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The Codex Alimentarius in its General Principles committee proposes the definitions of risk assessment and risk management linked to ingestion of food additives and food contaminants. Moreover, three European directives imply for all member states an evaluation of food additives intakes by general population and by possible "at risk groups of consumers". This work is conducted in the general case of European Scientific Cooperation and is coordinated by United-Kingdom. This paper describes the French approach, using a step-by-step procedure to evaluate food additives consumption. It emphasizes the importance of scientific works in this field of research to obtain french datas about french consumptions.

The observation in 1995 and 1996 of 12 cases of a new variant of Creutzfeldt-Jakob disease (V-CJD) in U.K. suggested a possible relation between this human cases and bovine spongiform encephalopathy (BSE). Recent papers about this topic are reviewed: BSE transmission to macaques, transmission of scrapie with embryo transfer, incidence of maternal transmission, PrP protein released by platelets, diagnostic test by detection of PrP protein in tissues of sheep, epidemiology of BSE, french regulations, identification of cattle in U.K.

Epithelial structures lining the proximal tubule and the yolk sac are characterized by a high rate of internalization followed by degradation of the proteins exposed to their apical pole. This function implies the expression by these epithelia of specialized proteins which have the ability to bind numerous ligands and/or lysosomal targeting properties. An improved knowledge of these molecules is needed since their expression in a limited number of epithelia may account for the specificity of some pathologies induced in particular by toxins. This paper deals with two such "candidate" proteins, gp330/megalin and gp280 which have been expressed in all species studied. gp280 is the target of teratogenic antibodies and is identified here as the receptor for intrinsic factor-cobalamin complexes but in all likelihood also binds other ligands. Antibodies to gp280 markedly stimulate the fusion of renal endosomes suggesting that it may play a role in targeting processes. gp330/megalin has been recently identified as the ligand of polybasic compounds such as gentamicin and is a key component in the internalization of the drug by tubular cells leading to renal toxicity. gp330/megalin also intervenes in endosomal fusion and some of its toxic properties may be mediated by this route.

The observation in 1995 and 1996 of 10 cases of a new variant of Creutzfeldt-Jakob disease (V-CJD) in U.K. suggested a possible relation between this human cases and bovine spongiform encephalopathy (BSE). Recent papers about this topic are reviewed : hypothesis of a possible genetic link between man and cattle, hypothesis of a acquired resistance against the agent of BSE after a previous infection by a less virulent agent of ovine origin, importance of polymorphism at codon 129 according to the hypothesis of a virus-induced amyloidosis, diagnostic test with cerebrospinal fluid, epidemiology of BSE and prediction of future BSE spread.

A gradual decrease in energy output for adults in the Western countries has been observed through the XXth century. The mechanization in industrial societies result in a decline of customary physical activity and consequently in the potentially vicious spiral of inactivity leading to deconditioning and thence, via loss of physiological capacity, to a further reduction in activity. The sedentary life has injurious effects on the health of individuals and specially increase the risks of cardiovascular disease. Furthermore there is a supposed relation between inactivity with obesity and hyperlipemia in young people and with osteoporosis in elderly. In contrast, many papers showed that high levels of physical activity have been associated with a diminished occurrence of hypertension, coronary artery disease, non insulin-dependent diabetes, colon cancers... In addition physical fitness is obviously related to the quality of life. Because of all these reasons several developed countries have elaborated plans of physical reconditioning for their people. In France some experimental actions have been completed but any national programme has been determined. Moreover it is now crucial to promote scientific researches about the fundamental biological mechanisms which explain the beneficial effects of physical training on the prevention and/or the treatment of several illness.

