One of the chief contemporary goals of neurologists and neuroscientists is to find a way to overcome the debilitating effects of brain diseases, especially neurodegenerative diseases. Since very few molecules have been found to be efficient in curing the patients and even halting the progression of the symptoms, cell therapy is now seen as an attractive alternative. Two therapeutic strategies are currently under investigation: i) the "substitution" strategy, based on grafts of cells capable of differentiating in the appropriate cells and restoring lost functions and ii) the "neuroprotective" or "conservative" strategy aiming to increase the resistance of spared cells to the toxicity of their environment and to reinforce the body's own mechanisms of healing. Twenty years ago, foetal neuroblasts were the first cells to be transplanted in the brains of patients with Parkinson's or Huntington disease. A phase II clinical trial is presently conducted in France for the latter disorder. However, the numerous ethical and technical issues raised by the use of embryonic and foetal cells have directed the focus of clinicians and researchers towards substitute cell types. In this review, we summarise the main findings of the most recent basic studies and clinical trials based on: i) the grafting of surrogate adult cells such as bone marrow mesenchymal stem cells and olfactory ensheathing cells; ii) the potential therapeutic applications of neuropoiesis - the persistent neurogenesis in the brain - as a source for tissue engraftment and as self-repair by a person's own indigenous population of pluripotent cells and iii) immune-based therapy (autologous activated macrophages and T cell vaccination) as well as administration of immunomodulatory molecules. Unexpectedly, it has been found that undifferentiated adult stem cells can display immune-like functions when they home in on an inflamed brain area while immune cells and immunosuppressors can improve functional and morphological recovery when administered within the appropriate time-window. On the one hand, outcomes from substitution therapy trials are encouraging. They pave the way for an enlarged use of various adult cell types for various neurological disorders. On the other hand, clinical benefits of the neuroprotective therapy, still under close scrutiny, look rather promising. It is likely that, in a close future, the two strategies will be combined in order to efficiently repair the pathological, the damaged or the senescent brain.

Dysimmune neuropathies, in common with other neuropathies, comprise an axonal impairment that it is primary or secondary to a demyelinating process. We consider here axonal impairment in the course of certain dysimmune neuropathies, such as the Guillain Barré syndrome, chronic inflammatory demyelinating polyradiculoneuritis and multiple conduction block neuropathy. We mention the fact that it is not always easy to evidence the axonal impairment, its severity and its potential for regeneration. The mechanisms of the axonal lesions stem essentially from the special and tight bonds between the axon and the Schwann cell, which in the central central nervous system are mirrored by the bonds between axons and oligodendrocytes. Indeed, myelinating Schwann cells modify the properties of the axon in the normal peripheral nervous system, and abnormal Schwann cells induce pathological modifications. The periods of appearance of the axonal impairment are nevertheless quite variable depending on the type of the dysimmune neuropathy: acute or chronic. Some Guillain-Barré syndromes may be distinguished by a severe axonal impairment, now well documented and referred to as AMSAN and AMAN. Various mechanisms of axonal impairment are discussed. The bond between axon and myelin means that any pathological process in Schwann cells leads to axonal impairment, with inflammatory processes having a direct impact on the axon: mechanism of typical 'by-stander effect', repressive role of endoneurial edema, direct dysimmune attack on axonal epitopes on the corresponding axolemma, especially on the GM1 gangliosides, intra-axonal accumulation of sodium and calcium due to disruption the voltage-dependent sodium/potassium ion channels, slow retrograde progression to anterior horn neurons and possibly also to posterior spinal cords. The treatment of the axonal impairment is not straightforward; it is based, in a first instance, on the direct relation between the severity of the demyelinating lesions and the axonal impairment. For the acute forms of typical Guillain-Barré syndrome, the value of plasma exchanges and intravenous immunoglobulins has demonstrated in double blind, randomized trials. For the chronic demyelinating inflammatory polyradiculoneuritis, corticotherapy, along with plasma exchange and the immunoglobulins, have also been shown to be effective. Immunosuppressor treatment has benefits, but it is hard to prove objectively. It is generally recognized that it is only useful if applied for a period of weeks, although this is currently a matter of debate. Other therapeutic options have been discussed and proposed, although to date there is a lack of proven efficiency: such treatments include neuroprotective agents and drugs which block sodium/potassium ion channels. It is increasingly difficult to propose new treatments with validated efficiency, due to the small number of patients presenting dysimmune neuropathies of the type discussed here that are both typical and suitable for inclusion in medium to long term studies.

