Transgenic mice bear stable, artificially induced genetic modifications that are transmitted to their offspring. They are prepared from cultured embryonic stem cells isolated from blastocysts. The stem cells are then transfected with a vector comprising a selection cassette and the sequence to be introduced, modified or suppressed, lying between two sequences identical to those flanking the target gene. The target gene is thereby "knocked out" and replaced by the selection cassette, through homogeneous recombination. Cells in which recombination has successfully taken place are sorted by detecting the selection cassette, and are injected into an embryo. This results in so-called mosaic mice which, after crossing, will give birth to mice that are either heterozygous or homozygous for the knocked out gene. A variety of genomic modifications can be obtained with this approach, including gene knock-out, insertion of multiple gene copies, introduction of a reporter gene under the control of the promoter of the gene of interest, and "conditional" mutations that are expressed in a given tissue or for a specific period of time. Transgenic mice can be used to examine the phenotype resulting from a null mutation or from the introduction of multiple gene copies, as well as factors controlling the synthesis of a specific protein, the phenotypic consequences of point mutations, and the genes involved in embryo development. Institutes have been created specifically to phenotype transgenic mice, frequently using non invasive techniques. The results thus obtained are collected in databases, thus allowing scientists to determine the minimal number of animals necessary for a given experiment.

Late loss of renal grafts is primarily due to progressive sclerosis, involving both immune and non immune processes. Activation of interstitial fibroblasts responsible for graft fibrosis is known to involve proliferation and activation of resident fibroblasts, recruitment of bone marrow-derived stem cells, and epithelial-mesenchymal transition, a more recently identifled mechanism. In this latter process, tubular epithelial cells lose their epithelial phenotype, acquire mesenchymal markers and properties, and participate in the fibrotic process. Whether or not these cells move into the interstitium is controversial. By using immunohistochemistry with specific antibodies against vimentin, beta cadherin, beta catenin and other fibroblastic markers, we found that tubular epithelial cells in kidney grafts can exhibit phenotypic markers of epithelial-mesenchymal transition as early as 3 months after transplantation, before the onset of fibrosis. These changes are associated with prolonged cold ischemia and clinical or subclinical acute rejection. In addition, changes observed at 3 months seem to be predictive of both the fibrosis score at 12 months and, interestingly, the progression of fibrosis between 3 months and 12 months. Finally, renal function at 2 years was significantly poorer in patients exhibiting epithelial changes at 3 months. These results suggest that the epithelial-mesenchymal transition plays a role in the progressive fibrosis of kidney grafts, and that its early inhibition could prevent the gradual decline in renal function and late graft loss.

To assess limbal epithelial cell growth kinetics in vitro using tissue retrieved from organ-cultured donor corneas.

It is a central dogma of female reproductive biology that oogenesis ceases around the time of birth in mammalian species. In 2004 and 2005, two studies were published by Johnson et al., in which they claimed that in the adult mouse ovary, neo-oogenesis takes place and originates from female germline stem cells that are present in either the ovarian surface epithelium or bone marrow. Following these publications, experiments showed that non-germinal stem cells could generate oocytes. However, in the mouse, ability of extra-ovarian stem cells to refurbish the ovary in new oocytes competent to ovulate, and subsequent existence of a spontaneous neo-oogenesis in the adult ovary in normal physiologic conditions, have been disputed. Morphologic studies performed in the adult mouse ovary showed that atresia of the immature follicle pool was strongly overestimated by Johnson et al., and that no intermediary stages of meiosis were seen. These observations led to the conclusion that adult female mice do not need neo-oogenesis for maintaining a normal reproductive function. However, a recent study have shown that female germline stem cells might be present in the ovarian surface epithelium in mice and humans. When sampled in GFP transgenic mice, cultured for a long period and transplanted into ovaries of sterilized mice, these cells underwent oogenesis and the mice produced offsprings. These new data support the possibility to experimentally restore fertility in women suffering from a premature ovarian failure.

Exposure to deleterious processes of metabolic, infectious, autoimmune or mechanical origin, alters the endothelium which progresses towards a proinflammatory and procoagulant activation, senescence and apoptosis. This "response to injury" of the endothelium plays a key role in the initiation and progression of cardiovascular disorders. In the last 10 years, identification in peripheral blood of circulating endothelial cells (CEC) and endothelial-derived microparticles (EMP) reflecting endothelium damage has led to the development of new noninvasive methods for endothelium exploration. Indeed, these biomarkers were associated with most of the cardiovascular risk factors, were correlated with established parameters of endothelial dysfunction, and were indicative of a poor clinical outcome. Moreover, they behave as biological vectors able to disseminate deleterious signals in the vascular compartment. More recently, this concept has been enlarged by the discovery of a potent repair mechanism based on the recruitment of the circulating endothelial progenitors cells (EPC) from the bone marrow, able to regenerate injured endothelial cells. Cardiovascular risk factors alter EPC number and function. Because the damage/repair balance plays a critical role in the endothelium homeostasis, CEC, EMP and EPC could be combined in an endothelium phenotype that defines the "vascular competence" of each individual. In the future, progress in standardization of available methodologies to measure these emerging biomarkers is a crucial step to establish their clinical interest for assessment of vascular risk and monitoring of vascular-directed therapeutics.

Macrophages are involved in the immune and the inflammatory response. The deregulation of their physiological properties is associated with several pathologies such as atherosclerosis and some cancers. Cytokines action on this blood lineage modulates p21WAF1/CIP1 expression. It appears that this protein may play a role in the inflammation regulation through PPAR (peroxysome proliferator-activated receptors) transcription factors, strongly linked to lipid metabolism. It could also be involved in the control of the proliferation of monocytes/macrophages, even if these cells are classically described as devoided of any proliferative capacity.

