Granulocytic sarcoma is a tumor composed of proliferating myeloblastic cells, generally found in the orbit. A brain localization is rare. We report the case of a 11-year-old boy treated in our unit for acute myeloblastic leukemia (AML 4 Eo. FAB). After 21 months of complete remission, he developed headache and facial palsy. The CT scan visualized the presence of two frontal and occipital masses. The spinal tap revealed blastic cells in the CSF. The study of the bone morrow showed medullar relapse. A new medullar and cerebro-meningeal remission was obtained with chemotherapy and radiotherapy. CSF and the bone marrow studies can help avoid stereotaxic biopsy can be avoided in this type of tumor

Diabetes mellitus places an enormous burden on patients, their relatives and the society. Current therapies do not provide sufficiently tight control of blood glucose to avoid diabetic complications. Some recent developments try to restore normal glucose homeostasis. Research is islet and stem cell transplantation is developing rapidly and this article summarizes the new approaches that could cure and not simply treat diabetes in the future.

Transplantation of fetal neural cells represents an attractive replacement strategy for the treatment of certain neurodegenerative diseases. This is the case with Parkinson's disease, which results from a selective loss of dopaminergic neurons of the substantia nigra. Experimentation with animal models has demonstrated the feasibility of this approach. Grafting studies in patients have shown that intrastriatal implantation of solid grafts or cells obtained from human fetal mesencephalon usually results in a clinical benefit in patients. Despite continuous methodological progress, transplantation requires both conceptual and technical improvements. Current research aims at preventing the extensive death of donor dopaminergic neurons during the grafting procedure. However, the possibility of new sources of cells is currently being investigated. These include xenogeneic porcine neurons, or human cells programmed to produce dopamine or neurotrophic factors. A promising approach is based on the use of pluripotent stem cells derived from the brain, the bone marrow or early embryos. It is hoped that it will be possible to tightly control their proliferation and differentiation into dopaminergic neurons. Hence, it seems possible that transplantation will be widely used in the clinic in the future.

Transplantation of fetal neural cells represents an attractive replacement strategy for the treatment of certain neurodegenerative diseases. This is the case with Parkinson's disease, which results from a selective loss of dopaminergic neurons of the substantia nigra. Experimentation with animal models has demonstrated the feasibility of this approach. Grafting studies in patients have shown that intrastriatal implantation of solid grafts or cells obtained from human fetal mesencephalon usually results in a clinical benefit in patients. Despite continuous methodological progress, transplantation requires both conceptual and technical improvements. Current research aims at preventing the extensive death of donor dopaminergic neurons during the grafting procedure. However, the possibility of new sources of cells is currently being investigated. These include xenogeneic porcine neurons, or human cells programmed to produce dopamine or neurotrophic factors. A promising approach is based on the use of pluripotent stem cells derived from the brain, the bone marrow or early embryos. It is hoped that it will be possible to tightly control their proliferation and differentiation into dopaminergic neurons. Hence, it seems possible that transplantation will be widely used in the clinic in the future.

We report the case of a 30-year-old woman with KID (keratitis ichthyosis deafness) syndrome consulting for massive corneal neovascularization. She had already undergone two unsuccessful penetrating keratoplasties in her left eye. Visual acuity was limited to no more than light perception because of the opacity and neovascularization of the graft. In the light of this case of limbal cell deficiency, we discuss the ophthalmologic manifestations of KID syndrome as well as its clinical characteristics, physiopathology, and mode of transmission.

The French bioethics law promulgated in 1994 and still in force prohibits nearly all forms of research on the human embryo. However, the concept of the patient-embryo developed in this discussion demonstrates that it is medically mandatory to proceed with such research. The project presented by the government in accordance with the obligatory revision of the 1994 law which was adopted by the Parliament in January 2002 accepts the principle of research on the embryo and embryo cells. An Agency for embryology, human reproduction, and human genetics (APEGH) will be in charge of controlling these activities.

