CHF excreted (p < 0.005) high concentrations of pentane (5.7 +/- 2.1 vs. control 3.6 +/- 1.2 nmol/l). Patients treated with captopril also had significantly higher (p < 0.05) excretion of pentane than the control patients (4.7 +/- 1.3 vs. 3.6 +/- 1.2 nmol/l). The dose of captopril was inversely proportional to the concentration of pentane excreted (r = 0.55, p < 0.05). Pentane excretion during captopril therapy was significantly lower before (p < 0.01) and after (p < 0.02) nonsulfhydril inhibitor therapy. CONCLUSION breath pentane is elevated in CHF and it can be reduced by a free radical scavenger. This reduction of pentane excretion is not a converting enzyme inhibitor class effect.

High breath pentane concentrations during acute myocardial infarction

To investigate whether reperfusion after myocardial ischaemia leads to free-radical-mediated peroxidation of membrane lipids and cell damage, we measured pentane, a product of lipid peroxidation, in the breath of 10 healthy control subjects and in 20 consecutive patients with suspected acute myocardial infarction. 10 of these patients showed no myocardial damage on electrocardiography (patient control group) and 10 satisfied standard diagnostic criteria for acute myocardial infarction. The three groups were well matched for age, sex, underlying disease, and smoking habits. The time from onset of chest pain to breath collection was similar in the patient control and acute myocardial infarction groups. The breath pentane concentration was higher (p less than 0.0001) in the acute myocardial infarction group (4.96 [1.15] nmol/l) than in the patient control (1.96 [1.04] nmol/l) and healthy control groups (1.71 [0.87] nmol/l). Lipid peroxidation during acute myocardial infarction reflects action of oxygen radicals and their potential for contribution to the pathogenesis of tissue damage.

Dyslipoproteinemia in the course of active rheumatoid arthritis.

Concentrations of serum lipids and serum very low-density lipoproteins and low-density lipoproteins (VLDL+LDL, originally called beta lipoproteins) were measured and agarose gel electrophoresis of serum lipoproteins was performed in 69 patients with active rheumatoid arthritis (RA), 40 patients with psoriatic arthritis (PA), 21 patients with osteoarthritis (OA), and 65 healthy blood donors. These lipid parameters were also compared in 21 RA and 40 PA patients during periods of severe disease activity (SA) versus minimal disease activity (MA). RA patients had significantly decreased concentrations of total serum lipids, total serum cholesterol, cholesterol in LDL, and cholesterol in high-density lipoproteins (HDL) compared with healthy blood donors. RA patients with SA had significantly decreased cholesterol in LDL and HDL compared with patients with MA. As the disease activity decreased, RA patients had normalization of almost all serum lipid concentrations. Electrophoresis of serum lipoproteins showed heterogeneous patterns in RA patients. Patients with PA also had some evidence of dyslipoproteinemia. Serum lipids changed with disease activity in PA patients in a manner similar to that in RA patients. These data show that patients with RA and PA have a dyslipoproteinemia that is related to disease activity.

BREATH PENTANE EXCRETION AS A MARKER OF DISEASE ACTIVITY IN RHEUMATOID ARTHRITIS

Activated inflammatory cells are capable of stimulating lipid peroxidation. In 27 patients with rheumatoid arthritis, we measured the pulmonary excretion of pentane, a product released during lipid peroxidation. We found highly significant correlations between pentane excretion and both joint inflammation (r = 0.88, p less than 0.001) and the erythrocyte sedimentation rate (r = 0.80, p less than 0.001). Patients treated with gold compounds or D-penicillamine excreted diminished amounts of pentane. The data suggest that lipid peroxidation may be related in part to the mechanism of injury in rheumatoid arthritis.

Determination of inflammatory bowel disease activity by breath pentane analysis

PURPOSE: Quantitative determination of breath pentane, an alkane generated by peroxidation of cellular fatty acids, has been used as a noninvasive determinant of inflammation. Herein we report the first examination of the relationship between breath pentane and intestinal inflammation in humans. METHODS: Patients (N=33), either with a known history of inflammatory bowel disease (IBD) with symptoms of relapse or with no known history of but having symptoms consistent with IBD, were evaluated with indium-111-labeled leukocyte imaging to assess the presence of active inflammation. At the time of the indium scan, the exhaled breath of the patients was obtainedviaa collecting tube. Gas chromatography was used to quantify the pentane content, and these values were compared with graded indium scans. RESULTS: The range of breath pentane found in our population (36 determinations in 33 patients) was from 0 to 38.4 nmol/ 1 of exhaled air. For patients with negative scans, the mean pentane was 2.1 nmol/l, for intermediate scans 3.1, for positive scans 4.3, and for nonintestinal nuclide imaging 5.5 [P=0.005 by analysis of variance (ANOVA)]. CONCLUSIONS: We have previously demonstrated the correlation of breath pentane with gross and histologic evidence of intestinal inflammation in a rodent colitis model. This current study also demonstrates that pentane analysis can be correlated with inflammatory bowel disease activity in humans.