Fundamental research performed in the author's laboratory led to the understanding of mechanisms of the mineralocorticoid biosynthetic pathway. Sensitive assays were then developed to allow measurement of the different mineralocorticoid metabolites in several biological fluids. Using these methods biological markers that contribute to the differential diagnosis between benign and malignant adrenal tumors were identified. In the present paper we report that the exploration of the entire mineralocorticoid pathway in the plasma of patients during basal state and after stimulation and/or inhibition test is a powerful tool to predict or validate diagnosis of adrenal malignancy. Moreover, mineralocorticoid exploration can help differentiate between two different types of malignancy, ie malignant cortical adrenaloma and metastases of other cancer. The biochemical mechanisms leading to the atypical mineralocorticoid metabolism in the case of malignant cortical adrenaloma are now under study.

In 1986, our institution published the first results of surgical resection of hepatocarcinoma in cirrhotic patients. The aim of this paper is to present long term results of this surgical management. From April 1978 to February 1992, 74 patients were operated on at the surgical clinic of University Medical Center of Rennes (35000) France. There were 60 hepatectomies and 14 transplantations. The mean age was 60.2 years +/- 9 years and the sex ratio: 70 males and 4 females. The etiology was alcoholic in 43 patients (58%), post hepatitis (B and C) in 22 patients (30%) and due to hemochromatosis in 9 patients (12%). According to the Child Pugh classification, 48 patients were Child A, 11 Child B and one Child C in the hepatectomy group and 9 patients Child A and 5 Child B in transplantation group. The operative mortality was 10% in hepatectomy group and 35.7% in liver transplantation group. Overall survival was 61.8% at 1 year, 47.1% at 2 years, 38.2% at 3 years and 20% at 5 years. 5 year survival is 21.4% after transplantation and 18.5% after resection. This difference is not significant. In conclusion, according to 5 years survival and to operative mortality the treatment of choice is hepatectomy in HCC in cirrhotic patients. However the best treatment is the prevention of cirrhosis.

This paper tries to review what is scientifically known about the predictive values of biological tests of HIV infection. The epidemiological situation for that infection is characterized by two facts: the very high values of sensitivity and specificity which are close to unity; the prevalence of seropositivity which is on average--at least in western countries--, very low (except for some small specific groups). Under those conditions, Negative Predictive Values are always very close to unity, and the percentage of false negative tests is extremely low. Things are quite different for Positive Predictive Value, which varies very rapidly with very small shifts or uncertainties about specificity and prevalence. In the case when prevalence is very low (general population screening) and at the same time specificity is not excellent (that means0.99 or even0.995), Positive Predictive Value is very poor and the proportion of false positive tests rather important. Indeed the analysis of scientific literature, using the method of "best synthesis evidence", reveals numerous discrepancies as to the value of specificity among different tests. Figures vary a lot from one study to another. It is not obvious which screening strategies are concerned by the results, which finally entail a strong statistical uncertainty. Finally, the figures published in the literature are given by high standard laboratories. One may fear the tests realized in routine laboratories are less reliable. As a conclusion, let us say that despite their very good quality, the biological tests, when used separately, should not be trusted without strong previous criticism when applied to samples of the general population. Any biological screening should be preceded by a clinical examination, including a precise inquiry, in order to detect people at risk, that means with a high prior probability. Clinical dialogue has moreover another great interest: it allows health consulting and education, and calls for personal responsibility for both seropositive and negative subjects. It is the best choice of method to reach a high preventive effectiveness.

This paper presents a summary of results which concern the neuronal mechanisms underlying the control of gaze. The development of techniques of recording from alert animals and combining functional analysis of neuronal activity with intracellular marking by horse-radish peroxidase has allowed a study of the neuronal mechanisms underlying the vestibulo-ocular reflex and the generation of saccades. The results of these analysis show that there is a close interaction at the level of the brainstem between this two elements of the oculomotor repertoire. This interaction involves both the action of premotor burst neurons involved in the generation of the saccade but also ponto-bulbar reticulo-spinal neurons belonging to the tecto-reticulo-spinal system and involved in the coordination between eye and head movements. This interactions has a very important consequence in the field of recuperation from vestibular lesions. It has been suggested that after vestibular lesions, in addition to local plasticity at the level of the vestibular nuclei it has been suggested that recuperation of function can be due to a functional creation of pseudo-vestibular reflexes by a sequence of blended saccades induced by the saccadic generator mechanisms and with the contribution of the reticulo-spinal system. These interactions have been studied in humans. We have also shown that after prism adaptation the non functional vestibulo-ocular reflex could be replaced by saccades confirming our previous studies in animals. In order to try to approach the neuronal mechanisms underlying these cortical influences we have been able to delineate by position emission tomography techniques the areas of the brain contributing to the generation of voluntary or remembered saccades (parietal cortex, frontal eye fields, supplementary motor eye field, cingulate gyrus, etc.). We have also shown that in patients with lesions of these areas the major deficit in the execution of saccades derived from vestibular information about body motion was the prefrontal cortex and SMA.

