[Treatment of the urethral sphincter insufficiency]. / Prise en charge de l'insuffisance sphinctérienne urétrale.

The intrinsic sphincter insufficiency is a cause of stress urinary incontinence. Its definition is clinical and based on urodynamics. It is mostly met with women, in context of the post-obstetrical period or older women in a multifactorial context. For men, it occurs mainly as complication of the surgery of the cancer of prostate or bladder. An initial, clinical and paraclinical assessment allows to confirm the diagnosis of intrinsic sphincter insufficiency, to estimate its severity, and to identify associated mechanisms of incontinence (urethral hypermobility, bladder overactivity) to choose the most adapted treatment. The perineal reeducation is the treatment of first intention in both sexes. At the menopausal woman, the local hormonotherapy is a useful additive. In case of failure or of incomplete efficiency, the treatment of the intrinsic sphincter insufficiency is surgical. Bulking agents, urethral slings, peri-urethral balloons and artificial sphincter are 4 therapeutic options to discuss according to history, the severity of the incontinence, the expectations of the patient.

[Medical treatment of renal cell carcinoma]. / Les médicaments du cancer du rein.

AIM: To describe drugs used in renal cell carcinoma. METHOD: Pubmed search for efficacy, mode of action and side effects for each molecule. Additional data were searched from the French regulatory agencies websites (HAS and ANSM). RESULTS: Since 2007, a total of three different therapeutic classes in the management of metastatic renal cell carcinoma are available. These three classes are tyrosine kinase inhibitors with sunitinib and sorafenib, the anti-VEGF antibodies (bevacizumab which is associated with alpha interferon in the treatment of advanced kidney cancer) and mTOR inhibitors with temsirolimus and everolimus. These targeted therapies are a major progress in the treatment of patients with metastatic kidney cancer. The side effects encountered with these molecules are numerous but serious side effects are less than 5% of all reported side effects. CONCLUSIONS: A better understanding of molecular mechanisms has enabled the development of new therapies for the treatment of metastatic renal cell carcinoma. In the future, a personalized approach taking into account the biology of each tumor could be created to provide a more targeted treatment.

[Chemotherapy in male external genital organs (testicular and penile cancer)]. / Chimiothérapie des organes génitaux externes chez l'homme (cancer du testicule et du pénis).

AIM: To describe drugs used in the chemotherapy of testis and penis neoplasms. MATERIAL: Bibliographical search was performed from the database Medline (National Library of Medicine, PubMed) and websites of the HAS and the ANSM. The search was focused on the characteristics, the mode of action, the efficiency and the side effects of the various drugs concerned. RESULTS: Nowadays, the chemotherapy is perfectly codified in adjuvant treatment or in first-line treatment of metastatic testis cancer. A single dose of carboplatin for seminoma testicular (stage I) in adjuvant treatment situation is one of the latest advances. Concerning penis cancer, the optimal protocols validated by a high level of evidence are missing. CONCLUSION: The chemotherapy in testis and penis neoplasms knew few advances in recent years. So, it is necessary to include patients in clinical research protocols.

[Drug therapy of urethral diseases]. / Les médicaments de l'urètre.

AIM: To describe drugs targeting urethra and prostate to treat dysfunctions such LUTS related to BPH, primary bladder neck obstruction (PBNO), detrusor sphincter dyssynergia (DSD) or sphincter deficiency (SD). METHOD: Pubmed search for efficacy, mode of action and side effects for each molecule. Additional data were searched from the French regulatory agencies web sites (HAS and ANSM). RESULTS: To treat LUTS related to BPH alpha-blockers (AB) and 5-alpha reductase inhibitors (5ARIs) have a clearer efficacy than plant extract. Daily Phosphodiesterase 5 inhibitors (PDE5Is) alone or in association with AB also demonstrate efficacy in this indication. AB are an option in PBNO and DSD related to multiple sclerosis. Although Botulinum toxin A derived molecules decrease urethral pressure in patient with DSD related to spinal cord injury or multiple sclerosis, efficiency remains to be demonstrated. Duloxetine a serotonin reuptake inhibitor increases urethral sphincter pressure and reduce stress urinary incontinence in women and men. Nevertheless, moderate efficacy combine with frequent side effects lead French regulation agency to reject its agreement. CONCLUSION: Armamenterium to treat urethral dysfunctions has recently increases. Two new therapeutic classes emerge: PDE5Is to treat LUTS related to BPH and an SRIs (Duloxetine) to treat stress urinary incontinence. Efficacy and safety evaluation of all the possible associations between drugs targeting urethra and/or bladder is needed to a subtler and more efficient pharmacologic modulation of lower urinary tract dysfunction.

