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Human serum paraoxonase (PON1) hydrolyzes oxidized lipids in low density lipoprotein (LDL) and could therefore retard the development of atherosclerosis. In keeping with this hypothesis, several case-control studies have shown a relationship between the presence of coronary heart disease (CHD) and polymorphisms at amino acid positions 55 and 192 of PON1, which we associated with a decreased capacity of PON1 to protect LDL against the accumulation of lipid peroxides, but some other studies have not. However, the PON1 polymorphisms are only 1 factor in determining the activity and concentration of the enzyme. Only 3 of the previous 18 studies directly determined PON1 activity and concentration. Therefore, we studied PON1 activity, concentration, and gene distribution in 417 subjects with angiographically proven CHD and in 282 control subjects. We found that PON1 activity and concentration were significantly lower in subjects with CHD than in control subjects (activity to paraoxon 122.8 [3.3 to 802.8] versus 214.6 [26.3 to 620.8] nmol. min(-1). mL(-1), P<0.001; concentration 71.6 [11.4 to 489.3] versus 89.1 [16.8 to 527.4] microg/mL, P<0.001). There were no differences in the PON1-55 and -192 polymorphisms or clusterin concentration between patients with CHD and control subjects. These results indicate that lower PON1 activity and concentration and, therefore, the reduced ability to prevent LDL lipid peroxidation may be more important in determining the presence of CHD than paraoxonase genetic polymorphisms.

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In experienced hands, antegrade left heart catheterization via a transeptal puncture is a safe and effective method of performing radiofrequency ablation on the left side of the heart. Persistence of atrial septal defect following transeptal puncture for mitral valvuloplasty has been widely reported although hemodynamically significant shunts are rare. To investigate the persistence of interatrial shunt following transeptal puncture in patients undergoing left-sided electrophysiological procedures using TEE. Fifty-one adult patients, 20 men, aged 19-82 (mean 42.4) years underwent 55 transeptal punctures. Either an 8 Fr Mullins or 8 Fr Swartz transeptal sheath was deployed in all cases. Of these, 28 consecutive patients were approached and 26 consented to undergo TEE. TEE was performed at least 3 weeks post transeptal puncture using a single-plane transducer for the first 18 patients, superseded by a multiplane transducer for the later cases. Both color flow Doppler and microcavitation contrast imaging of the interatrial septum were performed. One patient in the single-plane transducer group was excluded as the failed to swallow the TEE probe. In the remaining 25 patients studied, 9 men aged 21-82 (mean 44.1) years, TEE was performed at a mean of 12.2 (range 3-52) weeks post procedure. No evidence of interatrial shunt was detected by either color flow or contrast studies. Transeptal puncture used in electrophysiological procedures does not result in interatrial shunts persisting > 3 weeks post procedure.

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Human serum paraoxonase (PON1) is located on high density lipoprotein and has been implicated in the detoxification of organophosphates and possibly in the prevention of low density lipoprotein lipid peroxidation. PON1 has two genetic polymorphisms both due to amino acid substitution, one involving glutamine (A genotype) and arginine (B genotype) at position 192 and the other leucine (L genotype) and methionine (M genotype) at position 55. We investigated the effect of these polymorphisms on serum PON1 activity and concentration in 252 non-insulin dependent diabetes mellitus (NIDDM) individuals and 282 non-diabetic controls. Serum PON1 activity in the controls (214.6 nmol/min per ml (26.3-620.8)) was significantly higher than in NIDDM (158.7 nmol/min per ml (3.6-550.5) (P < 0.001) as was serum PON1 concentration (89.1 microg/ml (16.8-527.4)) compared to 76.7 microg/ml (3.6-443.8) (P < 0.01). In the control population MM homozygotes had significantly lower serum PON1 activity regardless of the 192 polymorphism whereas in NIDDM both LM and MM genotypes had lower serum PON1 activity than LL homozygotes only when the 192 AA genotype was present. Serum PON1 concentration was lower in NIDDM with AA/LM, AA/LL, AB/LL and AB/MM genotypes than in controls. Differences in PON1 activity were the major cause of differences in specific activity between genotypes. Neither the PON1 55 or 192 polymorphisms consistently influenced the serum lipid or lipoprotein concentrations in either population. Low serum PON1 activity in NIDDM may be related to an increased tendency to lipid peroxidation and may also increase susceptibility to toxicity from organophosphate exposure. Our findings thus raise the possibility that PON1 may be of importance in both the genetic and acquired predisposition to premature atherosclerosis and neuropathy in diabetes.

