Effect of TNF and LTA polymorphisms on biological markers of response to oxidative stimuli in coal miners: a model of gene-environment interaction. Tumour necrosis factor and lymphotoxin alpha.

INTRODUCTION: Interaction between genetic background and oxidative environmental stimuli in the pathogenesis of human lung disease has been largely unexplored. METHODS: A prospective epidemiological study was undertaken in 253 coal miners. Intermediate quantitative phenotypes of response to oxidant exposure, including erythrocyte glutathione peroxidase (GSH-Px) and catalase activities, were studied. Oxidant exposures studied were smoking habits and cumulative dust exposure assessed by job history and ambient measures. Disease phenotypes included subclinical computed tomography score at the first survey and x ray profusion grades twice, five years apart, to assess established coal workers' pneumoconiosis (CWP). Miners were genotyped for common functional polymorphisms in the gene for tumour necrosis factor alpha (TNF) and lymphotoxin alpha (LTA), two proinflammatory cytokines that have been implicated in the pathogenesis of chronic lung diseases. RESULTS: Regarding gene-environment interaction on intermediate phenotypes, results showed interaction of a promoter polymorphism at the -308 position in TNF with occupational exposure on erythrocyte GSH-Px activity with a significant association in those with high exposure (p=0.003), whereas no association was observed among those with low exposure (interaction p=0.06). Regarding gene intermediate phenotype interaction on clinical outcome, results showed an association of CWP prevalence with an NcoI polymorphism in LTA in those with low catalase activity (p=0.05), whereas no association was observed in those with high activity (interaction p=0.03). No other significant association was observed. CONCLUSION: The results suggest that interactions of genetic background with environmental exposure and intermediate response phenotypes are important components in the pathogenesis of CWP.

Cross sectional and longitudinal study on selenium, glutathione peroxidase, smoking, and occupational exposure in coal miners.

OBJECTIVES: To understand the variations of selenium (Se) concentration relative to changes in occupational exposure to coal dust, taking into account age and changes in smoking habits in miners surveyed twice, in 1990 and 1994. To better understand the relation of Se concentration with glutathione peroxidase activities (GSH-Px) in these miners. METHODS: In 1994, blood samples were obtained from active (n=131) and retired (n=40) miners without coal worker's pneumoconiosis, in whom Se concentration was available at both surveys and in whom International Labour Organisation (ILO) profusion grade had not been changed. Active miners were exposed to high dust concentrations (n=48) or low dust concentrations (n=83). Miners were classified into three subgroups according to their estimated cumulative exposure to dust, and into three subgroups according to their smoking habits. RESULTS: Selenium concentration and GSH-Px activities were significantly lower in active than in retired miners (Se adjusted means: 62.6 v 72.2 ng/ml p=0.01). Moreover, Se concentration was lower in miners exposed to high compared with those exposed to low dust concentrations (adjusted means: 59.4 v 65.8). In miners exposed to high dust concentrations, Se concentration was significantly lower whereas erythrocyte GSH-Px activity was significantly higher in the subgroup with estimated cumulative exposure >68 mg/m(3).y. In all miners, plasma GSH-Px activity was correlated with Se concentration (r=0.22, p<0.005). The 4 year Se changes were negatively related to exposure to high dust concentrations and positively related to change in exposure from high to retirement and to change from smoker to ex-smoker (p=0.01). CONCLUSION: The variations of Se concentration in relation to changes in occupational exposure to coal dust and in smoking habits, and the close correlation found between plasma Se concentration and GSH-Px activity suggest that both are required in antioxidant defence. These results agree well with the hypothesis that the decrease in Se concentration reflects its use against reactive oxygen species generated by exposure to coal mine dust and by smoking.

Relations between occupational exposure to coal mine dusts, erythrocyte catalase and Cu++/Zn++ superoxide dismutase activities, and the severity of coal workers' pneumoconiosis.

