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A WHO-coordinated study of the community control of hypertension in six countries (Cuba, Finland, France, Italy, Mongolia and Portugal) has shown that a comprehensive approach clearly improves the care of hypertensives in various populations. Hypertension control programmes were individually designed in each country and were implemented in defined communities. The intervention strategies varied between countries, the major components being: establishment of hypertension clinics and hypertension registers, involvement of health care personnel, and health education of the entire community. As a result of this programme, the blood pressure in the age group 30-59 years decreased on average by 3/2 mmHg among men and by 6/3.5 mmHg among women; the mean blood pressure level decreased twice as much in hypertensive subjects as in the entire population in the intervention areas of the study.

Mineralocorticoid and glucocorticoid receptors were measured in circulating mononuclear leukocytes in 5 patients affected by Conn's syndrome (3 cases of bilateral adrenal hyperplasia and 2 cases of adenoma plus unilateral hyperplasia). The number of the binding sites per cell resulted significantly lower (189 +/- 114, mean +/- SD), as compared with the normal controls (298 +/- 105). The affinity of aldosterone for the receptor was found to be not different than that of healthy control subjects. The capacity and the affinity of dexamethasone for glucocorticoid receptors ranged in the normal values. These data suggest a possible down-regulation of mineralocorticoid receptors in humans.

Circulating human leukocytes are known to possess glucocorticoid receptors, but the data in the literature on the affinity and capacity widely range. We here report our results on the determination of affinity and capacity of glucocorticoid receptors in both mononuclear and polymorphonuclear leukocytes using a Percoll gradient for separating cells. The mean affinity of mononuclear and polymorphonuclear cells was respectively 4.3 +/- 0.7 and 4.3 +/- 15 nM (mean +/- S.D., n = 6), and the capacity 4135 +/- 1950 and 1810 +/- 832 sites per cell. Previous reports using a Ficoll separation showed a lower affinity under the same conditions of incubation. From these findings we suggest that the separation with Percoll may give values closer to physiological than other separation techniques.

5-lipoxygenase-derived products of arachidonic acid are implicated in the pathophysiology of psoriasis, a common hyperproliferative and inflammatory skin disease. We therefore examined whether there is an activation of this enzymatic pathway in extracutaneous tissues. For this purpose, we measured the conversion of 14C-arachidonic acid by polymorphonuclear leukocytes from psoriatic patients and controls. No significant difference in the generation of leukotriene B4 and 5-hydroxyeicosatetraenoic acid by polymorphonuclear leukocytes was noted between the two groups. We conclude that in psoriasis there is no enhanced activity of the 5-lipoxygenase pathway in circulating polymorphonuclear leukocytes.

At a Meeting of Investigators on Epidemiological Studies of Atherosclerosis Determinants and Precursors, which was held in Geneva on 7-9 November 1983, representatives from 26 countries reviewed the current status of epidemiological studies in this area. Particular interest was shown in the following determinants of cardiovascular disease: blood pressure, blood lipid levels, body weight, pathological studies, and tobacco use. Working papers on each determinant were prepared, and recommendations were made on areas for research, and on the need for prevention programmes and pathological studies. This article summarizes the work of the meeting.

Three grams of nafazatrom (Bay g 6575), given orally to healthy male volunteers in a single dose, significantly reduce the formation of leukotriene B4 in polymorphonuclear leukocytes. LTB4 synthesis fell from 57.1 +/- 17.0 ng/10(7) PMNL, mean +/- S.D., in control to 34.3 +/- 14.4 ng/10(7) PMNL 3 hr after nafazatrom (2 P less than 0.001). In vitro, nafazatrom inhibited LTB4 formation in human PMNL in a dose dependent manner. At 1 microM nafazatrom LTB4 formation was reduced to 65% of the control value. Nafazatrom had no effect on the excretion of 2,3-dinor-6-keto-PGF1 alpha and 2,3-dinor-TXB2, the major urinary metabolites of endogenously synthesized PGI2 and TXA2, respectively. Serum levels of TXB2 in clotted whole blood also remained unchanged. The inhibitory effect of nafazatrom on leukotriene biosynthesis in human PMNL suggests a therapeutic potential of this drug in processes like allergy and chronic inflammation, where leukotrienes play a pathogenetic role.