[Drugs for sexual medicine]. / Les médicaments de la médecine sexuelle.

AIM: To describe drugs used in sexual medicine. METHOD: Pubmed search for efficacy, mode of action and side effects for each molecule. Additional data were searched from the French regulatory agencies web sites (HAS and ANSM). RESULTS: 5PDIs and intracavernous injection of alprostadil are first- and second-line therapies of erectile dysfunction. Dapoxetine is the first specific and approved treatment of premature ejaculation. Androgene supplementation improves sexual desire among patient with hypogonadism as much as initial serum testosterone levels are low. Female sexual dysfunctions pharmacology is to date less developed, although candidate drugs reach phase III clinical studies. CONCLUSION: Pharmacology is one but not the only therapeutic avenue in sexual medicine. Despite real breakthrough such as 5PDIs for erectile dysfunction, incomplete knowledge and understanding of physiology, pathophysiology and pharmacology of human sexual function reduces its development particularly for women.

[Anti-infective treatments in urology]. / Les traitements anti-infectieux non médicamenteux en urologie.

OBJECTIVE: To define the terms of use of vaccines, probiotics, and cranberry in urology. MATERIALS AND METHODS: A literature search was conducted on MEDLINE for all these treatments used in urology. Modes of action, indications in urology and adverse effects have been detailed for each treatment. RESULTS: Vaccines have been published in urinary tract infections. Products for bacterial interference such as probiotics are also used, their properties are described. As for the cranberry widely used in recurrent urinary tract infections, efficacy and mode of action are discussed. CONCLUSION: The anti-E. coli vaccines, cranberry and probiotics may be useful in urinary tract infection.

[Guidelines from the Infectious Disease Committee of the French Association of Urology and The Neuro-Urology Committee of the AFU: antibiotic prophylaxis for sacral neuromodulation]. / Recommandations de bonnes pratiques cliniques : antibioprophylaxie et neuromodulation des racines sacrées par le Comité d'infectiologie de l'Association française d'urologie (CIAFU) et le Comité de neuro-urologie de l'AFU.

INTRODUCTION: In urology, antibiotic prophylaxis is advised by the French Association of anesthesiology (SFAR) and the Infectious Disease Committee of the French Association of urology guidelines published in 2010. No guideline exists concerning the implantation of neuromodulation implants. MATERIAL AND METHOD: A literature analysis was performed on sacral modulation and antibiotic prophylaxis. Then guidelines were discussed by reviewers. Items that showed no consensus were then discussed again to arrive at recommendations. RESULTS: Antibiotic prophylaxis is recommended during the test phase as well as in the case of installation of sacral neuromodulation (Grade C). Antibiotic recommended (Grade B) are: cefotetan or cefoxitin, 2g dose by slow intravenous injection or amoxicillin-clavulanic acid at a dose of 2 g, intravenously or, in the case of allergy vancomycin at a dose of 15 mg/kg or the clindamycin has 600 mg intravenously. CONCLUSIONS: Despite the lack of high level of evidence, antibiotic prophylaxis seems necessary when setting up of electrode case of sacral neuromodulation.

[Transcutaneous tibial nerve stimulation in the overactive bladder syndrome in patients with Parkinson's syndromes]. / Stimulation transcutanée chronique du nerf tibial dans l'hyperactivité vésicale des syndromes parkinsoniens.