OBJECTIVES: To better understand the relations between occupational exposure, blood antioxidant enzyme activities, total plasma antioxidant concentration, and the severity of coal workers' pneumoconiosis (CWP). METHODS: Blood samples were obtained from miners without CWP exposed to low dust concentrations for > or = 4 years at the time of the study (n = 105), or exposed to high dust concentrations for > or = 14 years at the time of the study (n = 58), and from retired miners with CWP (n = 19). Miners without CWP were classified into three subgroups according to their estimated cumulative exposure to dust. Chest x ray films were obtained for each miner. Miners were classified in five subgroups according to their International Labour Organisation (ILO) profusion grades. Univariate tests were completed by multiple linear regression analyses. RESULTS: The estimated cumulative exposure to dust was strongly positively related to erythrocyte catalase activity and strongly negatively related to Cu++/Zn++ SOD activity only in miners exposed to high dust concentrations for > or = 14 years at the time of the study (F tests p = 0.006 and p = 0.004 respectively). Moreover, catalase activity was strongly related to the severity of CWP expressed as five subgroups of ILO profusion grades (F test p = 0.003); the greatest difference in the mean values was found between the group of 1/1 to 1/2 ILO profusion grades and the group of 2/1 to 3/3 ILO profusion grades. CONCLUSION: These results are in good agreement with the hypothesis that production of reactive oxygen species may be an important event in the exposure to coal mine dusts and the severity of CWP. Erythrocyte catalase and Cu++/Zn++ SOD activities are more closely related to recent exposure to high dust concentrations than to cumulative exposure, and could be considered as biological markers of exposure rather than as markers of early adverse biological effect.

Relationship of serum neutral endopeptidase E.C.3.4.24.11 activity to alcohol consumption.

Neutral endopeptidase (NEP) is an ubiquitous enzyme that inactivates numerous endogenous peptides in the brain, kidney, and lung in vivo. The origin of the circulating soluble form and its determinants are largely unknown. The relationships of smoking habits and alcohol consumption to serum NEP activity have been explored in a longitudinal epidemiological study conducted in 204 Lorraine coal miners. At both surveys, 4 years apart, NEP activity was significantly related to alcohol consumption (in grams/day) reported by questionnaire, with correlation coefficients of 0.26 (p = 0.001) in 1990 and 0.23 (p = 0.001) in 1994. The correlations of gamma-glutamyltransferase to NEP activity were even stronger with correlation coefficients of 0.71 (p = 0.0001) in 1990 and 0.79 (p = 0.0001) in 1994. Longitudinally, the change in NEP activity between the first and the second surveys was significantly correlated with change in alcohol consumption (r = to 0.18, p = 0.02) and with change in gamma-glutamyltransferase level (r = 0.60, p = 0.0001). Serum NEP activity was unrelated to smoking habits. Results support the hypothesis of a causal role of alcohol on serum NEP activity.

Can the evolution to pneumoconiosis be suspected in coal miners? A longitudinal study.

To assess whether the evolution to pneumoconiosis may be suspected in coal miners, we conducted a 4-yr longitudinal study of 80 dust-exposed miners with chest X-ray findings classified 0/1 or 1/0 according to the International Labor Organization (ILO) classification (exposed to coal mine dust, suspected of pneumoconiosis [ES group]) and two control groups having normal X-rays. The first of these latter two groups included 80 miners with similar exposure to that of the first group (exposure with normal X-rays [EN]), whereas the second group consisted of markedly less exposed miners (no exposure with normal X-rays [NN]). The protocol comprised a questionnaire on respiratory symptoms and smoking, assessment of cumulative coal-mine-dust exposure, X-rays, computed tomographic (CT) scans, and lung-function tests. The study was conducted in 1990 and 1994 by the same medical team. At the end of the follow-up, 24 members of the ES group had worsened X-ray findings, and 10 of them had X-ray findings classified as 1/1 or greater. In the EN and NN groups, six and one subjects, respectively, had worsened X-ray findings. At the first examination, subjects who developed pneumoconiosis had significantly lower values for FEV1/FVC ratio, maximum midexpiratory flow (MMEF), and maximal forced expiratory flow at 25% of vital capacity (FEF25%), and higher CT-scan micronodule scores. This latter score and FEF25% were significantly associated with the evolution to pneumoconiosis in the ES group, and scanner micronodule score and MMEF were significantly associated with this in all three groups combined. Worsening findings on X-ray and change to pneumoconiosis must be controlled in coal miners. The findings in this study offer the possibility of identifying miners who especially need follow-up and monitoring.