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Human serum paraoxonase (PON1) associated with high density lipoprotein (HDL) has been postulated to have a role in protecting low density lipoprotein (LDL) against oxidative modification, which has led to the proposal that PON1 is an anti-atherogenic, anti-inflammatory enzyme. PON1 has two genetically determined polymorphic sites giving rise to amino-acid substitutions at positions 55 (L-->M) and 192 (R-->Q) and therefore 4 potential alloenzymes. We have examined the effects of these molecular polymorphisms on the ability of HDL to protect LDL from oxidative modification. HDL protected LDL from oxidative modification, whatever the combination of PON1 alloenzymes present in it. However, HDL from QQ/MM homozygotes was most effective at protecting LDL while HDL from RR/LL homozygotes was least effective. Thus after 6 h of co-incubation of HDL and LDL with Cu2+ PON1-QQ HDL retained 57 +/- 6.3% of its original ability to protect LDL from oxidative modification, while PON1-QR HDL retained less at 25.1 +/- 4.5% (P < 0.01) and PON1-RR HDL retained only 0.75 +/- 0.40% (P < 0.005). In similar experiments HDL from LL and LM genotypes retained 21.8 +/- 7.5% and 29.5 +/- 6.6% (P = NS), respectively, of their protective ability, whereas PON1-MM HDL maintained 49.5 +/- 5.3% (P < 0.01). PON1 polymorphisms may affect the ability of HDL to impede the development of atherosclerosis and to prevent inflammation.

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1. The hydrolysis of organophosphate pesticides (OP) and nerve gases by serum paraoxonase (PON1) is an important factor determining their toxicity to mammals including man. The PON1 gene contains 2 polymorphic sites at amino acid positions 55 (L-->M) and 192 (G-->A, classically defined as the A and B genotypes) which result in several alloenzymes of PON1 in human serum. 2. The 192 polymorphism has previously been shown to affect PON1 activity. We have investigated the effect of both polymorphisms on the hydrolysis of paraoxon by serum from 279 healthy human subjects. 3. The 55 polymorphism significantly influenced PON1 activity. MM homozygotes had over 50% less activity towards paraoxon compared to the LL and LM genotypes regardless of the 192 genotype (P < 0.001). 4. Multiple regression analysis indicated that the 192 polymorphism, 55 polymorphism and serum PON1 concentration were responsible for 46, 16 and 13% of the variation in PON1 activity, respectively (all P < 0.001). None of the other parameters investigated significantly affected PON1 activity. 5. Therefore both PON1 polymorphisms affect the hydrolysis of paraoxon. AA/MM and AB/MM individuals may be potentially more susceptible to OP intoxication. 6. Genotyping individuals for both PON1 polymorphisms may provide a method for identifying those individuals at most risk of OP poisoning. The effect of PON1 polymorphisms on activity may also explain why some Gulf War Veterans have developed Gulf War Syndrome and some have not.

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Coronary artery bypass grafting (CABG) carries a high risk of acute pancreatitis. We report a pilot study to investigate whether pre-existing oxidative stress might underlie this susceptibility, in that a burst of free radical activity not only accompanies the reperfusion stage of CABG but seems to be a pivotal step in the pathogenesis of pancreatitis. Samples of peripheral venous blood were obtained on the morning of surgery from 8 consecutive patients (age, median and range, 62, 35-70 years) with > 75% stenosis in at least three coronary vessels and a further 8 (64, 49-70 years) who had received 1200 mg allopurinol in divided doses in the previous 48 h: the results were compared with profiles of 8 healthy controls (56, 50-60 years) with normal exercise ECG. None of the patients or controls currently smoked cigarettes and the majority drank alcohol on a social basis. Compared with controls, untreated patients had lower levels of glutathione (P < 0.001) and ascorbate (P < 0.05) in plasma, alpha-tocopherol (vitamin E as molar ratio of cholesterol, P < 0.025 and beta-carotene (P < 0.05) in serum. There was no difference in serum selenium levels, but values in patients and controls were lower than in younger controls from this area (P < 0.02). Samples from the patients contained higher concentrations of lipid peroxides than control samples (P < 0.25) but there was no evidence of excessive isomerisation of linoleic acid or oxidation of ascorbate and erythrocytes showed normal ATP and energy charge with no increase in membrane lipid peroxidisability. Treatment with allopurinol did not alter this pattern, such that the ratio of oxidised to total glutathione in plasma was higher among the 16 patients than 8 controls (P < 0.025). Habitually inadequate intakes are the best explanation for the patients' deficits in aqueous phase antioxidants; prescribed low cholesterol diets would exacerbate any prior insufficiency of lipid-phase antioxidants. Correction of these deficits during the months leading up to surgery should reduce the risk of CABG-induced acute pancreatitis.