OBJECTIVES: To evaluate the efficacy of chronic transcutaneous tibial nerve stimulation (TNS) on overactive bladder syndrome in female patients with Parkinson's disease (PD) and multiple system atrophy (MSA). PATIENTS AND METHODS: A prospective monocentric study enrolled six female patients with PD or MSA suffering from overactive bladder syndrome for a six-week study period. Daily sessions of 20 minutes of TNS were provided. The primary outcome measurement was the Patient Global Impression of Improvement (PGI-I scale). The secondary outcomes measurements were symptom and quality of life scores, bladder diary and urodynamics. The outcomes after 6 weeks of TNS were compared to baseline. RESULTS: TNS was considered as an effective treatment by five patients out of six (83%) who ask to pursue the treatment and were still doing it 6 months after the end of the study. A trend improvement was observed in only two of the secondary evaluation criteria the V8 median score 21/40 to 14/40 (P=0.2) and the maximum cystometric capacity increased from 211 mL ± 106 to 260 mL ± 226 (P=0.6) after SNT. CONCLUSION: Although urodynamics and symptoms scores did not show significant difference, an efficacy of TNS on overactive bladder in PD and MSA is possible. Additional placebo controlled works enrolling more patients are required to ensure these preliminary results.

[Sacral neuromodulation with InterStim™ system: Results from the French national register]. / Neuromodulation sacrée avec le système InterStim™ : résultats du registre national français.

AIM: To analyse current practice patterns and to evaluate (long-term) effectiveness and adverse events of sacral neuromodulation with InterStim™ Therapy based on data collected in a national register and to discuss the strengths and weaknesses of the register. PATIENTS AND METHODS: This is a French multicenter prospective observational trial including patients with a permanent implant (2003-2009). Voiding diary variables and patient satisfaction were analysed based on last follow-up visit since implantation. RESULTS: One thousand four hundred and eighteen patients (median age: 63 years, 1206 females) were included in the database (median follow-up: 12 months). One thousand and eighty-nine patients had non-neurological disease. The principal diagnosis was overactive bladder syndrome ([OAB], n=1170) and retention (n=151). Implantation occurred in 1358 patients; 1172 patients had greater than or equal to one registered follow-up. Clinical improvement of greater than or equal to 50% was seen in 447/527 patients with OAB at 12 months follow-up (median number of voids per 24 hours decreased from 15 at baseline to 8 at 12 months) and in 42/54 of patients with retention (median number of catheterization per 24 hours dropped from 5 at baseline to 0 at 12 months). Clinical improvement remained relatively stable up to 60 months. Median patient satisfaction with treatment was between 60 and 80%. Five hundred and twenty-four patients had at least one adverse event; loss of efficacy (n=244) occurred most frequently. CONCLUSIONS: In this large database sacral neuromodulation with InterStim™ Therapy seems to be an effective treatment through routine practice in the long-term (up to 60 months) for patients refractory to medical treatment.

[Two-years follow-up of radiofrequency thermotherapy for urination disorders due to benign prostatic hyperplasia]. / Résultat à deux ans de la thermothérapie prostatique par radiofréquence pour troubles mictionnels liés à l'HBP.

AIM: To describe medium-term functional results of Transurethral Needle Ablation (TUNA) to treat symptomatic benign prostatic hyperplasia (BPH) refractory to medical treatment. MATERIALS AND METHOD: Patients who completed at least 2 years follow-up after TUNA were systematically offered a reevaluation including: Flowmetry, PSA, symptom score (IPSS), satisfaction index visual analogic scale (VAS) and a treatment impact evaluation with a Likert scale (ranging from much worse to much improved). RESULTS: From December 2002 to January 2007, 45 patients were treated with TUNA under local regional anaesthesia (prostatic block). Twenty-seven of them were followed-up longer than 24 months (median follow-up 44 months [26-52]). Changes in the selected outcomes were: increase in Qmax from 9.5 mL/s preoperatively to 9 mL/s at 6 month and 11.5 mL/s after 2 years; increase in IPSS from 19.3 before TUNA to 16.3 at 6 month and 16.5 after 2 years. About subjective evaluation, 58% of patient gave a satisfaction VAS>or=6, and the improvement index was greater or equal to +1 in 67% of case. CONCLUSION: In this initial monocentric experiment, despite a modest improvement of objective parameters and a 20% of retreatment rate, TUNA give contentment and improvement sensation for 60% of patients who were treated for non-efficiency of medical treatment for benign prostatic hyperplasia.