Relationship of serum elastin peptide level to single breath transfer factor for carbon monoxide in French coal miners.

BACKGROUND: Clinical and epidemiological studies have given discordant results on the usefulness of the level of circulating elastin peptide (EP), a potential marker of both elastin destruction (a key phenomenon in pulmonary emphysema) and neosynthesis, for assessing structural changes in the lung extracellular matrix. The aim of the present study was to explore the relationship between levels of EP and forced expiratory volume in one second (FEV1) and single breath transfer factor for carbon monoxide (TLCO and KCO) in coal miners. METHODS: The study population comprised 227 working coal miners aged 34-50 years consisting of 75 miners heavily exposed to underground coal dust with pulmonary radiographs classified as 0/1 or 1/0 by the International Labour Office classification, 75 exposed miners with radiographs classified as normal (0/0), and 77 miners slightly exposed to coal dust with normal radiographs. The subjects answered a standardised questionnaire and performed spirometric tests and a carbon monoxide (CO) transfer test. RESULTS: No association was observed between EP levels and % predicted FEV1 (or FEV1/FVC). The level of EP increased significantly with decreased % predicted TLCO (r = -0.20). Miners in the lowest % predicted KCO quintile had higher EP levels than the rest (3.28 (1.37) vs 2.47 (1.16)). A significantly lower EP level was observed in miners with radiographs classified as 1/0 or 0/1, especially in those with round opacities, compared with miners with a normal radiograph, and in current smokers compared with the rest. CONCLUSIONS: The results of this study suggest that the level of EP may reflect some remodelling activity in emphysema and lung fibrosis.

Decrease in selenium status in relation to coal dust exposure.

Selenium (Se) plasma levels were studied in 222 coal miners to assess whether selenium is decreased in relation to coal dust exposure, taking age, alcohol, and tobacco consumption into account. Selenium levels decreased significantly with age and current tobacco consumption, among miners aged 34-50. Long-term and current exposure to coal dust were studied. The lowest Se values were observed for those with both long-term and current exposure (60.2 ng/ml), the highest for those never or slightly exposed (64.1 ng/ml); those with long-term exposure not currently exposed fell in an intermediate position (61.3 ng/ml). No relation was observed with alcohol consumption. The association of coal dust with low selenium remained significant after adjustment for age and smoking.

Associations of blood group-related antigens to FEV1, wheezing, and asthma.

Discordant results have been observed regarding the associations of chronic obstructive pulmonary diseases with secretor, Lewis, and ABO histo-blood groups, which are defined by glycosyltransferases. These enzymes build up oligosaccharide structures that play a role in the adhesion of environmental factors to epithelial cells. The objectives of the present study were to assess the role of all three systems, Lewis (Le), salivary ABH secretor (Se), and red cell blood group ABO, on lung function, wheezing, and asthma in a cohort of 228 coal miners studied cross-sectionally, considering the potential modifying effect of environmental factors on these associations. Asthma was significantly related to nonsecretor phenotype. Significantly lower lung function and higher prevalences of wheezing and asthma were observed in Lewis-negative or nonsecretor subjects of blood group O. Very low lung function values were observed in the small group of Lewis-negative nonsecretors who lack both Le and Se controlled fucoses (1% of Caucasians). Lewis-positive, salivary ABH secretors who have these two fucoses represent 70% of Caucasians. Among these subjects, lower lung function was observed in blood group A, and in a lesser extent in blood group B, i.e., with terminal alpha GaINAc or alpha Gal respectively, than in blood group O subjects. ABO, Lewis, and secretor phenotypes did not account for the potential genetic heterogeneity of subjects toward smoking, but alcohol consumption appeared to exert a protective effect on lung function in Lewis-negative subjects (10% of Caucasians). If confirmed in other populations, the magnitude of the effects observed regarding low lung function in Lewis-negative ABH nonsecretors, and the protective effect of Lewis negative on the deleterious effect of alcohol, may be of clinical importance. Further studies of the combined effects of various histo-blood group genetic systems seem worthwhile, particularly for airflow limitation, wheezing, and asthma, possibly with reference to susceptibility to infectious agents.