After a pregnancy, there is a transitory increase in the risk of breast cancer. During the pregnancy, the number of mammary epithelial cells increases massively. This increase seems partly due to the expansion of stem cells and proliferating intermediate cells. This proliferation of epithelial cells is accompanied by angiogenesis and by recruitment of stromal cells, as well as changes of the extracellular matrix. During any pregnancy, there is cell trafficking between mother and foetus. Hematopoietic or mesenchymal foetal stem cells are transferred in maternal circulation and could be used by the tumor as support cells and take part in the tumoral development. The study of the mechanisms of this specific oncogenesis may help to develop chemoprevention strategies.

Human papillomaviruses are small viruses belonging to the Papillomaviridae. More than 100 genotypes have been identified, causing benign (low-risk HPV) or malignant (high-risk HPV) cutaneous or mucosal lesions. The low-risk HPV6 and HPV11 provoke genital warts, while the high-risk HPV16 and HPV18 can cause cervical cancer. The HPVgenome includes several open reading frames that encode proteins involved in viral DNA replication (E1 and E2), viral gene expression regulation (E2), virus assembly (E4) and the immortalisation and transformation of infected epithelial cells (E5, E6 and E7; high-risk HPV only). The open reading frames L1 and L2 encode the two capsid proteins. HPV target stem cells of the squamous epithelium. The complete life cycle involves three phases, with sequential expression of viral genes leading to viral DNA replication and to the production of highly infectious virions. Viral DNA integration occurs with high-risk types and leads to the overexpression of two viral oncoproteins, E6 and E7. These proteins, in combination with E5, promote the immortalisation and transformation of infected cells.

In our unit, breast cancer patients suffering mild sequelae of conservative cancer treatment receive fat transfer (lipomodelling), following a precise protocol, based on mammographic and ultrasound examinations and MRI. Available data do not seem to indicate any deleterious impact on patient outcome, notably in view of radiological images, but recurrence (or rather occurrence of new ipsilateral or contralateral cancer) is frequent. The correlation between new or recurrent breast cancer and lipomodelling is high; misinterpretations are possible and frequently arise. The present paper is a description of five complex clinical cases and a discussion of the medicolegal issues that may possibly arise; it also provides tentative expert evaluation of the cases. Clinical findings are reported and analyzed. The second step is a discussion of the radiological impact of lipomodelling, and of the problems caused by the transfer of potentially malignant cells when no preoperative diagnosis of recurrence is made; the morphological and esthetic benefits of the method are described, as well as the potential beneficial impact of fat transfer, notably associated with lower breast density and injections of fat stem cells. Our conclusion is that specialized radiologists, as well as plastic surgery and oncology experts should address the question of fat transfer in operated breast cancer patients and give their reasoned opinion about potentially litigious cases. This would help minimize or solve the conflicts between patients, doctors and experts. Establishing common ground between the different stakeholders would allow the development of the technique, as lipomodelling is, according to our experience, a tremendous advance in the treatment of sequelae from conservative breast cancer surgery.

CXCR4 is a clinically relevant chemokine receptor that has first gained attention as one of the cofactors for HIV entry into target cells. Moreover, the receptor is involved in cancer cell migration to distant metastatic sites and immune effector recruitment in inflammatory diseases such as asthma and rheumatoid arthritis. Unfortunately, pharmacologic intervention is complicated by the vital function of CXCR4 in the organism. The most prominent of these functions is its role in stem cell homing. The CXCR4 chemokine ligand, produced by bone marrow stromal cells, leads both to migration of hematopoietic stem cells towards this niche and their retention in this compartment. As models of G-protein coupled receptor (GPCR) activation evolve, it becomes clear that multiple factors modulate the functional outcome of ligand binding to a receptor. Modulation of GPCR activity, for example by allosteric ligands, may permit more subtle therapeutic approaches adapted to long term treatment. In addition, GPCR signalling can be altered by hetero-oligomerization of GPCRs. In this perspective, it might be possible to achieve modulation of GPCR signalling by also targeting the oligomerization partner of a given receptor. This approach is described using the example of strategies that aim at the optimization of stem cell homing in the context of cord blood-derived hematopoietic stem cell transplantation.

