Isoprinosine and Imuthiol, two potentially active compounds in patients with AIDS-related complex symptoms.

Isoprinosine and Imuthiol are immunomodulators with a unique effect on T-cells. The possibility of using them in treating patients with acquired immunodeficiency syndrome related complex (ARC) was initially examined regarding their in vitro effects on peripheral blood mononuclear cells. In six ARC patients Isoprinosine (100 micrograms/ml) and Imuthiol (10 pg/ml) induced in vitro an early chromatin activation as measured by nuclear refringency test and potentiated phytohemagglutinin (5 micrograms/ml) in the same 20-min assay in the absence of fetal calf serum. In all patients an early phytohemagglutinin induced chromatin dispersion was observed with a dose related response before interleukin 2 production can occur. Isoprinosine and Imuthiol increased significantly both the percentage and the absolute number of T4+ cells when peripheral blood mononuclear cells were incubated for 4 days in RPMI supplemented with 10% fetal calf serum. No changes in T8+ cells were noted. Three homosexual ARC patients were then treated p.o. with Imuthiol (5-10 mg/kg/week) for 4 to 6 months. Without any deleterious effect a clinical improvement (in terms of adenopathy and opportunistic infection regression) and restoration of the response to recall antigens were observed in all three patients. One patient with less than 500 T4+ lymphocytes/mm3 exhibited a complete restoration of OKT profiles. In such patients clinical and immunological effects of Isoprinosine have already been reported by others. Altogether these preliminary results indicate that more data should be obtained on the effects of these two agents in ARC patients.

Segregation of three reciprocal translocations in the same family: t(3;4), t(5;10), and t(15;21).

A male infant with static antenatal encephalopathy and epilepsy was found to have a duplication of 5p12----5pter and deficiency of 10p13----10pter. Each of his parents was a carrier of a balanced reciprocal translocation. A third translocation was found in the maternal grandfather. The pedigree of each translocation and the segregation of parental reciprocal translocations are discussed.

Increased cell surface expression of histocompatibility class II I-A(d) in c-fos transfected clones of the P388D1 murine macrophage cell line.

Numerous biological functions of the monocyte-macrophage lineage are affected by the presence of immunomodulators. Enhancement in transcription of c-fos has been shown in the murine P388D1 macrophage line treated by LPS, TPA, Ca++ ionophore or dibutyryl cAMP. In order to study the effects of an increased c-Fos protein level on macrophage functions, we previously have established stable c-fos-overexpressing clones in the P388D1 cell line. Here we report that the expression of class II MHC antigens (I-A(d) antigen) is increased in these clones, particularly after IFN-gamma treatment. No variation in the cell surface expression of IFN-gamma receptor was observed. The increase of I-A(d) cell surface expression was well correlated with the level of I-A(d) mRNA. No inducible NO synthase activity and no increase of TNF-alpha release were observed in c-fos transfected cells. A slight increase of the basal expression of the main class II MHC transcription factor CIITA which is further amplified by IFN-gamma treatment, was observed in the c-Fos overexpressing clones. This suggests that the increased I-A(d) expression in clones could result from a transactivating action of the c-Fos protein on the CIITA factor.

Rat and human polymorphonuclear leukocyte derived lymphocyte stimulatory factors.

The kinetic release of lymphocyte activating factors by inflammatory rat polymorphonuclear leukocytes (PMNs) into culture fluid was studied. PMNs, collected from the pleural cavity of rats 4 hours after injection of either calcium pyrophosphate (CaPP) or normal plasma, released into the supernatant culture fluid, factors which enhanced the phytohaemagglutinin-induced proliferative response of normal lymph node cells or thymocytes, the optimal culture time being 24 hours. A major portion of these lymphocyte activating factors was found in the ultrafiltrates (less than 10,000 daltons) of PMN supernatants. The activities in both unfractionated supernatant and the ultrafiltrate were significantly enhanced if PMNs were exposed to Concanavalin A (Con A) or inflammatory exudate prior to supernatant production. Also, these were not species specific as rat PMN supernatant can stimulate the phytohaemagglutinin-induced response of human lymphocytes and, conversely, human PMN factors can stimulate rat thymocytes.

The enhancement of interleukin 2 like production after in vivo stimulation of rat lymphoid cells by an acute non specific inflammatory process.