Forced oscillation technique (FOT): a new tool for epidemiology of occupational lung diseases?

The aim of this study was to evaluate the usefulness of the forced oscillation technique (FOT) in the assessment of occupation-related airway changes. The forced oscillation technique and conventional lung function tests were applied in 80 underground coalface workers, aged 35-48 yrs, with chest roentgenogram films classified 0/1 or 1/0 according to the International Labour Office (ILO) classification (G group), and two control groups matched for age and smoking habits. The first control group, was made up of face-workers having normal chest radiographs, whilst the second comprised underground non-face-workers with normal chest radiographs. Spirometric, plethysmographic and transfer factor of the lungs for carbon monoxide single-breath (TL,CO,sb) indices revealed no significant differences between the three groups. As regards the forced oscillation technique, a higher value of resistance/frequency slope (Pa.L-1.s2) was found in the G group compared with the control groups; 2.11 vs 1.06 in the face-workers, and 1.58 in the underground workers. In all three groups, the forced oscillation technique indices (mean resistance (R), resistance at zero frequency (RO), resistance/frequency slope (S), and resonant frequency (fo)) were found to be higher in subjects having a decreased forced expiratory volume in one second (FEV1) (< or = 90% predicted) or a mildly obstructive pattern of ventilatory function, even though this did not reach statistical significance in each of the groups. These findings together with the feasibility and acceptability of the forced oscillation technique would suggest that it may be a suitable tool for epidemiological studies of occupational respiratory diseases.

[Respiratory symptoms and function of coal miners presenting radiological pulmonary abnormalities]. / Symptômes et fonction respiratoires des mineurs de charbon présentant des anomalies radiologiques pulmonaires.

Respiratory symptoms and lung function of 80 coal workers suspected of pneumoconiosis (pulmonary X-rays classified 0/1 or 1/0 according to International Labour Organisation classification) who worked for at least 10 years at face work (Ts) were studied in comparison with two control groups matched by age (+/- 2 years), height (+/- 5 cm), weight (+/- 10 kg) and smoking habits: the Tn group constituted by 80 coal workers who worked for at least 10 years at face work with normal pulmonary X-rays, and the HTn group constituted by 80 underground miners who worked mainly out of face work with normal pulmonary X-rays. The frequencies of cough, expectoration, chronic bronchitis or dyspnoea were significantly higher in Ts group than in the two others. The one-second forced expiratory volume to vital capacity ratio (FEV1/VC) was lower, closing volume to vital capacity (CV/VC) or to total lung capacity ratios (CV/TLC) were higher in Ts group than in the control groups. Unexpectedly, vital capacity (VC), one-second forced expiratory volume (FEV1), total lung capacity (TLC), compliance, diffusing capacity (DLCO) referred to alveolar volume (VA) were higher. In Ts group, the small rounded opacities were noted in the top part of the lung (56.9%), the irregular ones were distributed on the entire lung (65.5%). There were no relation between the category of small opacities and respiratory symptoms or lung function.

Mortality in retired coke oven plant workers.

A previous study on 536 retired coke oven plant workers in Lorraine Collieries (France) reported an excess of deaths from lung cancer (standardised mortality ratio (SMR) = 251) compared with the French male population. Occupational exposures during working life were retraced for each subject, but the number of deaths during the observation period (1963-82) was small, and smoking habits were known only for dead subjects. In 1988, the cohort was re-examined (182 deaths occurred between 1963 and 1987) and smoking habits were determined for all the subjects. This study confirmed the excess of lung cancer (SMR = 238, p < 0.001). It showed an excess of mortality from all causes (SMR = 141, p < 0.001), overall cancers (SMR = 133, p < 0.05), and cardiovascular diseases (SMR = 133, p < 0.05). A significant excess of deaths was found for subjects who worked near the ovens for all causes (145, p < 0.01), lung cancer (SMR = 252, p < 0.01), colon cancer (SMR = 381, p < 0.05), and cardiovascular diseases (SMR = 155, p < 0.05). A significant excess mortality was also found from all causes (176, p < 0.05) and stomach cancer (SMR = 538, p < 0.01) in subjects who worked in byproducts, from lung cancer (SMR = 433, p < 0.001) in those in the workshops, and from cirrhosis of the liver and alcoholism (SMR = 360, p < 0.01) in those underground; but, due to small numbers, these figures were not robust. An excess of mortality from all causes (SMR = 163, p<001), lung cancer (SMR = 228, p<0.05) and cardiovascular diseases (SMR = 179, p<0.01) was shown also for non-exposed or slightly exposed subjects. The fact that, on the whole, mortality of various exposed groups was similar to that of non-exposed or slightly exposed workers may be explained in part by the selection at hiring and the healthy worker effect. As an increased risk of lung cancer was noted among subjects who worked in the old generations of plant compared with the other workers (although the relative risk was not significant) it is concluded that the role of occupational hazards could not be excluded.