Numerous reports indicate that physical inactivity is one of the coronary risk factors; however, proof that exercise has a protective effect is still elusive. Nevertheless, to continue the existing controversy on the prophylactic value of physical activity seems to be inappropriate. On the one hand, a controlled trial is not feasible; on the other hand, physical activity is a physiological function that should be promoted anyway, regardless whether irrefutable evidence of its value in the prevention of coronary heart disease is available. Activity starting in childhood and continuing throughout life is a safe approach. In more general terms, habitual physical activity should be re-introduced into the pattern of life of contemporary society.

The essential implication of the notion of risk factor is that preventive action should be undertaken if certain factors, predisposing to cardiovascular diseases are present in an individual or in a group. Risk factors are thus categorized from the pragmatic point of view, according to the relative ease and practicability of prophylactic intervention -- and their justification. A brief review of the risk factors of the major cardiovascular diseases (coronary heart disease, hypertension, chronic pulmonary heart disease, stroke, rheumatic heart disease and congenital malformations) shows that the risk factor concept is the basis of preventive cardiology.

Rheumatic fever is declining rapidly in importance in the developed countries, but is still a major public health problem in the developing countries. Primary prevention techniques, consisting of the detection and antibiotic treatment of streptococcal infections of the pharynx, are both feasible and effective, but are also costly, as only 10-20% of all pharyngeal infections are due to the beta-hemolytic Streptococcus, and only a small proportion of those actually develop into rheumatic heart disease. A different concerted approach, which is both effective and economically entirely justifiable, is to use antibiotics as a prophylaxis to prevent secondary infection, i.e. relapses of rheumatic fever. A multi-centre study conducted by the WHO has shown that the cost of antibiotics used for secondary prevention was less than the savings resulting from the lower incidence and shorter hospital stays of recurrencies of rheumatic fever. Given economic restrictions, therefore, priority is given to organized and systematic secondary prevention.

Two sets of data, derived from the WHO Cooperative Hypertension Community Control Project and concerned with spontaneous changes of blood pressure over a period of five years, are described. The first deals with the community as a whole, studied through the examination of two independent random samples of the same population made five years apart. The second pertains to cohorts of hypertensive subjects included in the hypertension registers from various centres participating in the WHO programme and followed up for four years.The population blood pressure distribution showed a clear shift towards lower levels for both systolic and diastolic values. The mean changes, however, were smaller than 5 mmHg. In the subjects initially labelled as "hypertensive", the effects of "regression to the mean" were apparent both in the short-term evaluation (five months) and, more importantly, after four years of follow-up. In the latter case, the decreases were more remarkable in the first year but continued to show until the third year.These findings suggest that a "controlled" design is necessary not only in prospective clinical trials but also in community projects where the effects of an intervention on blood pressure are to be evaluated.

A comprehensive approach to the control of cardiovascular diseases on community level is a new venture. There is not yet enough experience in any country with this approach. However, the attempts to develop new approaches are fully justified, since the present stress on hospital care and treatment of the patients has only little changed the incidence of cardiovascular diseases among our populations.

The in vitro effect of aldosterone on intracellular sodium and potassium concentration was investigated in human mononuclear leukocytes (HML). HML were separated from blood by a Percoll gradient and intracellular Na+ and K+ were determined before and after incubation for 1 h at 37 degrees C. The intracellular (ic) Na+ and K+ concentrations after separation of HML were 17 +/- 5 and 59 +/- 18 mmol/kg wet cells (mean +/- SD, n = 6), respectively. In the absence of aldosterone the ic Na+ concentration decreased to 12 +/- 4, whereas the ic Na+ concentration remained constant at 18 +/- 8 mmol/kg wet cells when aldosterone (1.4 nM) was added to the incubation medium. In parallel, the ic K+ concentration decreased without added aldosterone but remained constant with aldosterone. The effect of aldosterone on the ic Na+ and K+ concentrations of HML was blocked by the aldosterone antagonist canrenone (140 nM). Cortisol at a physiological concentration (40 nM) did not alter ic Na and K concentrations in these cells. The results suggest that aldosterone binding to specific receptors in human mononuclear leukocytes significantly contributes to the regulation of monovalent cation levels in these cells. Thus, this easily accessible model of HML allows study of the effects of mineralocorticoids in relation to their receptors in intact cells in normal and pathological states.