Interleukin 2 (IL 2) production was studied in lymphoid cells from rats undergoing an acute non specific inflammatory reaction induced by intrapleural injection of calcium pyrophosphate. Spleen and lymph node cells derived from inflamed animals had an increased level of IL 2 like production compared to cells from normal animals. Thymocytes also showed enhanced IL 2 like production although the absolute levels were lower than spleen or lymph node cells. It has been suggested that the acute non specific inflammatory reaction is able to modify lymphocyte reactivity via IL 2 and interleukin 1 (IL 1). The nature of the humoral factors released by the inflammatory process which are capable of initiating these events is also discussed.

Influence of immunomodulators on T lymphocyte differentiation in ARC patients and resistance to LAV/HTLV III infection.

Isoprinosine and Imuthiol are non mitogenic immunomodulators active on T cell differentiation. In ARC patients, they modulate the circulating T cell receptor complex in terms of OKT4+ phenotype induction. This effect is not responsible for any expansion of the target population but for a partial inhibition of in vitro infection with LAV/HTLV III viral particles. At a clinical level, this means that these drugs may prove helpful in ARC patients when the virus has infected only a few helper cells.

Immunological investigation and immunotherapy in patients operated on for breast carcinoma.

The tumor-host relationship is an essential factor in the onset, development, and recovery from malignancies. A basic consideration in the treatment of cancer patients must therefore be to understand this relationship and attempt to modify it in order to favor the host. We here discuss the results of a study of the immunologic status of 91 breast cancer patients. The use of a battery of tests with five subcutaneous hypersensitivity antigens allowed us to detect some differences in the immunological profiles of patients with or without lymph node involvement. The effect of an immunostimulant fraction prepared from Corynebacterium granulosum, P40 is also analyzed. This fraction significantly modifies tumoral recurrence in DMBA-induced mammary cancers in the Sprague Dawley rat, causes regression of mammary permeation nodules following in situ injection and modifies the cutaneous reactions of one-half of the anergic breast cancer patients although regular re-challenge is still necessary.

[From bioethics to the new technology ethics]. / De la bioéthique à l'éthique des nouvelles technologies.

Just as what we can all "technoscience" is emerging in our everyday life, a reflection should be conducted concerning the implications of the scientific and technical progress within our society from now on globalised. We will tackle successively: 1. The ambiguities and paradoxes related to the development of new technologies: in the field of bioethics: artificial reproduction, mammal cloning, genetically modified organisms. towards the ethics of new technologies: ethics of information and communication technologies and ethics of space policy; 2. Nature, foundation and characteristics of the ethical approach; the precaution principle must be completed with two other principles: the principle of experience and the principle of vigilance; 3. The modalities of a democratic management of the ethical approach: it is a matter of defining the role of the three main actors, i.e.: experts, politicians and citizens representing public opinion. It is necessary to promote the ethical approach within a democratic context, that is to ensure a dialogue between experts, policy decision-makers and public opinion on all of the applications of science and technology. It is from such a permanent and renewed dialogue that will emerge the image we give from ourselves in the present world.

[Limb-girdle dystrophy and pregnancy: a case report]. / Myopathie des ceintures et grossesse: un cas.

A case of pregnancy with Limb-girdle dystrophy is presented. The course of pregnancy remained uncomplicated, the patient has been delivered at 42 week's gestation by cesarean section, performed for dystocia and fetal distress. Histological and immunohistochemical examinations of the myometrium were unable to show its involvement in the muscular disease. The influence of the muscular disease and the route of delivery for such patients are discussed.

[Histogenesis of the corpus callosum]. / Histogenèse du corps calleux.

The corpus callosum results from neocortical commissural axon fasciculation. Its development reflects the interhemispheric circuitry and then follows the successive steps of synaptogenesis. The first stage consists of callosal neuron differentiation, which allows the extention of the future callosal axon; this is an early event that occurs while neuronal migration to the cortical plate is still ongoing. Callosal axon guidance towards its specific target is the second step which includes reaching and crossing the midline and further target recognition with formation of initial synapses. This period extends from 12 to 22 post-conceptional weeks and corresponds to the following histological features: i) progressive invasion by callosal growth cones of the dorsal part of lamina reuniens through a preformed glial pathway; ii) appearence of the three parts of corpus callosum, namely truncus, rostrum and lastly the splenium. Both these stages are genetically controlled either directly by developmental gene expression (neurogenesis genes) or indirectly by the establishment of cue maps (spatial expression of extra-cellular matrix proteins). The third step is that of synapse remodeling by synaptic activity, giving rise to axonal elimination, macroscopically revealed by a transitory thinning of corpus callosum. This perinatal event contributes to the corpus callosum acquiring a mature topography. Finally, analysis of corpus callosum ontogenesis appears as a striking model of synaptogenesis study and provides physiopathological assumptions for a understanding of the corpus callosum agenesis.