The stem cell data presented and discussed during the symposium raise the hope that important medical progress can be made in several fields: neuro-degenerative diseases, those linked to cellular deficit, some aspects of aging linked to cellular degeneration, and the treatment of cancers that may harm normal tissues at risk of being infiltrated by malignant cells. Three main types of stem cells are available. (i) Those present in normal adult tissue: contrary to what was believed, some data suggest that certain adult stem cells have a great plasticity (they can differentiate into cells different from those in tissues from which they were taken) and can proliferate in vitro without losing their properties. Nevertheless, their use faces several obstacles: in ill or elderly subjects, then these cells can be limited in number or not multiply well in vitro. In this case, auto-grafting of the cells cannot be used. They must be sought in another subject, and allo-grafting causes difficult and sometimes insoluble problems of immunological tolerance. (ii) Embryonic stem cells from surplus human embryos, obtained by in vitro fertilisation, which the parents decide not to use: these cells have a great potential for proliferation and differentiation, but can also encounter problems of immunological intolerance. (iii) Cells obtained from cell nuclear transfer in oocytes: these cells are well tolerated, since they are genetically and immunologically identical to those of the host. All types of stem cells can be obtained with them. However, they do present problems. For obtaining them, female oocytes are needed, which could lead to their commercialization. Moreover, the first steps for obtaining these cells are identical to those used in reproductive cloning. It therefore appears that each type of cell raises difficult scientific and practical problems. More research is needed to overcome these obstacles and to determine which type of stem cell constitutes the best solution for each type of disease and each patient. There are three main ethical problems: (a) to avoid the commercialization of stem cells and oocytes (this can be managed through strict regulations and the supervision of authorized laboratories); (b) to avoid that human embryos be considered as a mere means to an end (they should only be used after obtaining the informed consent of the parents; the conditions of their use must be well defined and research programs must be authorized); (c) to avoid that research on stem cell therapy using cell nuclear replacement opens the way to reproductive cloning (not only should reproductive cloning be firmly forbidden but authorization for cell nuclear transfer should be limited to a small number of laboratories). Overall, it appears that solutions can be found for administrative and ethical problems. Harmonisation of international regulations would be desirable in this respect, in allowing at the same time each country to be responsible for its regulations. A last ethical rule should be implemented, not to give patients and their families false hopes. The scientific and medical problems are many, and the solutions will be long and difficult to find. Regenerative medicine opens important avenues for research, but medical progress will be slow.

Divergent and sometimes conflicting positions with respect to human stem cells and cell therapy do not merely reflect disagreement among scientists and conflicts of interest. They attest the ethical tension resulting from recent progress in understanding the earliest stages of development of the human being that can be observed in vitro. Can the extremely potent notion of the human person starting with conception apply to the very first stage of artificial in vitro fertilisation and disregard the fact that to be a real substitute for natural conception, implantation in the uterus that enables the oocyte to nest and a new human being to develop must also be included? Several arguments are presented that plead in favour of making a clear distinction between the status of in vitro cells obtained by artificial fertilisation and that of the embryo, which becomes a developing human being from the moment it implants in the endometrium of the uterus. This subject could have remained in the sphere of the individual conscience, but it has now become a theme for social debate! The revision of the French 1994 so-called Bioethics Laws, which was recently approved on first reading on 22 January 2002, authorizes research on spare embroys from in vitro fertilisation under certain conditions. However, for the sole reason that there is a risk of opening the door wide to reproductive cloning, which is unanimously rejected and condemned, all research on stem cells deriving from the nuclear transfer of a somatic cell is prohibited, irrespective of the distinction between cloning for therapeutic purposes and reproductive cloning. It is undeniable that if the efficacy of somatic stem cells could be demonstrated, they would offer a far more preferable solution, for several reasons, than those involving stem cells obtained from spare embryos from IVF or nuclear transfer. Nevertheless, how will a comparison of the two methods be possible if one of them is prohibited a priori? At present, many fear that French researchers will be prevented from doing essential research that, even if it has far to go, is indispensable if we wish to attempt to control the failures of natural procreation and open the way towards the new regenerative medicine that so many look forward to.

Since its beginning, at the turn of the 19th century, biology has been mostly--if not exclusively--analytical. Reductionism has progressively unveiled a series of structures buried into one another like Russian dolls. The study of the genome, the deepest structure of organisms, represents the triumph of reductionism. With the deciphering of the genome and the birth of what is called the 'proteome'--i.e. the study of the proteins and of their interactions--, a new stage appears. To the disorganisation that characterised two centuries of biology, a phase of reconstruction of living organisms is substituted. This is concerned first with interactions of proteins and of cells. In addition, one of the most remarkable tools for this latter research has been provided by embryonic stem cells.

