Female stress urinary incontinence (SUI) is mainly due to an excessive mobility of the cervico-urethral complex. Synthetic tapes placed without tension underneath the urethra to correct this hypermobility have revolutionized the surgical treatment of female SUI for the past fifteen years. The retropubic approach, namely the "tension-free vaginal tape" (TVT), was designed in 1996. It generates high SUI cure rates but is associated with a risk of intrapelvic bleeding and bladder and intestine perforation. The inside-out transobturator approach, which was developed eight years ago in our Institution, has since been used worldwide. The surgical technique is simple and reproducible and the incidence of peri- and post-operative complications is reduced. SUI cure rates are +/- 90% after a 3-5 years follow-up, similar to those obtained after the retropubic route. We have recently improved our original technique by using a shorter tape while, at the same time, minimizing the dissection required for its insertion. After a one year minimum follow-up, this new technique appears as safe and efficient as the traditional transobturator technique but is associated with reduced post-operative groin pain. We introduce for the first time the concept of the transobturator "midi sling".
Although very effective, some drugs have considerable side effects and are characterized by a relatively narrow therapeutic index. It is therefore sometimes required to regularly check their blood concentration in order to find the best compromise between optimal therapeutic efficacy and reduced toxicity. A therapeutic drug monitoring (TDM) is applied for immunosuppressants used in solid organ transplantation and for antiretrovirals used in the treatment of HIV infections. A first improvement of conventional TDM consists in trying to understand the origin of the inter-individual variability at the pharmacokinetic level in order to anticipate it and to propose individualized dose adjustment according to each patient's genetic characteristics. A complementary improvement consists in measuring the active biological dose of the drug directly in target tissues (lymphocytes for both pharmacological classes considered) and in studying genetic and other factors, influencing this parameter. In complement to conventional TDM, pharmacogenetics therefore allows a better individualization of drug therapy.
The evolutionary origin of Man in the African continent has imposed the requirement to resist endemic parasites, in particular African trypanosomes (prototype: Trypanosoma brucei). Therefore, human serum is provided with an efficient system of innate immunity against these parasites, as discovered by A. Laveran in 1902. However, two T. brucei clones, termed T. b. rhodesiense and T. b. gambiense, managed to escape this immunity system, enabling them to grow in humans where they cause sleeping sickness. We have identified the gene allowing T. b. rhodesiense to resist trypanolysis by human serum, which led us to discover that the trypanolytic factor is apolipoprotein L1 (apoL1). ApoL1 is a human-specific serum protein bound to HDL particles that also contain another human-specific protein termed "haptoglobin-related protein " (Hpr). Following the binding of hemoglobin (Hb) to Hpr, the apoL1-bearing HDL particles are avidly taken up by the trypanosome through their binding to a parasite surface receptor for the Hp-Hb complex. After endocytosis apoL1 kills the parasite by generating anionic pores in the lysosomal membrane. In our laboratory, mutant versions of apoL1 have been constructed, which are no longer neutralized by the resistance protein of T. b. rhodesiense and are therefore able to kill this human pathogen. Unexpectedly, we have recently discovered that similar mutants do actually exist in nature : in Africans and Americans of recent African origin, even a single allele of these mutants allows protection against infection by T. b. rhodesiense, but the price to pay is a high frequency of end-stage renal disease when doubly allelic. The evidence of natural selection of these apoL1 mutations despite their deleterious potential for kidneys highlights the importance of the resistance to trypanosomes in the evolution of Man. The mechanism by which mutant apoL1 triggers end-stage renal disease is currently studied.
Asthma is one of the most common chronic diseases, affecting 5-10% of the population worldwide. It is closely associated with the "atopic" hypersensitivity to environmental antigens ('allergens'), which is mediated by specific IgE driven by a T helper 2-type immune response, also promoting recruitment of eosinophils and mast cells and mucus overproduction. Our first research axis showed that allergen immunotherapy in patients with allergic rhinitis and asthma to grass pollen induces inhibition of the IL-9/ mast cells axis and a selective induction of allergen-specific IgA2 antibodies in serum, which correlated to nasal tissue expression of TGF-beta. We further showed that these IgA antibodies, whilst unable to inhibit IgE-facilitated allergen presentation by B cells as achieved by IgG4 antibodies, could trigger IL-10 expression in monocytes and dendritic cells through activation of p38 MAP-kinase and recruitment of sp1 and NFkappaB transcription factors. In addition, results in a murine model of asthma suggested a protective role of secretory IgA. A second research axis, exploring local immune responses to lung allergen exposure, identified the CCR4 pathway as critically mediating the recruitment of Th2 cells into the lung of atopic asthmatics. In patients with non-atopic (intrinsic) asthma, we recently reported on the local production of specific IgE to mite allergens (Der p), able to activate basophils in vitro, while lung challenge to Der p in vivo did not result into asthmatic responses. Altogether, we showed (1) that allergen immunotherapy triggers production of IgA2, which could be protective through induction of IL-10 in monocytes/dendritic cells and/ or by scavenging allergens within secretions, and (2) that allergen exposure, which triggers the recruitment of Th2 cells through the CCR4 pathway, induces locally the production of specific IgE, irrespectively of systemic atopic features, supporting the concept according which "second signals" condition in vivo the inception and exacerbations of asthma.