[Agenesis of the corpus callosum. Neuropathologic study and physiopathologic hypotheses]. / Agénésies du corps calleux. Etude neuropathologique et hypothèses physiopathologiques.

The neuropathological study of corpus callosum agenesis requires a two-phase approach: first it should analyze the putative causal factors, i.e. absence of callosal neurons, commissuration inability or synapse remodelling defect; secondly it has to detect any morphogenetic effects stemming from the absence of commissure such as nonregression of archicortical structures, ventricular enlargement or possible invasion of the remaining telencephaplic commissure by callosal neurons. Absence of callosal neurons due to abnormal corticogenesis gives rise to corpus callosum agenesis without callosal axon, that is without Probst's bundles. Conversely, corpus callosum agenesis occurring secondary to a commissuration default is associated with the presence of callosal axons which travel along the midline instead of crossing, that leads to the formation of Probst's bundles. This inability to cross the midline could be secondary to an obstacle, such as lipoma or as interhemispheric cysts, or primitive due to axonal guidance disturbance. In the latter situation, the commissural defect could affect the other cerebral commissures i.e. anterior or hippocampal commissures, or could become integrated into a more diffuse midline pathology involving both cerebral and extracerebral structures. Finally, it could be assumed that a synapse remodelling defect could lead to atrophy or hypertrophy of the commissure, that occurs in the absence of white matter pathology.

[Early nuclear modifications related to cellular activation: from histology to molecular cytopathology (1967-1997)]. / Modifications nucléaires précoces liées à l'activation cellulaire: de l'histologie à la cytopathologie moléculaire (1967-1997).

The nuclear chromatin structure and function are altered as soon as the first steps of cellular activation induced by membrane stimulation. Different studies carried on lymphatic tissues as well as isolated cell suspensions (lympho-monocytes) demonstrate that an early and transitory chromatin dispersion, visualised by nuclear refringency (1967), is related to the genome derepression allowing DNA transcription mechanism. This is linked to the expression of c-fos proto-oncogene and that of specific proteins synthesis. This occurs before c myc expression and could play a role in the regulation of surface antigens expression. Independent from the induction of cell proliferation, but related to cell differentiation, the early and transitory chromatin dispersion as well as the influence of c-fos related to proteic system activator (AP1) is discussed in referring to recent studies (1997), as well as the regulation factors of the chromatin filament structure.

[Fetal development and postnatal maturation of the longus colli muscle]. / Développement foetal et maturation postnatale du muscle longus colli.

In adults, the predominant expression of a slow phenotype in the m. longus colli corresponds to its important postural function. Morphologically, there is a dispersion in fiber size predominating on the fast type 2 fibers which are significantly smaller than the slow type 1 fibers. We deemed it of interest, therefore, to analyze the metabolic differentiation of the muscle longus colli during its development. This study has been carried out on six anatomical samples, in foetuses aged between 16 and 40 weeks of pregnancy and in an 18 month-old child. The histological study combined H&E staining and immunohistochemical techniques (using antibodies specific for the slow and the fast isoforms of the myosin heavy chains). Our results indicate that the m. longus colli differentiates during the foetal period in a way which is quite comparable to that of other skeletal muscles, such as the quadriceps. In this series, a major slow predominance with a significant dispersion in fiber size was first observed in the 18 month-old child. Thus, it can be concluded that the establishment of the adult phenotype of this muscle starts during postnatal life, following the development of the mechanisms holding up the head and neck and leading to the appearance of the cervical lordosis.

[Metabolic differentiation of the human longus colli muscle]. / Différenciation métabolique du muscle longus colli chez l'Homme.