In a cooperative study coordinated by WHO, stroke was registered between 1971 and 1974 in 17 centres both in developing and developed countries. A common operating protocol was used to obtain comparable data. Age-adjusted incidence of stroke shows moderate geographical variations, cerebrovascular accidents being common in all the contrasting populations studied in various parts of the world. Data were also obtained on the types of management of stroke patients, their survival rates, and functional prognosis. Control of hypertension, although known to be effective in the prevention of stroke, seemed to be insufficient in most countries. It is concluded that stroke registers may be used as a source of information for the planning and implementation of stroke control programmes in the community.

Exogenous DHA is converted by human platelets to 14- and 11- HDHE and by human neutrophils mainly to 7- HDHE . Human platelets prelabeled with 14C-DHA, 14C-EPA and 14C-AA and stimulated with thrombin release and metabolize DHA only in trace amounts as compared to EPA and AA. 14C-DHA is incorporated into the 2-position of platelet phospholipids and occurs predominantly in phosphatidylethanolamine. DHA and EPA were also incorporated by dietary means into phospholipids of platelets and neutrophils. In resting platelets free DHA as well as free AA and EPA are not detectable. In platelets stimulated ex vivo with thrombin DHA is not significantly released which is in contrast to EPA and AA. After stimulation, 14- HDHE is found only in trace amounts as compared to 12-HETE and 12- HEPE . In DHA enriched neutrophils formation of HDHEs cannot be demonstrated after stimulation with ionophore A 23187. We conclude that even after dietary enrichment of DHA in phospholipids of platelets and neutrophils the level of free DHA and/or formation of HDHEs might be too low to substantially affect arachidonic acid metabolism and related functions of these cells.

To analyze the role of prostaglandin E2 in maintaining ductal patency in premature newborns, we measured the PGE2 concentration in the lung lavage fluid of nine patients within 24 h before and 4-8 h after surgical ligation of a patent ductus arteriosus and in two patients before and after closure of the ductus following intravenous indomethacin. The concentration of PGE2 ranged from 240 to 3770 pg/ml (mean 1666 +/- 1256 pg/ml) before operative intervention and show a significant decrease to 0-300 pg/ml (mean 93 +/- 106 pg/ml, P less than 0.001, Student's two-tailed t-test) within a few hours after ligation of the ductus arteriosus. The same significant decrease could be seen in two patients with successful indomethacin therapy (0.25 mg/kg in three doses/day) with concomitant ductus closure. In contrast, when indomethacin was given in a reduced dose (0.1 mg/kg in three doses/day), only a slight effect on PGE2 synthesis could be seen without closure of ductus arteriosus. We suggest that the fall of PGE2 levels in lung lavage fluid reflects the local synthesis in the ductus arteriosus itself and is responsible for the decrease induced by surgical ligation or pharmacological inhibition by indomethacin.

The relationship between serum lipids and nutrition, physical activity and body mass index were studies with a multifactorial analysis of variance in a group of 160 adolescents of both sexes (Table I). These relationships are complex and difficult to demonstrate; they give rise, however, to certain considerations of presumptive characteristics possibly linked with adolescence.

In a cross-sectional epidemiological survey of the precursors of cardiovascular risk factors, 8-9- and 14-15-year-old boys and girls of Italian and Swiss origin were studied. Each of the 8 groups comprised about 100 participants chosen at random. In total 387 Italian and 410 Swiss participants of comparable socio-economic origin, and residing in Geneva, were studied under standardized conditions. The anthropometric measurements, the determinations of systolic and diastolic blood pressure and the lipoprotein lipids of both ethnic groups are presented and discussed in detail. The blood pressure values show only slight differences between the two ethnic groups, especially in the higher percentiles; significant differences exist, however, between the various anthropometric characteristics, some lipoprotein lipid measurements and sexual maturity. The blood pressure values are clearly correlated with body mass index, sexual maturity, anthropomorphic measurements, and heart rate. The results of the Geneva survey compare well with the reported results of other international studies.

The feasibility and effectiveness of a programme for the community control of rheumatic fever and rheumatic heart disease were studied in a cooperative multicentre project initiated and coordinated by the World Health Organization. The programme was carried out in seven centres in various developing countries of Africa, America, and Asia according to a common protocol, and is under way in a further eight countries in Latin America. Pilot community programmes were shown to be practicable and effective in reducing the burden of rheumatic heart disease in developing countries and their extension to cover entire populations should be encouraged.