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RW94 is a permitted additive in the food industry, which precipitates fatty acids in vitro. In vivo, this could result in reduced fatty acid absorption by the body, and may, therefore, influence the amount of fat excreted in the faeces. An investigation into the effects of RW94 on bodily fat absorption and excretion was undertaken. The safety, tolerability and efficacy of the product was compared with placebo in a group of 12 healthy volunteers, randomly assigned to receive either RW94 or placebo for a period of four days when dietary fat intake was controlled. After a 10-day washout period, the randomly assigned groups were crossed over to receive placebo and RW94, respectively, for a second 4-day period, when fat intake was similarly controlled. Five grams of RW94 administered orally 30 min after each meal resulted in a statistically significant increase in the amount of excreted faecal lipids compared with placebo (p < 0.05). Following high fat intake, total blood cholesterol was predictably raised in both placebo and RW94 groups, but was less markedly raised with RW94 than placebo. All subjects lost body weight during the study, but the loss while consuming RW94 was significantly greater (p < 0.05) than while consuming placebo. All subjects found the treatments acceptable, though an increased incidence of flatulence, rumbling stomach and abdominal discomfort was noted with RW94 compared with placebo. RW94 was comparable with placebo in respect of safety.

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BACKGROUND: Lp(a) lipoprotein has structural homology with plasminogen and has been shown to inhibit plasminogen activation in vitro. OBJECTIVE: To determine whether the serum concentration of Lp(a) lipoprotein present when streptokinase was given in acute myocardial infarction influenced the outcome as judged by electrocardiographic methods. PATIENTS AND DESIGN: Serum Lp(a) lipoprotein concentration was measured in 135 consecutive patients admitted with a diagnosis of acute myocardial infarction who received streptokinase treatment. Recovery from myocardial injury was assessed by the reduction in the sum of ST segment elevation measured from the J point (STJ) in the electrocardiogram immediately before streptokinase was given compared with that three hours later. RESULTS: The serum Lp(a) lipoprotein concentrations were measured within 12 hours of the onset of symptoms of myocardial infarction and were higher than in healthy reference populations. Recovery from myocardial infarction could be assessed from the STJ in 116 patients (86% of the series). Those in whom it could not had bundle branch block, left ventricular hypertrophy, did not survive three hours, or had started intravenous nitrate treatment or some other clinical procedure before or at the time the second electrocardiogram was to be recorded. Patients with reductions in STJ after streptokinase that were > 4 mm (the median decrease) had mean (range) serum Lp(a) lipoprotein concentrations of 41.0 (0.8-220) mg/dl and those with a smaller reduction in STJ had concentrations of 29.1 (1.7-151) mg/dl. The difference was not statistically significant. CONCLUSION: In this study Lp(a) lipoprotein concentration did not significantly influence the outcome of thrombolytic treatment with streptokinase.

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Forty-six of 110 consecutive admissions to the coronary care unit (CCU) were monitored by telemetry after discharge from the unit. One of three patients with sudden cardiac death was resuscitated successfully and four patients developed atrial fibrillation which resulted in investigation by echocardiography and treatment with anticoagulants. Significant ventricular ectopic activity was detected in four other patients. Arbitrary selection of patients resulted in those with complicated courses in the CCU being more likely to be monitored by telemetry after transfer to the ward than those which were uncomplicated. There were no cases of sudden cardiac death in patients who did not have telemetry. The cost of telemetry was 2,775 pounds per system. All 19 districts in the North-West region of the UK responded to a questionnaire. Five of the 19 used telemetry but only two of these used the technique routinely after discharge from the CCU whereas four used radiotelemetry to monitor patients on the ward when coronary care beds were unavailable. Eight districts wanted telemetry but needed funds. We conclude that radiotelemetry is an inexpensive way to detect serious arrhythmias in patients transferred from the CCU to the general ward. Monitored from the CCU, cardiac arrest can be immediately detected and treated by experienced staff. Asymptomatic atrial fibrillation leads to prompt investigation by echocardiography and possible treatment with anticoagulants. The importance of noticing major ventricular ectopic activity is likely to increase with the possibility of selecting patients with a high risk of life-endangering arrhythmias so that antiarrhythmic drugs or techniques such as automatic defibrillators can be used appropriately.(ABSTRACT TRUNCATED AT 250 WORDS)

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We have treated eight patients with various tumours producing hCG or AFP with the high risk gestational choriocarcinoma regimen EMA/CO. Marker response was seen in two of three tumours producing AFP and in all of five tumours producing hCG. Three further patients were treated with EpPt/OMB, a regimen used in relapsed germ cell tumors. All responded biochemically. All complete biochemical responses were accompanied by anatomical response. These responses may reflect particular sensitivity in the marker producing tumours and marker measurements would identify this subgroup. These findings do not preclude the possibility that these cytotoxic regimens may have activity against a wide range of solid tumours.

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