[Alternative treatments for interstitial cystitis]. / Les traitements de recours dans la cystite interstitielle.

Interstitial cystitis is the first cause of bladder pain. In case of failure of the usual treatments, several other modalities have been proposed. These therapeutic modalities are posterior sacral root neuromodulation, posterior tibial nerve stimulation, vanilloid agent intravesical instillation, intradetrusor botulinum toxin injections and surgery. A certain efficiency of each of these treatments in the interstitial cystitis has been reported. However, the evaluation of these treatments is limited and the level of evidence is too low to propose these treatments in routine.

YY1 is a positive regulator of transcription of the Col1a1 gene.

Both cell-specific and ubiquitous transcription factors in fibroblasts have been identified as critical for expression of the Col1a1 gene, which encodes the alpha1 chain of type I collagen. Here, we report that Yin Yang 1 (YY1) binds to the Col1a1 promoter immediately upstream of the TATA box, and we examine the functional implications of YY1 binding for regulation of Col1a1 gene expression in BALBc/3T3 fibroblasts. The Col1a1 promoter region spanning base pairs (bp) -56 to -9 bound purified recombinant YY1 and the corresponding binding activity in nuclear extracts was supershifted using a YY1-specific antibody. Mutation of the TATA box to TgTA enhanced YY1 complex formation. Mutation analysis revealed two YY1 core binding sites at -40/-37 bp (YY1A) and, on the reverse strand, at -32/-29 bp (YY1B) immediately adjacent to the TATA box. In transfections using Col1a1-luciferase constructs, mutation of YY1A decreased activity completely (wild-type p350 (p350wt), -222/+113 bp) or partially (p130wt, -84 bp/+13 bp), whereas mutation of YY1B blocked the expression of both promoter constructs. Cotransfection with pCMV-YY1 increased p350wt and p130wt activities by as much as 10-fold, whereas antisense YY1 decreased constitutive expression and blocked the increased activity due to pCMV-YY1 overexpression. The mTgTA constructs were devoid of activity, arguing for a requirement for cognate binding of the TATA box-binding protein (TBP). Electrophoretic mobility shift assays performed under conditions permitting TBP binding showed that recombinant TBP/TFIID and YY1 could bind to the -56/-9 bp fragment and that YY1B was the preferred site for YY1 binding. Our results indicate that YY1 binds to the Col1a1 proximal promoter and functions as a positive regulator of constitutive activity in fibroblasts. Although YY1 is not sufficient for transcriptional initiation, it is a required component of the transcription machinery in this promoter.

A neuro (endo)crine regulation of bone remodeling.

Bone remodeling is the normal physiologic process that is used by vertebrates to maintain a constant bone mass during the period bracketed by the end of puberty and the onset of gonadal failure in later life. Besides the well-characterized and critical process of local regulation of bone remodeling, achieved by autocrine and paracrine mechanisms, recent genetic studies have shown that there is a central control of bone formation, mediated by a neuroendocrine mechanism. This central regulation involves leptin, an adipocyte-secreted hormone that controls body weight, reproduction and bone remodeling, and which binds to and exerts its effect through the cells of the hypothalamic nuclei in the brain. This genetic result in mice is in line with clinical observations in humans and generates a whole new direction of research in bone physiology. BioEssays 22:970-975, 2000.

Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass.

Gonadal failure induces bone loss while obesity prevents it. This raises the possibility that bone mass, body weight, and gonadal function are regulated by common pathways. To test this hypothesis, we studied leptin-deficient and leptin receptor-deficient mice that are obese and hypogonadic. Both mutant mice have an increased bone formation leading to high bone mass despite hypogonadism and hypercortisolism. This phenotype is dominant, independent of the presence of fat, and specific for the absence of leptin signaling. There is no leptin signaling in osteoblasts but intracerebroventricular infusion of leptin causes bone loss in leptin-deficient and wild-type mice. This study identifies leptin as a potent inhibitor of bone formation acting through the central nervous system and therefore describes the central nature of bone mass control and its disorders.