Aldosterone binding sites in human mononuclear leukocytes were characterized after separation of cells from blood by a Percoll gradient. After washing and resuspension in RPMI-1640 medium, cells were incubated at 37 degrees C for 1 h with different concentrations of [3H]aldosterone plus a 100-fold concentration of RU-26988 (11 alpha, 17 alpha-dihydroxy-17 beta-propynylandrost-1,4,6-trien-3-one), with or without an excess of unlabeled aldosterone. Aldosterone binds to a single class of receptors with an affinity of 2.7 +/- 0.5 nM (means +/- SD, n = 14) and a capacity of 290 +/- 108 sites/cell (n = 14). The specificity data show a hierarchy of affinity of desoxycorticosterone = corticosterone = aldosterone greater than hydrocortisone greater than dexamethasone. The results indicate that mononuclear leukocytes could be useful for studying the physiological significance of these mineralocorticoid receptors and their regulation in humans.

Although both epidemiology and community medicine are difficult to define, the relationship between them can be described in practical terms. Examples are given in which cardiovascular epidemiological studies demonstrated the need (a) for improving existing community health care services, (b) for extending them, (c) for transposing them to new settings, (d) for starting preventive measures early in life, and (e) for inducing population-wide changes. However, community medicine has many limitations, calling for a better information base, and also calling for more epidemiological research.

High blood pressure readings are relatively frequent during dynamic exercise testing. However, because of the paucity of date concerning normal blood pressure values during exertion and the prognostic significance of exertion hypertension, the attitude to be adopted towards such patients is ill-defined. The present study proposes mean values for BP at a given workload, per age group (less than 20, 20-39, 40-59, greater than 60) and per sex. These values were computed from measurements during dynamic exercise tests performed by 303 subjects (177 male, 126 female) at 100 and 150 watts workloads. Systolic and diastolic pressures during exertion correlated positively with resting blood pressure values (p less than 0.001) and increased with age (p less than 0.001). Hypertension during exertion was defined as values more than 2 SD above mean values for the corresponding age group and sex. 20 subjects met these criteria in our study.

Ten percent of 10 to 14 year-old boys and girls (in European populations) already have fibrous plaques in their coronary arteries, according to an anatomical study of WHO. Corresponding epidemiological findings point out relatively high blood lipid concentrations (depending on family eating habits) and the early onset of smoking in school-age children. Primary prevention of atherosclerosis should therefore start in childhood, and WHO sponsors cooperative research in this field, including intervention studies in children and adolescents.

The depression of interleukin-2 synthesis represents a major dysfunction within the cascade of immunologic defects induced by mechanical and thermal trauma. This study was undertaken to elucidate the negative control mechanisms that were responsible for the deficiency of IL-2 production in polytraumatized patients. Peripheral blood mononuclear cells (PBMC's) from 29 patients (average age, 35.8 years; average ISS, 35) were separated on post-trauma days 1, 3, 5, 7, 10, 14, and 21 and cultured as untreated cells (C), cells treated with indomethacin (C + INDO), and cells depleted of adherent cells (C-AC). Cell cultures were assayed for proliferative responses to PHA, IL-2 synthesis, PGE2 production, gamma-interferon levels, and phenotyping studies. On all days post-trauma there was found a marked reduction of IL-2 production compared to controls with a highly significant nadir from day 5 to day 10 with an almost 80% inhibition of IL-2 (p less than 0.005). C + INDO cells showed increases of IL-2 synthesis over untreated cells ranging from 48% (Day 1) to 220% (Day 7). Removal of adherent cells (C-AC) did not reverse the suppression of IL-2 production. gamma-interferon levels were depressed in parallel with IL-2 levels but did not increase with C + INDO. The phenotyping of the PBMC's showed highly significant suppression of OKT3+, OKT4+, and IL-2R+ lymphocytes as well as a highly significant elevation of the monocyte (p less than 0.005) count. There was a highly significant increase of PGE2 synthesis from monocytes, due to the monocytosis and to a higher capacity of synthesis of the individual cells following trauma. PGE2 levels peaked on Day 5 and 7 post-trauma at 400% of control (p less than 0.005). These data suggest that the suppression of IL-2 synthesis post trauma is caused mainly by two factors: the excessive PGE2 output of inhibitory monocytes and inadequate function in immature and/or blocked lymphocytes. The partial restoration of IL-2 synthesis by indomethacin suggests that blockade of the cyclo-oxygenase pathway as an immunomodulating therapy may reverse some of the immunologic abnormalities in multiple trauma patients.