Lung function in retired coke oven plant workers.

Lung function was studied in 354 coke oven plant workers in the Lorraine collieries (Houillères du Bassin de Lorraine, France) who retired between 1963 and 1982 and were still alive on 1 January 1988. A spirometric examination was performed on 68.4% of them in the occupational health service. Occupational exposure to respiratory hazards throughout their career was retraced for each subject. No adverse effect of occupational exposure on ventilatory function was found. Ventilatory function was, however negatively linked with smoking and with the presence of a respiratory symptom or discrete abnormalities visible on pulmonary x ray films. The functional values were mostly slightly lower than predicted values and the most reduced index was the mean expiratory flow, FEF25-75%. The decrease in forced expiratory volume in one second (FEV1) was often parallel to that in forced vital capacity (FVC), but it was more pronounced for subjects who had worked underground, for smokers of more than 30 pack-years, and for subjects having a respiratory symptom. Pulmonary function indices were probably overestimated because of the exclusion of deceased subjects and the bias of the participants.

Morbidity in retired coke oven plant workers.

The effect of past occupational exposure on morbidity was studied in 354 coke oven workers in Lorraine Collieries (France) who retired between 1963 and 1982, and were still alive in 1988; 96% of them participated in this study. Occupational exposure to respiratory hazards during the working life was retraced for each subject. No significant association between the occupational exposure and the frequency of ischemic cardiopathies, arterial hypertension, gastro-duodenal ulcers, and respiratory symptoms was revealed. However, subjects who had worked on the Ovens, in the Workshops, and in the Byproducts showed a prevalence of arterial hypertension significantly higher than the non- or slightly exposed subjects. The healthy worker effect phenomenon, the exclusion of deceased subjects, and the small size of this retiree population may conceal possible differences between exposure groups.

Effects of SR 44866, a potassium channel opener, on action potentials of rabbit, guinea pig, and human heart fibers.

The effects of various concentrations (3 x 10(-8) - 1 x 10(-5) M) of SR 44866, a K+ channel opener, on action potential (AP) characteristics were investigated in isolated rabbit sinoatrial node (SAN), rabbit Purkinje fibers, guinea pig ventricle, human atrium, and human papillary muscle. SR 44866 (up to 1 x 10(-5) M), like cromakalim and pinacidil, did not modify SAN AP and automaticity of the rabbit heart. In atrial, Purkinje and ventricular fibers of animal and human hearts, SR 44866 did not significantly change membrane resting potential, AP amplitude, or maximum rate of phase 0 (dV/dtmax). The main AP modifications induced by SR 44866 were concentration-dependent reductions in plateau amplitude and AP duration (APD): IC50 2 x 10(-7), 7 x 10(-7), 1.4 x 10(-6), 2.5 x 10(-6), and much greater than 10(-5) M for human atrium, human ventricle, guinea pig ventricle, rabbit Purkinje, and rabbit atrium, respectively. In isolated guinea pig heart, SR 44866 induced decreases in contractions (IC50 1.7 x 10(-6) M) and coronary perfusion pressure (CPP) (IC50 2.1 x 10(-8) M) with a very slight reduction (5% at 1 x 10(-6) M) in spontaneous heart rate (HR). Negative inotropic effect (guinea pig) and APD shortenings (guinea pigs and humans) of SR 44866 (1 x 10(-6) and 3.10(-6) M) were antagonized by glibenclamide (3 x 10(-7) to 3 x 10(-6) M), a specific blocker of cardiac K+ATP channels. The data support the hypothesis that SR 44866 activates ATP-sensitive K+ channels, which are present in the atria and ventricles of the human heart but not in pacemaker cells of rabbit SAN.