The increased susceptibility of human newborns to infections is usually ascribed to the immaturity of the neonatal immune system. The neonatal immune system has never met microbial antigens, and thus the repertoire of its adaptative arm (T and B cells) is entirely pre-immune, or "naïve". However this neonatal pre-immune repertoire is similar to the adult pre-immune repertoire, and cord blood natural killer cells studies show that the innate immunity cells harbor the full killing machinery that characterize mature cells. Moreover, human neonates are able to show an adult-like allogeneic response. Taken together, several lines of evidence suggest that the neonatal immune system, although naïve, is fully mature. However, newborns display phenotypic and functional differences with adults in both adaptative and innate arms. Specific properties may explain these differences, as high number of regulatory T cells, low plasmacytoid dendritic cell response to stimuli and high IL-10 production. These properties are in line with the high susceptibility of newborns to infections and the low incidence of graft-versus-host-disease after cord blood transplantation. To explain these differences, we introduce a new model. Although naive, the neonatal immune system is mature, and these functional differences are due to a message originating from the placenta and aimed at inducing the foetus tolerance to its mother. Full understanding of the involved mechanisms will help to protect the newborn against infections and to improve cord blood transplantation outcome.

Mucosae and skin are exposed to environmental antigens and are natural entry routes for most infectious agents. To maintain immunological tolerance and ensure protective immunity against pathogens, epithelial surfaces are surveyed permanently by antigen-presenting dendritic cells (DCs). Many DC subsets have been described in epithelial tissues, depending on the inflammatory state and the type of epithelium. Identification of the DC subset able to induce cytotoxic CD8+ T cells against antigens delivered via mucosae or skin, is a major issue for the development of efficient anti-infectious and anti-tumoral vaccines. Until recently, it was commonly accepted that Langerhans cells (LC), the prototype of immature DCs residing in skin and certain mucosae, can capture and process antigens and, in response to danger signals, undergo a maturation program allowing their migration to the draining lymph nodes for priming of naïve T cells. This concept likely needs to be revisited. Recent evidence from animal models revealed that resident epithelial tissue DCs, including LCs, do not play a direct role in T cell priming, but may contribute to maintenance of peripheral tolerance. Alternatively, DCs newly recruited into muco-cutaneous tissues exposed to pro-inflammatory stimuli are responsible for efficient priming and differentiation of CD8+ T cells into cytolytic effectors. These DC originate from blood monocytes and can cross-present protein antigens to CD8+ T cells, which subsequently give rise to specific CTL effectors. Remarkably, components derived from bacteria, virus and chemicals capable to enhance CCL20 production in epithelia, promote CCR6-dependent DC recruitment and behave as adjuvants allowing for cross-primed CD8+ CTL. These advances in the dynamic and function of epithelial tissue DC provide a rationale for the screening of novel CD8+ T cell adjuvants and the design of novel mucosal and skin vaccines.

While medicine has made remarkable progress over the last decades, its development has also raised numerous ethical and legal issues. In this context, the question arises as to what framework is needed for research, organ transplants, and medically assisted reproduction. A balance has to be found between scientific freedom, the imperatives of public health and the protection of people ' welfare, rights and human dignity. Those questions have led to the adoption of multiple national laws as well as ethical and legal norms at the international level. The judiciary is also often involved in settling legal issues raised in this context, long before the legislature manages to provide a legislative or regulatory framework. In this analysis of the role of the judges in bioethics, the present paper aims at offering a comparative view of case law in different countries (France, Germany, Switzerland and the United Kingdom) concerning the status of the embryo. In life sciences, the status of the embryo is at the heart of the debate as it determines the very notion of human life. The hypothesis suggested by the organisers of the workshop fbr which this paper has been prepared was that a custom was emerging from national cases related to this question. Our analysis concerning the status of the embryo does not confirm this hypothesis. On the contrary, courts are reluctant to take the place of the legislature in dealing with this delicate issue. Even when judges take novel positions on the protection of the embryo, we can notice a wide range of judicial solutions that raise a serious doubt about the actual existence of an international custom that could be binding in the various legal orders.