Data analysis concerning tobacco smoking among children and teenagers stresses the need for health education in order to fight against this alarming trend at earliest age. In Montpellier (France) the Cancer Prevention Center of Epidaure develops in collaboration with the Ministry of Education, health education programs on this subject. This paper describes different actions sponsored by the Europe Against Cancer Program. It includes the creation of original and new educational tools. Some of which are aimed at health education training programs for the teachers. It also covers visits to the Epidaure Museum and school projects on smoking prevention. All of these programs are based on the following principles common to all actions carried out at Epidaure: the respect and consideration of children's cultural specificities and knowledge, the adequation of the messages to the social and family environment and that of the school itself, as well as the importance of the body and well being through positive messages.

Sheep Scrapie is the archetype of ESST It has been described for more than 200 years but the first scientific papers were published less than 60 years ago. The link between doctors and veterinary surgeons enabled our knowledge to develop. First, a Slow Virus was evoked, then Hadlow DVM (USA) suggested using brain filtrates from deceased patients of Kuru in order to inoculate primates or small rodents; this was carried out by the team of D.C. Gajdusek. The complete absence of immune reaction has made the label "slow Virus" give way to "Non Conventional Transmissible Agent" (NCTA). The few human cases of ESST have all been transmitted to mice, rats, hamsters... S.B. Prusiner (San Francisco) has given us an enormous boost with the notion of Prion, a protein molecule derived from an ordinary small membrane protein. Having recourse to transgenic mice has enabled American and European teams to demonstrate the essential role of genetics in the forming of the Transmissible Agent which is certainly Not Conventional. Those responsible for the Health of Cattle in U.K. will not contradict us. Future Research will be fascinating and will open a new chapter in the Medical Science concerning Mammals.

We previously reported that the most frequent cases of chronic pancreatitis were the consequence of pancreatic lithiasis and that there were different forms of pancreatic lithiasis with different etiologies and composition of calculi. The most frequent form is the calcic lithiasis, generally due to nutritional disorders. The second most frequent form is proteic lithiasis. In this paper, we report 1.) Ten hereditary cases on a total of 36 patients presenting with proteic lithiasis (age at clinical onset 15 +/- 12 years); 2.) one hereditary case on a total of 150 patients with proteic lithiasis. In these two different maladies, the transmission seems to be dominant, autosomal with incomplete penetrance. Hereditary pancreatitis is therefore a group of at least two different diseases, hereditary protein lithiasis, the most frequent one and hereditary calcic lithiasis exceptional.