Flow cytometry is an objective, sensitive and quantitative technique which allows rapid and simultaneous analysis of several parameters on a great number of cells. Hence, flow cytometry is particularly suitable for the analysis of complex cell populations, rare events and quantitative studies. In immunohematology, flow cytometry is a very powerful approach to the study of mixed red cell populations (hematopoietic chimerism, transfusion or bone marrow transplantation), the detection of low frequency cell populations (reticulocytes, fetomaternal hemorrhage) and the quantitative analysis of red blood cell antigens.

Several promising approaches to the treatment of renal cancer have been developed over recent years. Two independent North American and European studies have demonstrated the value of nephrectomy in patients with metastatic disease: the overall survival of patients treated with interferon was improved by nephrectomy, essentially in patients with a good general status. Several publications have also emphasized the value of surgery for metastases. New experimental approaches have also been developed. Dendritic cells fused with tumour cells induced 4 complete remissions and 2 partial remissions in a series of 17 patients. Allogeneic haematopoietic stem cell transplantation induced lasting remissions in 10 out of 17 patients. The National Cancer Institute team, in the United States, has developed this approach for patients with an HLA-compatible relative. Finally, various molecules with promising antiangiogenic properties are currently under development in renal cancer.

Cardiac transplantation still remains the only radical treatment of end-stage heart failure but organ shortage results in the lengthening of the waiting period during which hemodynamic decompensation may occur and then require temporary circulatory support. Improvement in these assist devices now allows to permanently implant some of them which then appear as true alternatives to cardiac transplantation when this technique is contra-indicated. In parallel to these "mechanical" options, "biological" strategies have been designed, which are primarily based on cell therapy. Thus, autologous skeletal myoblast transplantation has yet entered the clinical arena, on the basis of experimental data suggesting the functional efficacy of these cells once implanted into infarcted myocardium. However, the clinical benefits of this approach still need to be validated by randomized trials. Gene therapy appears more complex to implement clinically, because of the multiplicity of candidate genes and the persisting issues associated with vectors and gene transfection systems.

THE DEVELOPMENT OF CELL THERAPY: The stakes in the management of heart failure have become such that new therapeutic strategies have to be developed. Among the cell, molecular and genetic approaches aimed at reinforcing the deficient heart muscle by restoring its functional potential, cell therapy is the favored option in clinical application perspectives. IN THE FIELD OF ISCHEMIC HEART FAILURE: All the experimental data have shown that implantation of contractile cells in the post-infarction areas led to improved cardiac function. INTERESTING PRELIMINARY RESULTS: For ethical and immuno-biological reasons, the successful transplantation of autologous skeletal myoblasts has led our team to conduct a phase I clinical trial. Although the results of this study are preliminary with regard to cardiac function, they suggest the validity of the cell transplantation concept and allow one to hope that this new treatment method will have its place among the therapeutic arms of heart failure.

The haematopoietic stem cell (HSC) has been first described in the mouse and now identify in human as well. Exposed to a cocktail of growth factor, this HSC can self re-new and/or differentiate into the three lineages we have in the peripheral blood. These HSC are of major importance in the clinics since they can be used for some marrow (or stem cell) transplantation, and lead to the cure of a number of malignant and non malignant hemopathies. We have today three sources of HSC: the bone marrow, the mobilized peripheral blood stem cell and the cord blood. Bone marrow used to be the classical source of HSC after harvesting by aspirations in the iliac crest. However, this approach is now supplanted by the recovery of HSC in peripheral blood using a cell separation after four days of G-CSF administration. These are several advantages of this technique, but the most important one is the more rapid hematopoietic recovery after transplantation, reducing the risk of infection and transfusion. A recent source of HSC is the umbilical cord blood. At the moment of delivery, the cord blood is extremely enriched in HSC due to the migration of these cells from the liver to the bone marrow stroma, where they will persist after birth. We have learned that the marrow stroma display a major role in the regulation of hematopoiesis and the pathogenesis of several malignant hemopathies can be explained by disturbance in the function of stromal cell. We have particularly studied the patho-genesis of chronic lymphocytic leukaemia. We have also observed that a subpopulation of stromal cells, the mesenchymal cells are of major importance in the microenvironment. In addition, the plasticity of these cells is demonstrated in vitro and we have currently a research program investigating its differentiation in neural cells. All these observations bring new promises in the treatment of hemopathies but also in some other neurological degenerative diseases.