Pseudohypoaldosteronism, a syndrome characterized by salt wasting and failure to thrive, usually presents in infancy as high urinary levels of sodium despite hyponatremia, hyperkalemia, hyperreninemia, and elevated aldosterone levels. We have investigated this syndrome for the possibility of abnormal Type I or "mineralocorticoid-like" receptors, which have intrinsic steroid specificity indistinguishable from that of renal mineralocorticoid receptors and are found in many tissues and cells, including mononuclear leukocytes. We have studied three patients with pseudohypoaldosteronism: the 28-year-old index case in Melbourne (Patient 1) and two siblings in Munich, eight and two years of age (Patients 2 and 3); clinically, Patient 3 had a less severe case than his sister. Percoll-separated control monocytes bound [3H]aldosterone with high affinity (Kd approximately 3 nM) and limited capacity (150 to 600 sites per cell). On repeated examination, no [3H]aldosterone binding was found in monocytes from Patients 1 and 2; in Patient 3, the levels were 62 sites per cell, more than 2 S.D. below those of the control. Levels in the parents of the Munich patients (first cousins) were normal. It appears that pseudohypoaldosteronism is caused by a Type I receptor defect, that the defect may be complete or partial, that transmission may be autosomal recessive, and that the study of patients with pseudohypoaldosteronism may indicate physiologic roles for Type I receptors in nonepithelial tissues.

Incorporation and conversion of icosapentaenoic acid (20:5, n - 3) by human polymorphonuclear leukocytes were studied in volunteers (n = 6) ingesting a normal Western diet supplemented with icosapentaenoic acid (approximately equal to 4 g daily). Ingestion of icosapentaenoic acid leads to formation of biologically less active leukotriene B5 (LTB5) from polymorphonuclear leukocytes (PMNL) stimulated with ionophore A23187. LTB5 was identified on HPLC by UV absorption and by GC/MS and showed a behavior identical to that of in vitro synthesized LTB5 produced by incubation of human PMNL with icosapentaenoic acid. The ratio of icosapentaenoic acid/arachidonic acid (20:4, n - 6) in cellular phospholipids increased from 0.045 during control to 0.28 after the supplemented period. LTB5 increased from undetectable values to 70.2 +/- 18.7 pmol of LTB5 per 10(7) PMNL during the experimental period. Synthesis of LTB4 did not change significantly (control, 218.8 +/- 89.1; icosapentaenoic acid-enriched diet, 253.6 +/- 18.7 pmol per 10(7) PMNL). The ratio of LTB4/LTB5 corresponded to the ratio of arachidonic acid/icosapentaenoic acid in PMNL phospholipids. Our findings prove that LTB5, which is 10 to 30 times less potent than LTB4 to cause aggregation, chemotaxis, and degranulation of PMNL, can be formed in vivo in man after dietary icosapentaenoic acid. This may modify the contribution of leukotrienes in processes in which these metabolites are of pathogenetic relevance.

Five alk(en)ylsulfinothioic acid alk(en)yl-esters isolated from onions and four synthetic thiosulfinates inhibited 5-lipoxygenase of porcine leucocytes, histamine release and leukotriene B4 and C4 biosynthesis of human polymorphonuclear leucocytes, thromboxane B2 biosynthesis by human platelets and allergen- and PAF-induced bronchial obstruction of guinea-pigs. The anti-asthmatic and anti-inflammatory effects of onions depend in part on the thiosulfinate moiety: (Formula: see text).