Our purpose is to provide a review of studies performed since forty five years, concerning interactions of natural or synthetic estrogens and progestins. In this paper, the terms synergism and antagonism have to be considered in a broader sense than usually done. In addition to the classical concepts of succession and of simultaneity synergism between estradiol and progesterone, notions of "saving" and of "necessity" synergism came from decidualization studies in the rabbit (1949). The necessity synergism put definitively and end to the idea that estradiol was only a female hormone and progesterone a mother one. Our research in the field of ovum implantation showed also that estrogens might be secreted by mammalian ova (1949), which is now well established. The participation of estrogens to the process of decidualization in the rat suggested even (1958, 1959) their role in the starting implantation. From 1960, synthetic estrogens and progestins were tested, in a first step especially ethynylestradiol and chlormadinone acetate. In the rabbit and in the rat, these new tools permitted us to dissociate the hormonal needs of embryonic growth and of morphogenesis (1965). The studies related to the effects of these analogs upon the adrenal gland, as upon the hypophysis (1963), led to their clinical use in the treatment of advanced breast cancers, and the studies concerning their effects in the ovulation to the discovery of the antiovulatory synergism of synthetic estrogens and progestins (1966, 1982). These observations are in agreement with the Courrier rules with regard to the relationships between the relative, but also absolute, quantities of estradiol and of progesterone administered, and the obtained biological effects. Nevertheless, progestins exist with incomplete or, on the contrary, superfluous pharmacological activities. In the extreme, the estrogenic properties of norethisterone take precedence over its progestogenic properties when administered doses are growing (1977). These phenomena have now to be understood at a molecular level. Though explanations are presently available for some processes, many of them remain to day unexplained, and inversely other explanations are coming into sight.

This paper studies the expansion of drug addiction in Lebanon during the years of civil war (1973-1990). A social and historical review of the problem of drugs in Lebanon is presented as an introduction. The profile of the lebanese drug addict is studied in its various components: 1) The average age at hospitalization is around 30 years; the first intake of drugs between 13 and 35 years (mean 20). 2) The sex ratio is 8:2 male to female. The war has especially affected men in their encounter with drugs. 3) Heroin is the most widely used product (80.5%), often in combination with other drugs like hashish or cocaine. Only 17% use it intravenously, the rest by inhalation. 4) There is a certain "democratization" of the phenomenon of drug addiction (23% from the lower socioeconomic class). 5) A preponderance of drug addicts in the big cities like Beirut and Tripoli. 6) Only 20% have an underlying psychopathology responsible for the intake of drugs (psychosis, neurosis). The war has been found conducive to the eclosion of drug addiction by increasing the prevalence of the products, the psychological fragility of the lebanese people, the economic crisis and the more permissive sociocultural context.

In an "on a given day" study, we analysed the prevalence and causes of drug-related and non-drug-related iatrogenic illnesses for educational and preventive purposes. Forty-three hospital departments of various specialties and involving 62 APNET members participated in the study. From a total of 112 cases reported, 109 were considered iatrogenic illnesses on the basis of the French criteria for adverse effects. Four major types of iatrogenic illness were defined, as follows: I--drug-related cases (n = 83); II--miscellaneous cases (n = 6); III--cases due to therapeutic instrumentation (n = 16); IV--cases due to diagnostic instrumentation (n = 4). Overall, 6.28% of the patients admitted presented an iatrogenic illness; 67 (61.46%) of the 109 cases concerned women and 66 (60.55%) concerned patients aged 65 years or more. The types of illness in the "drug-induced" and "miscellaneous" categories were endocrine and metabolic disturbances (n = 14), gastrointestinal conditions (n = 13) and hematological disorders (11 cases of bone marrow aplasia). Instrument-related iatrogenic illnesses comprised cardiovascular conditions (n = 6), locoregional anatomic lesions (n = 5), infectious complications (n = 3), bleeding (n = 3) and others (n = 3). Seventeen incidents were benign, 38 dangerous and 51 serious; there were three deaths. The main drug categories concerned in the 89 cases of "drug-related" and "miscellaneous" iatrogenic illnesses were as follows: cardiovascular agents (n = 20), antiinflammatory and analgesic drugs (n = 18), hormone and nutritional treatments (n = 11) and neuropsychiatric drugs (n = 11). Instrument-related iatrogenic illnesses chiefly involved venous approaches (n = 8), surgery (n = 4), intensive care procedures (n = 2), renal dialysis (n = 2) and radiation therapy (n = 2). The main causes of drug-related iatrogenic illnesses were self-treatment (n = 8), poor compliance (n = 8), and therapeutic errors (n = 27) [non-respect of a contraindication (n = 2), wrong indication (n = 6), excessive dose (n = 13), over-prolonged treatment (n = 2) and other errors (n = 4). A cost-analysis of 74 of the 109 cases gave a minimum figure of 2 million French francs. The human and financial costs of iatrogenic illnesses show that risk-prevention measures are required; these will be dealt with in a later paper, but should be based on stricter regulations and educational programmes aimed at doctors, patients, the general public, the pharmaceutical industry and the health authorities.