Electrophysiological effects of penticainide (CM 7857) in isolated human atrial and ventricular fibers.

The intracellular electrophysiological properties of a new antiarrhythmic agent, penticainide (5 x 10(-6) to 5 x 10(-5) M) were studied in isolated driven human right atrial appendage and papillary muscle superfused with oxygenated Tyrode's solution. In atrial fibers, penticainide decreased the amplitude, maximum rate of rise (dV/dtmax), plateau amplitude, and duration (APD) of action potentials (AP). In ventricular fibers, the main AP modification induced by penticainide was a dV/dtmax diminution. All those effects were frequency and concentration dependent. Penticainide decreased resting potential at 5 x 10(-5) M only. Ventricular APD variations were relatively weak: in most of the cases, 5 x 10(-6) M decreased APD and 5 x 10(-5) M shortened long APD (greater than 300 ms) and lengthened short APD (less than 300 ms). The class I antiarrhythmic property (dV/dtmax decrease) of penticainide was rate dependent in both human fibers and was obtained at lower drug concentrations than those used in other species. The relatively rapid rate of onset and the rather slow recovery kinetics of dV/dtmax block suggest a common mechanism of action of penticainide on sodium channels in human heart and others mammals.

Electrophysiological effects of some antidepressant drugs on canine cardiac Purkinje fibres.

The electrophysiological effects of several antidepressant drugs, imipramine, metapramine, minanserin, nomifensine, and amineptine, were studied in canine cardiac Purkinje fibres at concentrations between 10(-6) mol.litre-1 and 10(-4) mol.litre-1. Metapramine (10(-5) mol.litre-1) decreased the action potential amplitude, the action potential duration, and Vmax. In addition, imipramine or metapramine induced a pronounced increase of conduction time and conduction block at 10(-4) mol.litre-1, whereas with mianserin and nomifensine a 10(-4) mol.litre-1 concentration was necessary to induce a decrease of Vmax and conduction velocity. With the exception of conduction time and action potential duration, amineptine was not able significantly to change the electrophysiological indices of canine Purkinje fibres. The decrease of Vmax observed with imipramine, metapramine, and with high concentration of mianserin and nomifensine confirms that the antiarrhythmic action of these agents might be related principally to their class I antiarrhythmic effects. The fact that amineptine, which is not antiarrhythmic, does not decrease Vmax reinforces this suggestion.

Mortality due to respiratory cancers in the coke oven plants of the Lorraine coalmining industry (Houillères du Bassin de Lorraine).

The main activity of the Houillères du Bassin de Lorraine (Lorraine Collieries), employing 23,000 operatives and executives, is coalmining. The coke production is carried out by two coke oven plants with a workforce of respectively 747 and 552 workers. The coal coking process entails the emission of noxious products such as polycyclic aromatic hydrocarbons (PAH) from the ovens. The influence of occupational exposure on mortality due to respiratory cancers, and particularly to lung and upper respiratory and alimentary tracts cancer, was investigated among a cohort of 534 male workers from the two coke oven plants who had retired from work between 1963 and 1982. The job history of each subject has been precisely reconstructed by indicating the duration of exposure on the ovens, close to the ovens, and in maintenance occupations. The cohort mortality has been analysed according to the method of indirect standardisation with reference to the French male population and by a case-control study concerning the consumption of tobacco per cohort. The mortality due to lung cancer is 2.51 times higher than expected. This excess of mortality differs, but not significantly, between the two coke oven plants (standardised mortality ratio equals 3.05 and 1.75 respectively). It is not significantly higher among subjects exposed for more than five years, directly exposed on the ovens or working near the ovens or at maintenance occupations on the ovens (SMR = 2.78), than among those exposed for less than five years (SMR = 2.35) or those not exposed at all. Even taking into account the excess of mortality due to lung cancers in the Moselle district (1.6 time that of France), the excess of lung cancers does not seem to be explained by the regional factor, or by tobacco and alcohol consumption. Although no significant relation was offered between lung cancer and the duration of exposure to PAH, even when taking smoking habits into account, the carcinogenic role of occupational nuisances cannot be excluded.