The cervical muscles have a dual postural and dynamic function, in order to ensure both the stability and the motility of the cervical spine. The functional duality together with the complexity of the cervico-cephalic system render the study of the cervical muscles difficult, and their physiology is not fully understood in humans. This study has been carried out on ten samples from the m. longus colli, taken during a surgical procedure in patients aged between 36 to 62 years. The histological study combined enzyme histochemical (ATPases) and immunohistochemical techniques (using antibodies specific for the slow and the fast isoforms of the myosin heavy chains). Our results indicate that, in all cases, the m. longus colli is composed of muscle fibers with peripheral nuclei and with a relative dispersion in size. Histochemically, the type 1 and type 2 fibers express exclusively either the slow or the fast myosin heavy chain. From a quantitative point of view, the proportion of the slow fibers varies between extreme values of 30 and 73%; in addition, the dispersion in fiber size predominates on the fast type 2 fibers which are smaller than the slow type 1 fibers. Thus, most of the muscles that we have studied have histologically a slow predominance. This predominant expression of a slow phenotype in the m. longus colli corresponds to its important postural function, in addition to its phasic role during the flexion of the cervical spine.

[Growth of spinal muscles in the human fetus]. / Croissance des muscles spinaux chez le foetus humain.

The spinal muscles, located in the paravertebral region, derive embryologically from the medial part of the somites. It has been shown in different animals that their differentiation occurs within the somite itself following the action of diffusible factors of chordal, neural and epiblastic origin. In these animal species, it thus appears that several factors determine the potential of migration as well as the muscular specification of the somitic cells. In 13 human foetuses, aged from 12 to 40 weeks of pregnancy, without any neuro-muscular disorder, transversal sections of both the vertebral and the paravertebral regions have been made at the level of the thorax and of the abdomen. Following rapid fixation, decalcification and paraffin embedding, semi-serial histological sections of 10 microns have been stained with H&E or Masson's trichrome and examined under light microscopy. Our results confirm that the primordia of the spinal muscles are present before the end of the embryonic period proper. The main modifications observed during foetal life concern the overall growth of the muscular mass, with a neat preeminence of the lombar region after 18 weeks. The differentiation of the individual muscle fibers is similar to that observed in other territories in the developing organism, with a craniocaudal gradient of maturation. Thus, if myogenic specificities really exist in the medial part of the somites in humans, it is likely that they concern the initial mechanisms involved in the activation of the myogenic program and not the mechanisms leading to the subsequent differentiation and growth of the fibres.

The French national program for the prevention and control of AIDS.

The French policy concerning the fight against the acquired immunodeficiency syndrome (AIDS) is a complete and well-balanced one, using information not only for the general awareness of the general population, but also with the help of specific actions aimed at high risk groups. Screening is mandatory for blood, organ and cell donors, but it must absolutely respect individual rights and the rules of ethics. Therefore it must be voluntary and totally respect privacy and professional confidence. France does not undertake screening at the border, but does inform people traveling to and from the country. The monitoring and medical care will be given daily for ambulatory patients, and in specific hospital services according to the symptoms of the others. To save money and to be more efficient, tests will be grouped in specific laboratories. Research is, with prevention, the only hope of stopping the spread of AIDS. More than 50 laboratories are at this moment working, and important funds and materials have been allocated. International cooperation is needed, along with the coordination of the World Health Organization, and the action undertaken by the European Community, to establish the most efficient methods of preventing the spread of this new viral infection that now concerns the whole world.

Research on the human genome and patentability--the ethical consequences.

The genome is one of the primordial elements of the human being and is responsible for human identity and its transmission to descendants. The gene as such ought not be appropriated or owned by man. However, any sufficiently complete description of a gene should be capable of being protected as intellectual property. Furthermore, all utilisations of a gene or its elements that permit development of processes or new products should be patentable. Ethics, in the sense of moral action, should come into play from the very first stages of research into the human genome. Protection of intellectual and industrial property is of purely legal concern and need not provoke ethical consideration. By contrast, the use of the results of, and in particular the commercialisation of products deriving from, research into the human genome, ought to be subjected to ethical consideration and control. Considering the economic and societal stakes of such research, ethical analysis ought to be at an international level if mistakes and unforeseen risks of conflict are to be avoided.

Early nuclear structural changes of transformed human amniotic cells (WISH) in presence of type IV collagen detected by the nuclear refringency assay.

An early nuclear activation of transformed human amniotic epithelial (WISH) cells triggered by type IV collagen is visualized by a modification of the nuclear refringency obtained by mercury binding on condensed chromatin. This phenomenon is quantified by the nuclear refringency test. The nuclear activation of WISH cells by basement membrane collagen is also shown by the DNase I sensitivity of chromatin and by the measurement of mRNA synthesis. These nuclear phenomena are concomitant with WISH cell attachment and laminin synthesis. Reversible effects on nuclear refringency, cell attachment, and laminin synthesis are tested by the addition and removal of different metabolic inhibitors.