This communication is the synthesis of ten years of researchers of comparative anatomy done by the author or under his control on fossil Hominids, three million years old, found by his expeditions in Eastern Ethiopia. It brings, for the first time, the odd picture of a skeleton adapted to arboricolism and bipedalism together. The rachis has already the curves of an erect being but with at least a thoraco-lumbar cyphosis a bit more elongated than in our own rachis; the pelvis is wide and shallow like the pelvis of a biped but with many particular features like the width of the iliac wings, a great biacetabular diameter, the small size of the coxo-femoral joints; the femur is short with a special long neck, a very oblique diaphysis like in Man and an intercondylar fossa, deep and wide like in chimp; the tibia is also short, its spines very tight in such a way that the knee shows a great laxity. The foot is short and flat, with an abducted hallux and long curved toes; the scapular, elbow and wrist joints show, at the opposite of the knee joint, a great solidity, but both characteristics of the hind and fore-limb joints are not in contradiction: they are, as in chimpanzees again, functionally adapted to climbing and moving in the trees where are needed firm grip of the hands as well as mobility of the knee and of the foot. It seems that the early Australopithecine' bipedalism was original, different from ours and quite instable: short steps were necessary to maintain equilibrium as well as a strong rotation of the pelvis around the vertebral axis (50 to 60 degrees on each side). This analysis is then demonstrating a real evolution of bipedalism which was not at all, at once, the bipedalism of Homo sapiens, as it has been claimed. This paper is also showing that bipedalism anatomic organization is taking place from the pelvis to the foot and not the other way round. At last, as we have found, also in Ethiopia, stone-tools more than three million years old in association with Australopithecus, it seems that the very first made tools were the invention of prehumans who did not have yet the hands completely free from locomotion.

The purpose of this paper is to report on a form of duodenal ulceration associated with a major hypersecretion that we described in 1984. This entity belongs to the group of endocrine duodenal ulcer diatheses of which the Zollinger-Ellison Syndrome (ZES) in the prototype. We have recently in 1989 reported a series of patients with clinical and pathologic features indistinguishable from those of the Zollinger-Ellison syndrome but without hypergastrinemia. We have also found that the plasma and the tumor tissues of these patients contains a potent non-gastrin secretagogue.

This paper studies the effects of the war on the civilian and military lebanese populations from 1975 to 1987. A review of the literature on war psychiatry is presented as an introduction in order to estimate its applicability to Lebanon, and it seems that all the morbid conditions described in the different wars are to be found in Lebanon. A study on the military population was undertaken, focusing on the comparison of the morbid conditions before and during the war. It shows that war has led to a decrease of malingering and generalized anxiety disorders but to an increase of neurotic and psychotic reactions. A comparison of these conditions with those found in Vietnam shows a greater proportion of generalized anxiety and post-traumatic stress disorders among Marines in Vietnam. The milicians of the Lebanese Forces differ from the Lebanese Army soldiers by a higher proportion of antisocial personality disorders and anxiety neuroses. Among the civilian population war does not seem to have significantly modified in-patient morbidity in the main psychotic, affective and neurotic diagnostic categories. Drug abuse whose frequency has considerably increased during the war is studied in detail. In conclusion, the author analyzes the factors having contributed to the relative psychological resistance of the Lebanese population.

The rare syndrome of embryonic testicular regression or agonadism with XY karyotype is described in this paper in a sibship of 7 including 3 cases of regression at a earlier time (in three amenorrheic sisters and on case of tardive and incomplete regression in a brother with bilateral testicular hypotrophy. The antigen H-Y is present in the three sisters. The pathogenesis of this syndrome, compared with that of pure gonadal dysgenesis is discussed.