It has long been believed that cerebral lesions were irreversible in the adult human brain. However, the spontaneous improvement in functional outcome observed in the following weeks after cerebral ischemia suggests plasticity phenomenons involving postischemic neuronal network reorganization. Regarding the large prevalence of stroke in industrialized countries, and the few available treatments, the understanding of cerebral plasticity has become an important issue but also a potential source of new therapeutic approaches in stroke. Thus, "constraint induced therapy" and repetitive transcranial magnetic stimulation (rTMS) are based on the concept of local but also remote consequences of the ischemic focal lesion. Cell-therapy is based on the capacity of stem cells to respond to hypoxic signals and adapt their phenotype to the host organ, but above all to release cytokines locally and boost endogeneous repair mechanisms. We could consider to perform in the future a sequential treatment with fibrinolysis, stem cell therapy, repetitive transcranial magnetic stimulation and constraint-induced therapy in the same patient.

Kidney involvement is frequent in hematologic malignancies. It is associated with adverse outcome and treatment difficulties. It can affect every area of the renal parenchyma (tubules, interstitium, glomerulus, vessels). Various mechanisms could be implicated: deposits of immunoglobulin fractions or crystals, renal infiltration by malignant cells, urinary tract obstruction, paraneoplastic or storage glomerulopathies… Diagnostic strategy relies on the clinical presentation: acute renal failure, chronic kidney disease, glomerular proteinuria with or without nephrotic syndrome, tubular proteinuria, hydroelectrolytic disorders. In this review, we detail the diagnostic tests that are needed for the detection and the follow-up of renal involvement in hematologic malignancies, and clarify the indications of renal biopsy. We propose diagnostic strategies of renal involvement in myeloma, Waldenström's disease, high grade lymphomas and acute leukemias, low grade lymphomas and chronic leukemias. The adverse effects of treatments (chemotherapy, radiotherapy, stem cell graft …) are not addressed in this review.

Plexiform neurofibroma (NFP) is a benign nervous tumour typically involving the head and neck region due to the rich innervation of the latter. It is considered pathognomonic of neurofibromatosis type 1(NF1). This report describes an unusual case of neurofibroma and discusses its singular presentation, namely an isolated cutaneous tumour of late onset and with myofibroblastic histology.

OCT4 encoded by pou5f1 is one of the most ancient and early transcription factors identified in the embryo. It has been longwise recognized as a gatekeeper for pluripotency of embryonic stem (ES) cell. Uncovered twenty years ago, its fame was built up from its key role in maintaining embryonic stem cell pluripotency in 1998. Since, OCT4 was reported to also instruct stem cell fate through a gene dosage effect. It reached recently a novel glorious hit with its master role in reprogramming somatic cells.

Centrosomes are essential protagonists during cell division through microtubule nucleation and spindle formation which are key to the harmonious distribution of sister chromatids in the two daughter cells. However, during the past decade, a wealth of new observations has extended their role beyond mitosis, particularly in the asymmetrical partition of cell fate determinants. Remarkably, asymmetric centrosome inheritance per se, through the segregation of differently aged mother -centrioles, seems to regulate the differential behaviour of daughter cells, in part through asynchronous expression of primary cilia, governing the response to environmental signals. It is thus understandable why any quantitative or qualitative dysfunction of centrioles contributes to genomic -instability and thus -tumorigenesis.

Several clinical trials on cell therapy have recently been conducted in the treatment of urinary incontinence. The cell preparation procedures and the inclusion criteria were different for each study. The feasibility of this technology, however, seems acquired. The indications for treatment and the long-term effects have yet to be specified. Cell therapy for urinary incontinence is only conceivable within the context of a clinical trial at this time. We encourage all investigator-urologists involved in a clinical trial on cell therapy to make themselves known on the website http://clinicaltrials.gov so as to inform the community and encourage the technique's development.

Recurrence of cardiovascular events and mortality remain high after acute coronary syndromes. A Swiss multicentric study, "Inflammation and acute coronary syndromes (ACS)--Novel strategies for prevention and clinical managements", is currently underway with the support of the Swiss National Science Foundation. The study includes a clinical research subproject of which the aim is to assess the impact of the ELIPS program (multi-dimEnsionaL prevention Program after acute coronary Syndrome) on the recurrence of cardiovascular events after an ACS. The basic research sub-projects aim to investigate novel cardiovascular risk biomarkers and genetic determinants of recurrence and to study the role of stem cells after an ACS. Another sub-project will evaluate intracoronary imaging techniques and the efficacy of different types of stents.

Asymmetric cell division is the process by which a single cell gives rise to two different daughter cells. This process is important to generate cell diversity during the development of multicellular organisms, as well as for stem cell self-renewal in adults. Current knowledge on so-called cancer stem cells suggests that a loss of asymmetry during their division could lead to overproliferation and favour tumorigenesis, highlighting the importance of deciphering the mechanisms governing asymmetric cell division. Two mechanisms can lead to an asymmetric cell division: asymmetry can either be governed by proximity to a given cellular environment (or niche), in which case the mechanism is referred to as extrinsic, or the mother cell polarizes itself without external intervention, in which case the mechanism is referred to as intrinsic. In the last 20 years, our understanding of intrinsic mechanisms leading to asymmetric cell division has progressed, largely after studies carried out in model organisms such as the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster. These models allowed the identification of molecular complexes used by nearly all the cells that divide asymmetrically, including human cells. Here we review the main intrinsic mechanisms of asymmetric cell division as described in model organisms and discuss their relevance towards mammalian tumorigenesis.