The place of bone allograft in contemporary orthopaedic surgery is discussed. Bone allograft can be prepared from retrieved femoral heads for fracture or osteoarthritis and are used as a filling material. Demineralized bone matrix is a cortical bone that has been exposed to a demineralizing solution. Doing so, the growth factors of the bone are exposed and will be able to induce the formation of new bone cells from the host. This osteoinductive capacity makes the graft more active in the process of its incorporation and has been successfully used in the conservative treatment of aneurismal bone cysts. Massive bone allografts can be used as a full segment of a long bone to reconstruct part of the skeleton either alone with fixation or with a prosthetic device. Except demineralized bone, any other types of bone allograft serve as a biologic passive support for the migrating cells from the host. Cellular therapy is another approach that allows, considering the extensive use of in vitro expanded bone, forming cells originating either from the bone marrow or the fat tissue of the patient. However, this approach needs further clinical validation before being fully considered in patient.
Our work aims at the identification of new diagnostic and prognostic markers in rheumatoid arthritis (RA), using synovial biopsies in patients. We first demonstrated that the molecular signatures identified in these biopsies enable us to differentiate patients with early RA from patients suffering from other inflammatory conditions. Next, we performed transcriptomic studies in synovial biopsies harvested from patients with severe RA before and twelve weeks after initiation of TNF blocking or rituximab (depleting anti-CD20 antibody) therapy. These studies enabled us to identify specific molecular signatures targeted by these therapies in the synovium, and novel markers of response to therapy. Our results open interesting perspectives in terms of potential biomarkers, which could be used in order to improve diagnostic performances and therapeutic decisions based on individual molecular characteristics of the patients.
The evolutionary origin of Man in the African continent has imposed the requirement to resist endemic parasites, in particular African trypanosomes (prototype: Trypanosoma brucei). Therefore, human serum is provided with an efficient system of innate immunity against these parasites, as discovered by A. Laveran in 1902. However, two T. brucei clones, termed T. b. rhodesiense and T. b. gambiense, managed to escape this immunity system, enabling them to grow in humans where they cause sleeping sickness. We have identified the gene allowing T. b. rhodesiense to resist trypanolysis by human serum, which led us to discover that the trypanolytic factor is apolipoprotein L1 (apoL1). ApoL1 is a human-specific serum protein bound to HDL particles that also contain another human-specific protein termed haptoglobin-related protein (Hpr). Following the binding of hemoglobin (Hb) to Hpr, the apoL1-bearing HDL particles are avidly taken up by the trypanosome through their binding to a parasite surface receptor for the Hp-Hb complex. After endocytosis apoL1 kills the parasite by generating anionic pores in the lysosomal membrane. In our laboratory, mutant versions of apoL1 have been constructed, which are no longer neutralized by the resistance protein of T. b. rhodesiense and are therefore able to kill this human pathogen. Unexpectedly, we have recently discovered that similar mutants do actually exist in nature : in Africans and Americans of recent African origin, even a single allele of these mutants allows protection against infection by T. b. rhodesiense, but the price to pay is a high frequency of end-stage renal disease when doubly allelic. The evidence of natural selection of these apoL1 mutations despite their deleterious potential for kidneys highlights the importance of the resistance to trypanosomes in the evolution of Man. The mechanism by which mutant apoL1 triggers end-stage renal disease is currently studied.
Osteonecrosis of the femoral head is a rare disease that affects young patients and is characterized by the occurrence of a necrotic lesion in the femoral head, loss of mechanical resistance of dead bone and collapse of the femoral head. Patients complain of hip pain and loss of function that could lead to total hip replacement. So far, osteonecrosis was considered as a vascular disease due to vascular section or compression leading to bone necrosis. We studied the physiopathology of the osteonecrosis considering it as a bone disease. We demonstrated as well as other teams that the number of mesenchymal stem cells, precursors of bone cells and osteoblastic cells, were reduced in patients with osteonecrosis. We initiated a controlled double blind trial to study the efficacy of stem cells implantation--obtained from concentrated bone marrow--in the osteonecrosis zone. This study showed that bone marrow implantation could delay disease progression to the fractural stage and improve hip pain and joint symptoms. We then tried to improve this treatment by developing a bone cell therapy product formed of osteoblastic cells. A novel cell therapy product formed ofosteoblastic cells, PREOB was developed. PREOB was tested in a randomized, controlled phase II trial in osteonecrosis of the femoral head and showed its superiority compared to concentrated bone marrow. Today, this cellular therapy product is developed by Bone Therapeutics, a spin-offcompany of the Universite libre de Bruxelles. Other bone diseases are characterized by reduced activities of stem cells that are unable to meet the need of bone remodelling due to a non-union fracture, for example. Clinical studies also showed that concentrated bone marrow could be implanted into the non-union. However, its efficacy was dependent on the number of implanted stem cells. The cellular therapy product is currently tested in a phase I trial with promising preliminary results. Cellular therapy for bone diseases is a novel therapeutic approach that evolves from stem cells to the use of the differentiated cells of interest.