Products of the 5-lipoxygenase pathway were analyzed after different stimuli in human polymorphonuclear leukocytes prelabeled with 3H-arachidonic acid. Upon stimulation with the Ca2+ ionophore, A23187, polymorphonuclear leukocytes generate 118.2 +/- 18 pg [3H]dihydroxyeicosatetraenoic acids (diHETEs, including 3H-leukotriene B4 and its 6-trans-stereoisomers), after exposure to serum coated zymosan (35.8 +/- 9 pg) and N-fMet-Leu-Phe (39.5 +/- 9 pg). Conversion of 3H-arachidonic acid paralleled its release after A23187 and fMet-Leu-Phe exposure leaving only 13.8 +/- 7% and 13.6 +/- 3% of the released 3H-arachidonic acid unmetabolized, respectively. In contrast, after stimulation with serum-coated zymosan only a small fraction of the released 3H-arachidonate was converted to 5-lipoxygenase products leaving 73.0 +/- 5% of the released 3H-arachidonic acid unmetabolized. In parallel, leukotriene B4 synthesis was studied in unlabeled polymorphonuclear leukocytes, resulting in 40 +/- 15 ng upon A23187 stimulation, 4 +/- 0.9 ng upon stimulation with fMet-Leu-Phe and 1.8 +/- 0.9 ng after serum-coated zymosan, showing a different ratio of leukotriene B4 to 3H-diHETE for A23187 in contrast to serum-coated zymosan and fMet-Leu-Phe. These results indicate that the coupling between the release of the precursor fatty acid and the metabolism via the 5-lipoxygenase pathway differs greatly between different stimuli.

Thirty-nine patients with chronic inflammatory bowel disease were studied in a 7-month, double-blind, placebo controlled cross-over trial of dietary supplementation with fish oil, which provided about 3.2 g n-3 fatty acids per day. At control, biopsies from inflamed mucosa contained higher levels of arachidonic acid than uninvolved mucosa. Dietary n-3 fatty acids were well tolerated and incorporated into plasma and enteric mucosa phospholipids at the expense of n-6 fatty acids. The arachidonic acid-derived prostanoid generation was reduced by fish oil and the extension and severity of macroscopic bowel involvement was moderately improved. In patients with Crohn's disease, clinical activity was unchanged by fish-oil supplementation. In patients with ulcerative colitis, clinical disease activity fell during fish oil supplementation and thereafter; this was not significant however. Despite a moderate reduction in inflammatory lipid mediators by dietary n-3 fatty acids and limited morphological improvement in chronic inflammatory bowel disease, the clinical benefit seems to be confined to patients with ulcerative colitis.

The binding of agonists (liquorice derivatives) and antagonists (spironolactones and cyproheptadine) to Type I aldosterone binding sites was evaluated in human mononuclear leucocytes and compared with data previously obtained using kidney cytosol or kidney slices from adrenalectomized rats. The affinity of spironolactones (spironolactone and canrenone) is equivalent in all the preparations. In contrast, carbenoxolone and glycyrrhizic acid show no affinity for aldosterone binding sites in mononuclear leucocytes, but bind to receptors in kidney cytosol. The possible explanation of the discrepancies is that, in cytosolic preparations, the two latter compounds may undergo hydrolysis into glycyrrhetinic acid which does possess a measurable affinity for mineralocorticoid receptors in all the preparations.

The macrophage exerts its stimulatory and regulatory functions within the specific immune response via the interleukin 1 (IL-1) and prostaglandin E2 (PGE2), respectively. In a screening study of macrophage-related variables following injury, a total of 58 patients (mean age, 32 years; mean injury Severity Score, 38), macrophagic phenotyping with the monoclonal antibody Leu M3 and serial measuring of the antagonistic monokines IL-1 and PGE2 and of the macrophage-activating lymphokine interferon gamma were carried out on posttrauma days 0, 1, 3, 5, 7, 10, 14, and 21. The posttraumatic course was characterized by significant monocytosis, showing a peak value of 32% of Leu M3-positive cells compared with 15% of these cells in normal control subjects. During the posttrauma course, the macrophagic PGE2 output was significantly elevated up to eightfold on days 5 and 7 compared with that of control subjects (0.441 +/- 0.14 ng/mL vs 0.052 +/- 0.01 ng/mL). Conversely, macrophagic IL-1 synthesis was significantly suppressed until day 10. Levels of interferon gamma were suppressed to a significant degree during the two-day observation period, with a trend to slow recovery at the end of week 3. These data suggest that a negative regulatory macrophagic function may be the event initiating posttraumatic immunosuppression. To restore impaired macrophagic T-helper cell interaction, cyclo-oxygenase inhibition and substitution of interferon gamma may be useful to potentiate facilitatory macrophagic function and to block inhibitory macrophagic activity.