Gaucher disease and Fabry disease are lysosomal storage disorders characterized by the accumulation of sphingolipids. In both cases, the goal of gene therapy is to permanently provide tissues with enzyme levels allowing to avoid storage of the undigested substrates. Different gene therapy strategies must however be designed as Gaucher disease is due to a deficiency in the membrane-associated enzyme glucocerebrosidase, whereas Fabry disease is caused by a deficiency in the soluble enzyme alpha-galactosidase. Indeed, a soluble enzyme can be provided to tissues is trans by gene-modified cells whereas gene transfer has to target the most affected cells in the case of membrane-bound enzymes. Thus, in non-neurological Gaucher disease (type 1), the hematopoietic tissue has to be targeted as the deficiency affects the monocyte/macrophage lineage. Following promising preclinical studies, clinical protocols have been initiated to explore the feasibility and safety of retroviral transfer of the glucocerebrosidase gene into CD34+ cells from patients with type 1 Gaucher disease. Although gene-marked cells were detected in vivo, the level of corrected cells was very low, a finding indicating that improved vectors along with partial myeloablation may be necessary. Here, lentiviral vectors should enable more gene transduction into the hematopoietic target cells. As concerns the diffuse neurological lesions in types 2 and 3 of Gaucher disease, they will probably be especially difficult to target by gene therapy because of the non soluble nature of glucocerebrosidase. Finally, over the last few years, Fabry disease has become a compelling target for gene therapy as an etiology-based treatment strategy. Indeed, several recent studies aiming at creating a large in vivo source of alpha-galactosidase have yielded positive long-term results in the Fabry knock-out mouse model.

The study of the establishment of embryonic axes during early development has shown that this process is a very early event (occurRing either during ovogenesis or during fertilization) for invertebrates and for lower vertebrates. In mammals, it was considered that this establishment appears late during development because of the great plasticity of blastomeres. Recent data in the mouse embryon show that the mammalian ovocyte is a polarized cell, the polar body corresponding to the animal pole of this cell. The blastomeres that are generated by the zygote divide asynchronously. The first that divides is the one which inherits the plasma cell membrane where fertilization takes place. This blastomere will preferentially give rise to the cells of the embryonic pole of the blastocyst whereas the other yields the cells of the abembryonic pole. The mammalian ovocyte is thus a polarized cell with an already established animal-vegetal axis. The point of sperm entry will determine the embryonic-abembryonic axis.

Human hair follicles progress independently through the anagen, catagen, telogen and latency phases that correspond to growth arrest and hair shedding before initiation of a new anagen phase. Hair follicles are self-renewing and contain reservoirs of multi-potent stem cells. Identification of the messenger molecules and pathways operating in the growth and cycling of hair follicles, have provided substantial data. However, only a limited number of these signals is well understood. The specific response of hair follicle cells to these signals is correlated with the expression of their corresponding receptors. What regulates these responses? In this review, we will focus on the hair cycle and its control mechanisms. We will provide some elements in answer to these questions and present some of the markers of hair follicle cells, and hormonal and vascular growth factors, which may regulate respectively hair follicle cell metabolism and cycle, and the neuropeptide impact on hair follicle response and hair growth. The results of our study show the modifications in various expression patterns of receptors in dermal papilla cells, and demonstrate the cross-interaction between these different components. In conclusion, we present an accumulation of evidence suggesting that the regulation of hair growth requires a combination of hormonal, vascular and neuropeptide approaches that will provide further insight in defining new treatments for hair loss.

Paraneoplastic pemphigus is an autoimmune mucocutaneous disease usually associated with neoplasia as lymphoid proliferations. We report the original case of a patient who had developed a mycosis fongoide preceded by a paraneoplastic pemphigus. To our knowledge, this association has never been reported before. Cutaneous manifestations of mycosis fongoide as pigmentary change are known. This mycosis fongoide was particular in its progressive cutaneous hyperpigmentation.