Electrophysiological studies of penticainide (CM 7857), a new antiarrhythmic agent, in mammalian myocardium.

The intracellular electrophysiologic properties of a new antiarrhythmic substance, penticainide, were studied in isolated rabbit, dog, and guinea pig myocardial preparations superfused or perfused with oxygenated Tyrode's solution. "Therapeutic" concentrations of penticainide (1.5 to 3 X 10(-5) M) had little effect on sinus node automaticity; sinoatrial conduction was slightly delayed. In atrial, Purkinje and ventricular fibers, amplitude, and maximal rate of rise of phase O (dV/dtmax) were decreased by penticainide; Purkinje-ventricle conduction velocity was depressed. Penticainide did not significantly modify action potential duration (APD) of rabbit atria and dog ventricle and reduced APD and effective refractory period (ERP) of dog Purkinje and guinea pig ventricular fibers. Penticainide reduced APD heterogeneity of Purkinje-ventricle junction with a preferential effect at the gate and decreased tension amplitude of perfused papillary muscle in dog heart. The effect of penticainide on dV/dtmax was voltage and rate dependent; the resting block was weak. Thus, penticainide is a class 1 antiarrhythmic agent with properties of class 1B agents such as APD reduction and properties of class 1C agents such as slow recovery kinetic of rate-dependent block.

[Brazil: agricultural modernisation and food production restructuring in the international crisis]. / Bresil: modernisation agricole et restructuration alimentaire dans la crise internationale.

PIP: This study examines the complex relationship of capital accumulation, external debt, and food supply in Brazil, a country which has simultaneously increased its food exports and its unsatisfied demand for food imports in the context of the world economic crisis. In Brazil, the substitution of export cash crops for subsistence crops has been accompanied by a profound but incomplete restructuring of the basic food supply and model of consumption, a restructuring made possible by declining real cost of the new foods. The gap between the extremely rapid evolution of consumption, especially in the urban areas, and the possibilities of concomitant transformation of production is the characteristic feature of the change occuring in Brazil. The current diet of the developed countries evolved over a relatively long period and was based on the declining real cost of basic foodstuffs made possible by increasing labor productivity. Between 1800-1900, the real cost of a kilo of bread was halved, while that of meat remained stable. In France and the US respectively, 80 and 90% of the principal cereals are consumed by animals, while in developing countries most grains are directly consumed. Numerous indices suggest that Brazil has begun to differentiate its food regime in the direction of decreased consumption of cereals, tubers, and legumes, and increased consumption of animal products, with grains increasingly consumed indirectly by animals. Since the early 1970s, Brazil has developed a powerful processed food industry which supports intensive breeding of poultry and, to a lesser extent, pork and milk cattle. However, low income population groups have been forced to reduce their consumption of traditional foodstuffs, whose real prices have undergone relative increases, without achieving a satisfactory level of consumption of the new products. Brazilian food problems result not from insufficient production of food but from the choice of a strongly internationalist model of development in the mid-1960s which required insertion into the world economy, notably through a search for new export sectors. The agricultural sector was assigned 3 functions: producing food as cheaply as possible, increasing the proportion of exportable crops, and substituting some of the foods imported. Brazil evolved in 2 decades from a classic agroexporter to a more complex structure reflecting the semiindustrialized state of the economy. The share of processed agricultural goods increased accordingly. The foods produced for the internal market have been changing at the same time that a new hierarchy of exportable products has evolved. Agricultural policy involved recourse to market mechanisms and cheap credit focused on the south and southeastern regions, large and medium sized producers, and a few products including soy, coffee, sugar cane, and cotton. Just 3% of credits went to the traditional foodstuffs beans and manioc. The most serious consequence of the internationalization of the agricultural economy has been a dangerous increase in the vulnerability of low income groups to world food price fluctuations.^ieng