A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development.

The molecular mechanisms controlling bone extracellular matrix (ECM) deposition by differentiated osteoblasts in postnatal life, called hereafter bone formation, are unknown. This contrasts with the growing knowledge about the genetic control of osteoblast differentiation during embryonic development. Cbfa1, a transcriptional activator of osteoblast differentiation during embryonic development, is also expressed in differentiated osteoblasts postnatally. The perinatal lethality occurring in Cbfa1-deficient mice has prevented so far the study of its function after birth. To determine if Cbfa1 plays a role during bone formation we generated transgenic mice overexpressing Cbfa1 DNA-binding domain (DeltaCbfa1) in differentiated osteoblasts only postnatally. DeltaCbfa1 has a higher affinity for DNA than Cbfa1 itself, has no transcriptional activity on its own, and can act in a dominant-negative manner in DNA cotransfection assays. DeltaCbfa1-expressing mice have a normal skeleton at birth but develop an osteopenic phenotype thereafter. Dynamic histomorphometric studies show that this phenotype is caused by a major decrease in the bone formation rate in the face of a normal number of osteoblasts thus indicating that once osteoblasts are differentiated Cbfa1 regulates their function. Molecular analyses reveal that the expression of the genes expressed in osteoblasts and encoding bone ECM proteins is nearly abolished in transgenic mice, and ex vivo assays demonstrated that DeltaCbfa1-expressing osteoblasts were less active than wild-type osteoblasts. We also show that Cbfa1 regulates positively the activity of its own promoter, which has the highest affinity Cbfa1-binding sites characterized. This study demonstrates that beyond its differentiation function Cbfa1 is the first transcriptional activator of bone formation identified to date and illustrates that developmentally important genes control physiological processes postnatally.

Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation.

The osteoblast is the bone-forming cell. The molecular basis of osteoblast-specific gene expression and differentiation is unknown. We previously identified an osteoblast-specific cis-acting element, termed OSE2, in the Osteocalcin promoter. We have now cloned the cDNA encoding Osf2/Cbfa1, the protein that binds to OSE2. Osf2/Cbfa1 expression is initiated in the mesenchymal condensations of the developing skeleton, is strictly restricted to cells of the osteoblast lineage thereafter, and is regulated by BMP7 and vitamin D3. Osf2/Cbfa1 binds to and regulates the expression of multiple genes expressed in osteoblasts. Finally, forced expression of Osf2/Cbfa1 in nonosteoblastic cells induces the expression of the principal osteoblast-specific genes. This study identifies Osf2/Cbfa1 as an osteoblast-specific transcription factor and as a regulator of osteoblast differentiation.

c-Krox binds to several sites in the promoter of both mouse type I collagen genes. Structure/function study and developmental expression analysis.

We have previously shown that c-Krox is a zinc finger protein that can increases the transcriptional activity of the mouse alpha1(I) collagen promoter through its binding to two GC-rich sequences (Galéra, P., Musso, M., Ducy, P., and Karsenty, G. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 9372-9376). In this report we show that c-Krox can bind to an additional site in the promoter of the alpha1(I) collagen gene and to three sites in the promoter of the alpha2(I) collagen gene, the other gene coding for type I collagen. One of the binding sites present in both promoters is adjacent to the CCAAT box. We have performed a structure/function analysis of c-Krox locating the transactivation domain in the zinc finger and C-terminal domains and the dimerization domain in the C-terminal end of the protein. We also demonstrate that c-Krox is an early response gene, whose expression is detectable as early as 9.5-day postcoitum in mouse embryos. Whole-mount in situ hybridization shows that c-Krox is expressed in dermatomes, the somite derivatives that generate dermis, and section in situ hybridization shows that c-Krox and alpha1(I) collagen mRNAs colocalized in skin but not in bone during development. This result is consistent with the predominant expression of c-Krox in skin in postnatal life. Thus, our findings suggest that c-Krox is one transcription factor controlling the coordinated expression of the two type I collagen genes in skin.