Clinical relapse in systemic lupus erythematosus: Correlation with antecedent elevation of urinary free light-chain immunoglobulin

This paper reports preliminary evidence suggesting that measurements of free light-chain Ig (FLIg) in urine may represent quantitative markers ofin vivo polyclonal B-cell activation. Thus, longitudinal levels of urinary FLIg in patients with systemic lupus erythematosus (SLE) may be used to track or monitor thein vivo immunopathologic B-cell activity of SLE and be helpful in predicting a disease relapse. Our findings showed that dramatic rises in urinary FLIg occurred during asymptomatic intervals that preceded by 4–8 weeks the first symptomatic signs of acute SLE relapse. These results suggest that a sizable lead time may exist between the occurrence of immunopathologic B-cell stimulation and the resultant symptoms and tissue damage of immune complex-induced acute inflammation. In these studies the measurement of urinary FLIg was accomplished by an indirect method using ng-sensitive radioimmunoassays (RIAs) that measured isotypic IgG, IgA, IgM, total κ-Ig, and total λ-Ig. As a control for the assessment of renal tubular function and the excretion of low molecular weight proteins in SLE patients, longitudinal measurements of beta-2-microglobulin (B2M) and lysozyme were made using a novel solid-phase3H-biotin RIA technique.

Quantitative determination of pentane in exhaled air correlates with colonic inflammation in the rat colitis model

Oxygen radicals play a key role in inflammation and inflammatory tissue damage. Quantitative determination of pentane, a hydrocarbon generated by membrane lipid peroxidation initiated by oxygen radicals, in expired air has been used as a noninvasive determinant or index of inflammation in various conditions. Herein we report the first examination of the relationship between exhaled pentane and colonic inflammation in a rodent model of colitis. Colitis was induced in rats (n=33) using the trinitrobenzene-sulfonic acid (TNB) model of colitis. Exhaled air was collected in a closed chamber on randomly selected animals on days 1, 2, 4, 7, 11, 13, 15, 20, and 25 post-TNB treatment, and pentane was assayed by means of gas chromatography. Gross and microscopic evidence of inflammation was compared with exhaled pentane levels. Pentane levels varied from 0.0 to 14.6 nmol/l of air and were significantly increased in TNB-treated rats compared with control rats only on days 7 to 15 after treatment (P<0.05). Gross inspection showed severe colonie inflammation through the first week (mean score =4.7 out of a possible 5), persistent inflammation on days 7 to 15 (3.2), and healing and fibrosis from the end of week two until day 25 (1.9 to 0). Histologic evaluation confirmed a progression of inflammation from acute ulceration to chronic inflammation to fibrosis and scarring. We have demonstrated that pentane exhalation is increased after the induction of colonie inflammation, with a seven-day lag time, and returns rapidly to normal as acute inflammation resolves. This suggests that pentane exhalation can be used as a noninvasive measure of colonic inflammation in rodent models of colitis and perhaps clinically in humans.

Secretion of plasminogen activator by cerebral astrocytes and its modulation.

Plasminogen activator (PA) has been related to the neuron migration during brain development. PA has also been shown to degrade myelin basic protein. We present data to show that neonatal Balb/c astrocytes show PA activity on 125I-fibrin coated plates. Secreted and cell associated fibrinolytic activity is detected only in the presence of plasminogen. Modulants like concanavalin A and phorbol myristate acetate enhance PA production and this function involves a transcriptional event. Dexamethasone inhibits baseline as well as concanavalin A induced enhancement of PA activity. These results raise the possibility that astrocytes may have an active role in myelinoclastic disorders and CNS developmental defects.

Cholesterol crystals in synovial and bursal fluid

Cholesterol crystals were found in two patients with classic rheumatoid arthritis (RA). In one patient, cholesterol crystals were found in synovial fluid from both shoulder joints, and in the second they were in an olecranon bursa. To examine the possible systemic etiology of cholesterol crystals in synovial and bursal fluid, lipid concentrations and the presence of serum antilipoprotein antibodies were measured. Antilipoprotein antibodies were not found. The concentration of lipid and lipoproteins, as well as the normal pattern of lipoprotein on agarose gel, eliminates the possibility of hyperlipoproteinemia. Results seemed to exclude a systemic etiology for the formation of cholesterol crystals in synovial and bursal fluid in the RA patients. It appears that several local factors such as defective drainage, local destruction, increased permeability of synovial membrane, and intraarticular (bursal) bleeding are possible etiologies.

Antilipoprotein antibodies in rheumatoid arthritis

Antibodies against very low-density lipoproteins and low-density lipoproteins (aLA) were found in 26 of 69 (38%) patients with active rheumatoid arthritis (RA) but not in any control subjects (ie, 40 patients with psoriatic arthritis, 21 patients with osteoarthritis, and 65 healthy blood donors). In 21 RA patients (30%), lipoproteins were found in the dissociated components of circulating immune complexes. RA patients with aLA had significantly decreased cholesterol levels in all lipoprotein fractions and total serum lipids, while serum triglycerides were significantly increased compared with RA patients without aLA. Anticardiolipin antibodies as measured by the Venereal Disease Research Laboratory test were not found in any subject in this study. These findings suggest a possible autoimmune origin of dyslipoproteinemia in some patients with active RA.