The discovery of the dynamic electrical properties of bone is at the origin of the therapeutical application of the electromagnetic fields in Orthopaedics and Traumatology. The first empirical treatment of non-union, fresh fractures and osteonecroses allowed the observation of several effects which, without justifying a systematic clinical application, encouraged further fundamental research. The results of this work realized during 35 years are summarized in the present article. After exposure to specific electromagnetic fields, we observed a modification of the DNA activity and an increased production of RNA. During enchondral ossification, the amount of acid GAGS increased faster and the ossification of the primary ossification point is accelerated. On fresh fractures, the rigidity of the callus increased faster. Finally, the microarrays analyses show an upregulation of mRNA involved in cellular differentiation and proliferation. The mRNA responsible of the production of BMP-2 is significantly increased, explaining the main results observed after the expense of experimental models of the bond tissues. All the observed results are in favour of an acceleration of the cellular differentiation at the expense of the proliferation.
Breast cancer remains by far the most frequent cancer in women, for that matter it is the most frequent cancer in Belgium affecting both men and women. At the moment, more than 9000 cases are detected annually. The development of screening allows us, fortunately, to detect lesions and stages earlier, in that way locoregional treatmenthas considerably evolved. Since the seventies, radical mastectomy, which consists of the removal ofthe mammary gland, the axillary glands (lymph nodes) and sometimes the pectoral muscle, has been progressively replaced by conservatory treatment. This consists of a wide excision of the tumour with a safety resection margin, followed by a complete removal of the axillary glands (lymph nodes) then followed by a course of external radiotherapy testing treated six weeks daily on a five days week basis. During the nineties, in cases with certain precise indications, the complete axillary gland removal has been replaced by the removal of the first gland chain (lymph node chain) called sentinel nodes. This technique avoids all morbidity associated to the complete lymph node removal. Finally, very recently, the classic external radiotherapy has been replaced by partial radiotherapy delivered exclusively in a few minutes during the surgical operation. Therefore, we can offer patients with early stage lesions a locoregional treatment carried out in one to two hours with an in-stay hospitalisation of two nights. This new technique manifestly offers a better locoregional control of the illness and very likely enhances (improves) their chances of recovery.
The introduction of new sequencing technologies is revolutionizing virus discovery and providing a new means to demonstrate the safety of vaccines. Since these methods do not depend on prior assumptions of the types of viruses that may be present, they have detected viruses missed by other methods like degenerate or, family specific, PCRs. We have used massively parallel sequencing (MP-Seq) to detect new viruses in bovine serum and in the faeces of animals. When applied to sequencing the transcriptome, MP-Seq can reveal latent or silent infections. While the sequencing technology is impressive, it is bioinformatics that is the key to its successful application.
Reconstruction of long-segment tracheal defects requires a vascularized allograft. We report successful tracheal allotransplantation after indirect revascularization of the graft in a heterotopic position. Immunosuppressive therapy was administered before the operation, and the allograft was wrapped in the recipient's forearm fascia. Once revascularization was achieved, the mucosal lining was replaced progressively with buccal mucosa from the recipient. At four months, the tracheal chimera was fully lined with mucosa, which consisted of respiratory epithelium from the donor and buccal mucosa from the recipient. After withdrawal of immunosuppressive therapy, the tracheal allograft was moved to its correct anatomical position with an intact blood supply. No treatment-limiting adverse effects occurred.
Since the first successful liver transplantation (LT) in 1963 by Starzl, enormous progresses have been made in this field of medicine. The author looks back at the recommendations put forward at the 1983 NIH Consensus conference on liver transplantation in order to show the enormous progresses that have been made in his field during the last four decades. Today almost none of the original indications and contraindications remain in place. Despite the extension of indications, results of LT continuously improved. The attention of the transplant physicians should from now onwards be focused on the achievement of an immunosuppressive free (or tolerant) status in order to further consolidate the excellent obtained long-term results.
